August 24, 2016
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"Today the U.S. Food and Drug Administration granted approval for Ninlaro (ixazomib) in combination with two other therapies to treat people with multiple myeloma who have received at least one prior therapy.

Multiple myeloma is a form of bl"...





Included as part of the PRECAUTIONS section.


Peripheral Neuropathy

VELCADE 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 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 relapsed multiple myeloma trial comparing VELCADE 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 VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule [see DOSAGE AND ADMINISTRATION]. In the VELCADE 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 [see ADVERSE REACTIONS]. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.


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 [see ADVERSE REACTIONS].

Cardiac Toxicity

Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE 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 VELCADE versus dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE 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 VELCADE 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 VELCADE. 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 VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy.

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

In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE 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 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.

Gastrointestinal Toxicity

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


VELCADE 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 VELCADE. Measure platelet counts prior to each dose of VELCADE. Adjust dose/schedule for thrombocytopenia [see Tables 2 and 4 and DOSAGE AND ADMINISTRATION]. Gastrointestinal and intracerebral hemorrhage has occurred during thrombocytopenia in association with VELCADE. Support with transfusions and supportive care, according to published guidelines.

In the single-agent, relapsed multiple myeloma study of VELCADE 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 VELCADE 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 VELCADE versus Dexamethasone

Pretreatment Platelet Count* Number of Patients
Number (%) of Patients with Platelet Count < 10,000/μL Number (%) of Patients with Platelet Count 10,000-25,000/μL
≥ 75,000/μL 309 8 (3%) 36 (12%)
≥ 50,000/μL- < 75,000/μL 14 2 (14%) 11 (79%)
≥ 10,000/μL < 50,000/μL 7 1 (14%) 5 (71%)
* A baseline platelet count of 50,000/μL was required for study eligibility
** Data were missing at baseline for 1 patient

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 ( ≥ 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 VELCADE 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 VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

Embryo-fetal Risk

Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. 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 [see Use In Specific Populations].

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 . VELCADE could have a potential effect on either male or female fertility.

Use In Specific Populations


Pregnancy Category D [see WARNINGS AND PRECAUTIONS].

Risk Summary

VELCADE may cause fetal harm when administered to a pregnant woman. 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. Bortezomib caused embryo-fetal lethality in rabbits at doses lower than the clinical dose.

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.

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

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, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

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

The activity and safety of VELCADE 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. VELCADE 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 VELCADE. There was no evidence that the addition of VELCADE had any impact on the CR rate.

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

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 VELCADE arm and 120 (36%) on the dexamethasone arm. Median time to progression and median duration of response for patients ≥ 65 were longer on VELCADE compared to dexamethasone [5.5 mo versus 4.3 mo, and 8.0 mo versus 4.9 mo, respectively]. On the VELCADE 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 VELCADE patients ≤ 50, 51-64 and ≥ 65 years old, respectively [see ADVERSE REACTIONS; Clinical Studies].

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

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, VELCADE should be administered after the dialysis procedure [see CLINICAL PHARMACOLOGY].

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 [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Patients With Diabetes

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

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 10/9/2015


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