VELCADE

Bortezomib is a dipeptide boronic acid derivative and proteasome inhibitor used to treat multiple myeloma and mantle cell lymphoma.

The 26S proteasome is a protein complex that degrades ubiquitinated proteins in the ubiquitin-proteasome pathway: reversible inhibition of the 26S proteasome, leading to cell cycle arrest and apoptosis of cancer cells, is thought to be the main mechanism of action of bortezomib.

However, multiple mechanisms may be involved in the anticancer activity of bortezomib.

Bortezomib was first synthesized in 1995.

In May 2003, bortezomib became the first anticancer proteasome inhibitor that was approved by the FDA under the trade name VELCADE.

I, II, III, and Intravenous clinical trials are undergoing to investigate the therapeutic efficacy of bortezomib in leukemia, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, and solid tumours.

Bortezomib is indicated for the treatment of adults with multiple myeloma or mantle cell lymphoma.

Bortezomib works to target the ubiquitin-proteasome pathway, an essential molecular pathway that regulates intracellular concentrations of proteins and promotes protein degradation.

The ubiquitin-proteasome pathway is often dysregulated in pathological conditions, leading to aberrant pathway signalling and the formation of malignant cells.

In one study, patient-derived chronic lymphocytic leukemia (CLL) cells contained 3-fold higher levels of chymotrypsin-like proteasome activity than normal lymphocytes.

By reversibly inhibiting proteasome, bortezomib prevents proteasome-mediated proteolysis.

Bortezomib exerts a cytotoxic effect on various cancer cell types in vitro and delays tumour growth in vivo in nonclinical tumour models.

Bortezomib inhibits the proteasome activity in a dose-dependent manner.

In one pharmacodynamic study, more than 75% of proteasome inhibition was observed in whole blood samples within one hour after dosing of bortezomib.

Proteasome subunit beta type-5 Inhibitor Proteasome subunit beta type-1 Inhibitor.

Following intravenous administration of 1 mg/m and 1.3 mg/m 2 doses, the mean C max of bortezomib were and 112 ng/mL, respectively.

In a twice-weekly dosing regimen, the C max ranged from 67-106 ng/mL at the dose of 1 mg/m and 89-120 ng/mL for the 1.3 mg/m 2 dose.

In patients with multiple myeloma, the C max of bortezomib followig subcutaneous administration was lower than that of Intravenous-administered dose; however, the total systemic exposure of the drug was equivalent for both routes of administration.

There is a wide interpatient variability in drug plasma concentrations.

The mean distribution volume of bortezomib ranged from approximately 498-1884 L/m in patients with multiple myeloma receiving a single.

• or repeat-dose of 1 mg/m 2 or 1.3 mg/m 2.

Bortezomib distributes into nearly all tissues, except for the adipose and brain tissue.

Bortezomib is primarily metabolized by

CYP2D6 and CYP2C9 are also involved in drug metabolism, but to a smaller extent.

Oxidative deboronation, which involves the removal of boronic acid from the parent compound, is the main metabolic pathway.

Metabolites of bortezomib are pharmacologically inactive and more than 30 metabolites have been identified in human and animal studies.

Hover over products below to view reaction partners Bortezomib Bortezomib metabolite M1 Bortezomib metabolite M26 Bortezomib metabolite M25 Bortezomib metabolite M5 Bortezomib metabolite M3 Bortezomib metabolite M4 Bortezomib metabolite M2 Bortezomib metabolite M28 Bortezomib metabolite M27 Bortezomib metabolite M8 Bortezomib metabolite M33 Bortezomib metabolite M6 Bortezomib metabolite M3 Bortezomib metabolite M34 Bortezomib metabolite M23 or M24 Bortezomib metabolite M23 or M24.

Bortezomib is eliminated by both renal and hepatic routes.

The mean elimination half-life of bortezomib ranged from 40-193 hours following a multiple dosing regimen at a 1 mg/m 2 dose.

The half-life ranged from 76-108 hours after multiple dosing of 1.3 mg/m 2 bortezomib.

Following the administration of a first dose of 1 mg/m and 1.3 mg/m 2, the mean mean total body clearances were and 112 L/h, respectively.

The clearances were and 32 L/h after the subsequent dose of and 1.3 mg/m 2, respectively.

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Lowest published toxic dose (TD Lo ) in mouse was 5 mg/kg/14D following intraperitoneal administration of an intermittent dose and 1.6 mg/kg/12D following subcutaneous administration of a continuous dose.

The therapeutic dose of bortezomib is individualized in each patient to prevent overdose.

Fatal outcomes occurred in humans following the administration of more than twice the recommended therapeutic dose of bortezomib.

The symptoms from overdose included the acute onset of symptomatic hypotension and thrombocytopenia.

As there is no known antidote for bortezomib overdosage, monitoring of vital signs and appropriate supportive care should be initiated when drug overdosage is suspected.

In monkeys and dogs, increased heart rate, decreased contractility, hypotension, and death were observed with the intravenous dose as low as two times the recommended clinical dose on a mg/m2 basis.

A case of a slight increase in the corrected QT interval leading to death occurred in dog studies.

Bortezomib is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol.

Reactions have included anaphylactic reactions.

Bortezomib is contraindicated for intrathecal administration.

Fatal events have occurred with intrathecal administration of bortezomib.

• Patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions.

• Contraindicated for intrathecal administration.

• For subcutaneous or intravenous use only.

Each route of administration has a different reconstituted concentration.

Exercise caution when calculating the volume to be administered.

• The recommended starting dose of bortezomib for injection is 1.3 mg/m 2 administered either as a to 5 second bolus intravenous injection or subcutaneous injection.

• Retreatment for Multiple Myeloma: May retreat starting at the last tolerated dose.

• Hepatic Impairment: Use a lower starting dose for patients with moderate or severe hepatic impairment.

• Dose must be individualized to prevent overdose. 2.1 Important Dosing Guidelines Bortezomib for injection is for intravenous or subcutaneous use only.

Do not administer bortezomib for injection 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 bortezomib for injection is 1.3 mg/m 2.

Bortezomib for injection is administered intravenously at a concentration of 1 mg/mL, or subcutaneously at a concentration of 2.5 mg/mL.

Bortezomib for injection retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with bortezomib for injection and who have relapsed at least six months after completing prior bortezomib for injection treatment.

Treatment may be started at the last tolerated dose.

When administered intravenously, administer bortezomib for injection as a to 5 second bolus intravenous injection. 2.2 Dosage in Previously Untreated Multiple Myeloma Bortezomib for injection is administered in combination with oral melphalan and oral prednisone for 9, six week treatment cycles as shown in Table 1.

In Cycles to 4, bortezomib for injection is administered twice weekly (Days and 32).

In Cycles to 9, bortezomib for injection is administered once weekly (Days and 29).

At least 72 hours should elapse between consecutive doses of bortezomib for injection.

Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma Twice Weekly Bortezomib for Injection (Cycles to 4) Week 1 2 3 4 5 6 Bortezomib for injection (1.3 mg/m 2 ) Day 1 -

• Day 4 Day 8 Day 11 rest period Day 22 Day 25 Day 29 Day 32 rest period Melphalan (9 mg/m 2 ) Prednisone (60 mg/m 2 ) Day 1 Day 2 Day 3 Day 4 -

• rest period -

• rest period Once Weekly Bortezomib for Injection (Cycles to 9 when used in combination with Melphalan and Prednisone) Week 1 2 3 4 5 6 Bortezomib for injection (1.3 mg/m 2 ) Day 1 -

• Day 8 rest period Day 22 Day 29 rest period Melphalan (9 mg/m 2 ) Prednisone (60 mg/m 2 ) Day 1 Day 2 Day 3 Day 4 -

• Platelet count should be at least 70 x 10 9 /L and the absolute neutrophil count (ANC) should be at least 1 x 10 9 /L.

• Nonhematological toxicities should have resolved to Grade 1 or baseline Table 2: Dose Modifications During Cycles of Combination Bortezomib for Injection, Melphalan and Prednisone Therapy Toxicity Dose Moidification or Delay Hematological toxicity during a cycle: If prolonged Grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle Consider reduction of the melphalan dose by 25% in the next cycle If platelet count is not above 30 x 10 9 /L or ANC is not above 0.75 x 10 9 /L on a bortezomib for injection dosing day (other than Day 1) Withhold bortezomib for injection dose If several bortezomib for injection doses in consecutive cycles are withheld due to toxicity Reduce bortezomib for injection dose by one dose level (from 1.3 mg/m to 1 mg/m 2, or from 1 mg/m to 0.7 mg/m 2 ) Grade 3 or higher nonhematological toxicities Withhold bortezomib for injection therapy until symptoms of toxicity have resolved to Grade 1 or baseline.

Then, bortezomib for injection may be reinitiated with one dose level reduction (from 1.3 mg/m to 1 mg/m 2, or from 1 mg/m to 0.7 mg/m 2 ).

For bortezomib for injection-related neuropathic pain and/or peripheral neuropathy, hold or modify bortezomib for injection as outlined in Table 5.

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

Dose modifications guidelines for peripheral neuropathy are provided. 2.4 Dosage in Previously Untreated Mantle Cell Lymphoma Bortezomib for injection (1.3 mg/m 2 ) 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 3.

Bortezomib for injection is administered first followed by rituximab.

Bortezomib for injection is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a ten day rest period on Days to 21.

For patients with a response first documented at Cycle 6, two additional VcR-CAP cycles are recommended.

Table 3: Dosage Regimen for Patients with Previously Untreated Mantle Cell Lymphoma Twice Weekly Bortezomib for Injection (6, Three Week Cycles) * Week 1 2 3 Bortezomib for injection (1.3 mg/m 2 ) Day 1 -

• Day 4 -

• Day 8 Day 11 rest period Rituximab (375 mg/m 2 ) Cyclophosphamide (750 mg/m 2 ) Doxorubicin (50 mg/m 2 ) Day 1 -

• rest period Prednisone (100 mg/m 2 ) Day 1 Day 2 Day 3 Day 4 Day 5 -

• Platelet count should be at least 100 x 10 9 /L and absolute neutrophil count (ANC) should be at least 1.5 x 10 9 /L.

• Hemoglobin should be at least 8 g/dL (at least 4.96 mmol/L).

• Nonhematologic toxicity should have recovered to Grade 1 or baseline Interrupt bortezomib for injection treatment at the onset of any Grade 3 hematologic or nonhematological toxicities, excluding neuropathy.

For dose adjustments, see Table 4 below.

Table 4: Dose Modifications on Days 4, 8, and 11 During Cycles of Combination Bortezomib for Injection, Rituximab, Cyclophosphamide, Doxorubicin and Prednisone Therapy Toxicity Dose Modification or Delay Hematological Toxicity Grade 3 or higher neutropenia, or a platelet count not at or above 25 × 10 9 /L Withhold bortezomib for injection therapy for up to 2 weeks until the patient has an ANC at or above 0.75 × 10 9 /L and a platelet count at or above 25 × 10 9 /L.

• If, after bortezomib for injection has been withheld, the toxicity does not resolve, discontinue bortezomib for injection.

• If toxicity resolves such that the patient has an ANC at or above 0.75 × 10 9 /L and a platelet count at or above 25 × 10 9 /L, bortezomib for injection dose should be reduced by 1 dose level (from 1.3 mg/m to 1 mg/m 2, or from 1 mg/m to 0.7 mg/m 2 ).

Grade 3 or higher nonhematological toxicities Withhold bortezomib for injection therapy until symptoms of the toxicity have resolved to Grade 2 or better.

For information concerning rituximab, cyclophosphamide, doxorubicin and prednisone, see manufacturer's prescribing information. 2.6 Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma Bortezomib for injection (1.3 mg/m 2 /dose) is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a ten day rest period (Days to 21).

For extended therapy of more than eight cycles, bortezomib for injection 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 to 35) .

Patients with multiple myeloma who have previously responded to treatment with bortezomib for injection (either alone or in combination) and who have relapsed at least six months after their prior bortezomib for injection therapy may be started on bortezomib for injection at the last tolerated dose.

Retreated patients are administered bortezomib for injection twice weekly (Days 1, 4, 8, and 11) every three weeks for a maximum of eight cycles.

Bortezomib for injection may be administered either as a single agent or in combination with dexamethasone.

Bortezomib for injection therapy should be withheld at the onset of any Grade 3 nonhematological or Grade 4 hematological toxicities excluding neuropathy as discussed below.

Once the symptoms of the toxicity have resolved, bortezomib for injection therapy may be reinitiated at a 25% reduced dose (1.3 mg/m 2 /dose reduced to 1 mg/m 2 /dose; 1 mg/m 2 /dose reduced to 0.7 mg/m 2 /dose).

For dose modifications guidelines for peripheral neuropathy, see section 2.7. 2.7 Dose Modifications for Peripheral Neuropathy Starting bortezomib for injection subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients with preexisting severe neuropathy should be treated with bortezomib for injection only after careful risk-benefit assessment.

Patients experiencing new or worsening peripheral neuropathy during bortezomib for injection therapy may require a decrease in the dose and/or a less doseintense schedule.

For dose or schedule modification guidelines for patients who experience bortezomib for injection-related neuropathic pain and/or peripheral neuropathy, see Table 5.

Table 5: Recommended Dose Modification for Bortezomib for Injection-Related Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy Severity of Peripheral Neuropathy Signs and Symptoms* Modification of Dose and Regimen Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or loss of function No action Grade with pain or Grade 2 (moderate symptoms; limiting instrumental Activities of Daily Living (ADL) † ) Reduce bortezomib for injection to 1 mg/m 2 Grade with pain or Grade 3 (severe symptoms; limiting self care ADL ‡ ) Withhold bortezomib for injection therapy until toxicity resolves.

When toxicity resolves reinitiate with a reduced dose of bortezomib for injection at 0.7 mg/m 2 once per week.

Grade 4 (life-threatening consequences; urgent intervention indicated) Discontinue bortezomib for injection * Grading based on NCI Common Terminology Criteria CTCAE v4.0 † Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money, etc. ‡ Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden 2.8 Dosage in Patients with Hepatic Impairment Do not adjust the starting dose for patients with mild hepatic impairment.

Start patients with moderate or severe hepatic impairment at a reduced dose of 0.7 mg/m 2 per inject.

Each single-dose vial of bortezomib contains 3.5 mg of bortezomib as white to off-white lyophilized powder.

NDC 31722-303-31 3.5 mg single-dose vial Unopened vials may be stored at controlled room temperature 25ºC (77ºF); excursions permitted from 15ºC to 30ºC (59ºF to 86ºF) .

Retain in original package to protect from light.

Follow guidelines for handling and disposal for hazardous drugs, including the use of gloves and other protective clothing to prevent skin contact 1.

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

There are no studies with the use of bortezomib 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 to 4% and to 20%, respectively.

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/m in the rat and 0.05 mg/kg; 0.6 mg/m in the rabbit) when administered during organogenesis.

These dosages are approximately 0.5 times the clinical dose of 1.3 mg/m 2 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/m 2 based on body surface area).

Pregnant rabbits given bortezomib during organogenesis at a dose of 0.05 mg/kg (0.6 mg/m 2 ) experienced significant postimplantation loss and decreased number of live fetuses.

Live fetuses from these litters also showed significant decreases in fetal weight.

Safety and effectiveness have not been established in pediatric patients.

The activity and safety of bortezomib 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, nonrandomized cooperative group trial.

An effective reinduction multiagent chemotherapy regimen was administered in three 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.

Bortezomib was administered at a dose of 1.3 mg/m as a bolus intravenous injection on Days 1, 4, 8, and of Block and Days 1, 4, and of Block 2.

There were 140 patients with ALL or LL enrolled and evaluated for safety.

The median age was ten 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 prespecified 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 was compared to that in a historical control set of patients who had received the identical backbone therapy without bortezomib.

There was no evidence that the addition of bortezomib had any impact on the CR rate.

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

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

Of the 669 patients enrolled in the relapsed multiple myeloma study, 245 (37%) were 65 years of age or older: 125 (38%) on the bortezomib arm and 120 (36%) on the dexamethasone arm.

Median time to progression and median duration of response for patients ≥ 65 were longer on bortezomib compared to dexamethasone [5.5 mo vs 4.3 mo, and 8.0 mo vs 4.9 mo, respectively.

On the bortezomib arm, 40% (n=46) of evaluable patients aged ≥ 65 experienced response (CR+PR) vs 18% (n=21) on the dexamethasone arm.

The incidence of

Grade and 4 events was 64%, 78% and 75% for bortezomib patients ≤ 50, 51 to and ≥ 65 years old, respectively.

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