Sangrel injection is used to treat multiple myeloma (blood plasma cell cancer) in patients with or without a prior history of treatment, and mantle cell lymphoma.
Sangrel interferes with the growth of cancer cells, which are then eventually destroyed by the body. Since the growth of normal body cells may also be affected by Sangrel, other effects will also occur. Some of these may be serious and must be reported to your doctor. Other effects, such as a skin rash, may not be serious but may cause concern. Some effects may not occur until months or years after the medicine is used.
Sangrel is to be given only by or under the supervision of your doctor.
Sangrel indications
An indication is a term used for the list of condition or symptom or illness for which the medicine is prescribed or used by the patient. For example, acetaminophen or paracetamol is used for fever by the patient, or the doctor prescribes it for a headache or body pains. Now fever, headache and body pains are the indications of paracetamol. A patient should be aware of the indications of medications used for common conditions because they can be taken over the counter in the pharmacy meaning without prescription by the Physician.
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Multiple Myeloma
Sangrel for Injection is indicated for the treatment of patients with multiple myeloma.
Mantle Cell Lymphoma
Sangrel for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.
How should I use Sangrel?
Use Sangrel as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Drinking extra fluids while you are taking Sangrel is recommended. Check with your doctor for instructions.
Sangrel is given as an injection into a vein or under the skin at your doctor's office, hospital, or clinic. Sangrel is not intended to be injected into the spinal cord. Contact your health care provider if you have any questions.
It is very important that each dose is given at the scheduled time. If you miss a dose of Sangrel, contact your doctor right away to establish a new dosing schedule. Do not use 2 doses at once.
Ask your health care provider any questions you may have about how to use Sangrel.
Uses of Sangrel in details
There are specific as well as general uses of a drug or medicine. A medicine can be used to prevent a disease, treat a disease over a period or cure a disease. It can also be used to treat the particular symptom of the disease. The drug use depends on the form the patient takes it. It may be more useful in injection form or sometimes in tablet form. The drug can be used for a single troubling symptom or a life-threatening condition. While some medications can be stopped after few days, some drugs need to be continued for prolonged period to get the benefit from it.
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Use: Labeled Indications
Mantle cell lymphoma: Treatment of mantle cell lymphoma in adults.
Multiple myeloma: Treatment of multiple myeloma in adults.
Off Label Uses
Antibody-mediated rejection in cardiac transplantation (treatment)
Based on the American Heart Association's Scientific Statement for Antibody-Mediated Rejection in Cardiac Transplantation, Sangrel, in combination with other immune therapies, may be a reasonable agent for the secondary treatment of patients with antibody-mediated rejection (AMR) of the cardiac allograft. There are currently no large randomized trials evaluating treatments for AMR in cardiac transplantation; recommendations are based on consensus.
Data from a small single-center, single-agent phase II trial suggest that Sangrel may be beneficial for the treatment of relapsed/refractory cutaneous T-cell lymphomas such as mycosis fungoides may be beneficial for treatment of Waldenström macroglobulinemia.
Based on recommendations from the Eighth International Workshop on Waldenström Macroglobulinemia, Sangrel therapy is recommended in patients with Waldenström macroglobulinemia with high IgM levels, symptomatic hyperviscosity, cryoglobulinemia, cold agglutinemia, renal impairment, or in patients where chemotherapy with alkylators or nucleoside analog should be avoided.
Sangrel description
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Sangrel (originally PS-341 and marketed as Velcade by Millennium Pharmaceuticals) is the first therapeutic proteasome inhibitor to be tested in humans. The boron atom within Sangrel catalytically binds the active site of the 26S proteasome with high affinity and specificity, thereby resulting in cell cycle arrest and apoptosis. In normal cells, the proteasome is involved in degradation of ubiquitylated proteins that have been tagged for destruction because they are damaged or unneeded by the cell. However, in cancerous cells, proteasome activity degrades pro-apoptotic proteins such as p53 that would normally result in programmed cell death of the dysfunctional cells. Proteasome inhibitors such as Sangrel interrupt this process, resulting in destruction of cancerous cells. Sangrel is approved in the U.S. for treating relapsed multiple myeloma and mantle cell lymphoma. In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease.
Sangrel dosage
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Sangrel Dosage
Applies to the following strength(s): 3.5 mg
The information at Drugs.com is not a substitute for medical advice. Always consult your doctor or pharmacist.
Usual Adult Dose for:
Lymphoma
Multiple Myeloma
Additional dosage information:
Renal Dose Adjustments
Liver Dose Adjustments
Dose Adjustments
Precautions
Dialysis
Other Comments
Usual Adult Dose for Lymphoma
DOSAGE IN PREVIOUSLY UNTREATED MANTLE CELL LYMPHOMA:
1.3 mg/m2 as a bolus IV injection twice weekly in combination with IV rituximab, cyclophosphamide, doxorubicin, and oral prednisone for two weeks (days 1, 4, 8, and 11) followed by a ten day rest period (days 12 through 21)
Comments:
-The three week period is considered a treatment cycle.
-A minimum of 72 hours should elapse between consecutive doses of Sangrel.
-For patients with a response first documented at cycle 6, two additional cycles (for a total of 8 cycles) are recommended.
FOR USE IN THE TREATMENT OF RELAPSED MANTLE CELL LYMPHOMA:
-Usual dose: 1.3 mg/m2 as a bolus IV injection or subcutaneously twice weekly for two weeks (days 1, 4, 8, and 11) followed by a ten day rest period (days 12 through 21). Therapy extending beyond 8 cycles may be administered by the standard schedule or may be given once weekly for 4 weeks (days 1, 8, 15, and 22), followed by a 13-day rest (days 23 through 35).
Uses: For the treatment of mantle cell lymphoma
Usual Adult Dose for Multiple Myeloma
FOR USE IN THE TREATMENT OF PREVIOUSLY UNTREATED MULTIPLE MYELOMA:
-Usual dose: 1.3 mg/m2 administered as a 3 to 5 second bolus IV injection or subcutaneously in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles:
-In cycles 1 through 4, Sangrel is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29, and 32). In cycles 5 through 9, Sangrel is administered once weekly (days 1, 8, 22, and 29).
Comments:
-At least 72 hours should elapse between consecutive doses of Sangrel.
FOR USE IN THE TREATMENT OF RELAPSED MULTIPLE MYELOMA:
-Usual dose: 1.3 mg/m2 as a bolus intravenous injection or subcutaneously twice weekly for two weeks (days 1, 4, 8, and 11) followed by a ten day rest period (days 12 through 21). Therapy extending beyond 8 cycles may be administered by the standard schedule or may be given once weekly for 4 weeks (days 1, 8, 15, and 22), followed by a 13-day rest (days 23 through 35).
Comments:
-Sangrel may be administered alone or in combination with dexamethasone.
-The three week period is considered a treatment cycle.
-A minimum of 72 hours should elapse between consecutive doses of Sangrel.
-Patients with multiple myeloma who have previously responded to treatment with Sangrel (either alone or in combination) and who have relapsed at least 6 months after their prior therapy may be started on the last tolerated dose.
Use: For the treatment of multiple myeloma (who had previously responded to treatment with this drug and who have relapsed at least 6 months after completing treatment)
Renal Dose Adjustments
No adjustment recommended.
Liver Dose Adjustments
Moderate to severe hepatic impairment (bilirubin levels greater than 1.5 times the upper limit of normal range [ULN]): Starting doses should be reduced to 0.7 mg/m2 in the first cycle. Dose escalation to 1 mg/m2 or further dose reduction to 0.5 mg/m2 may be considered in subsequent cycles based on patient tolerability.
Dose Adjustments
DOSE MODIFICATION GUIDELINES FOR COMBINATION THERAPY WITH Sangrel, MELPHALAN AND PREDNISONE:
Prior to initiating any cycle of therapy with Sangrel in combination with melphalan and prednisone:
-Platelet count should be greater than or equal to 70 x 10^9/L and the ANC should be greater than or equal to 1.0 x 10^9/L.
-Non-hematological toxicities should have resolved to grade 1 or baseline.
Hematological toxicity during a cycle:
-If prolonged grade 4 neutropenia, thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle, then reduction of the melphalan dose by 25% in the next cycle should be considered.
-If the platelet count is less than or equal to 30 x 10^9/L or ANC less than or equal to 0.75 x 10^9/L on a Sangrel dosing day (other than day 1), then the Sangrel dose should be withheld.
-If several Sangrel doses in consecutive cycles are withheld due to toxicity, the Sangrel dose should be reduced by 1 dose level (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2)
-Nonhematological toxicities greater than or equal to grade 3: Sangrel therapy should be withheld until symptoms of the toxicity have resolved to grade 1 or baseline. Then, Sangrel may be reinitiated with one dose level reduction (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2).
DOSE MODIFICATION GUIDELINES FOR Sangrel WHEN GIVEN IN COMBINATION WITH RITUXIMAB, CYCLOPHOSPHAMIDE, DOXORUBICIN, AND PREDNISONE:
Prior to the first day of each cycle (other than Cycle 1) of therapy with Sangrel in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone:
-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)
-Non-hematologic toxicity should have recovered to Grade 1 or baseline
Sangrel therapy should be interrupted at the onset of any Grade 3 hematologic or non-hematological toxicities, excluding neuropathy.
Hematological toxicity during a cycle:
-Grade 3 or higher neutropenia, or a platelet count not at or above 25 x 10^9/L:
Withhold Sangrel therapy for up to 2 weeks until the patient has an ANC at or above 0.75 x 10^9/L and a platelet count at or above 25 x 10^9/L. If, after Sangrel has been withheld, the toxicity does not resolve, discontinue Sangrel. If toxicity resolves such that the patient has an ANC at or above 0.75 x 10^9/L and a platelet count at or above 25 x 10^9/L, the Sangrel dose should be reduced by 1 dose level (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2)
-Grade 3 or higher non-hematological toxicities: Withhold Sangrel therapy until symptoms of the toxicity have resolved to Grade 2 or better. Then, Sangrel may be reinitiated with one dose level reduction (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2).
DOSE MODIFICATION GUIDELINES FOR RELAPSED MULTIPLE MYELOMA AND MANTLE CELL LYMPHOMA:
-Sangrel should be withheld at the onset of any grade 3 nonhematologic or grade 4 toxicities excluding neuropathy. Once the symptoms of the toxicity have been resolved, Sangrel therapy may be reinitiated at a 25% reduced dose (1.3 mg/m2 is reduced to 1 mg/m2, 1 mg/m2 is reduced to 0.7 mg/m2).
-Patients with preexisting severe neuropathy should be treated with Sangrel only after a careful risk/benefit assessment.
DOSE MODIFICATION GUIDELINES FOR ALL PATIENTS ON Sangrel:
For patients who experience Sangrel related neuropathic pain and/or peripheral sensory neuropathy the following modifications in the dose or regimen is recommended:
-Grade 1 (paresthesias and/or loss of reflexes) without pain or loss of function - no action is required.
-Grade 1 with pain or Grade 2 (interfering with function but not with activities of daily living) - reduce the dose of Sangrel to 1 mg/m2.
-Grade 2 with pain or Grade 3 (interfering with activities of daily living) - withhold Sangrel therapy until toxicity resolves. Once the toxicity resolves, reinitiate therapy with a reduced dose of Sangrel at 0.7 mg/m2 and change the frequency to once a week.
-Grade 4 (permanent sensory loss that interferes with function) - discontinue Sangrel.
Precautions
Safety and effectiveness have not been established in pediatric patients (less than 18 years of age).
Consult WARNINGS section for additional precautions.
Dialysis
Because dialysis may reduce Sangrel concentrations, the drug should be administered after the dialysis procedure.
Other Comments
The manufacturer product information should be consulted for current reconstitution, dilution and administration recommendations.
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification
Amisulpride (Oral): May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy
Ascorbic Acid: May diminish the therapeutic effect of Sangrel. Management: Patients should avoid taking vitamin C supplements and vitamin C-containing multivitamins during their Sangrel therapy. It is probably unnecessary to advise patients to avoid foods/beverages that contain vitamin C (e.g., citrus fruits, etc.). Consider therapy modification
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy
Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy
CYP2C19 Inducers (Moderate): May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Sangrel. Avoid combination
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Sangrel. Monitor therapy
Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification
Dabrafenib: May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP2C19 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Green Tea: May diminish the antineoplastic effect of Sangrel. Avoid combination
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Monitor therapy
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Multivitamins/Fluoride (with ADE): May diminish the therapeutic effect of Sangrel. Specifically, the vitamin C (ascorbic acid) found in many multivitamins may impair the clinical effects of Sangrel. Management: Patients should avoid taking extra vitamin C supplements and vitamin C-containing multivitamins during their Sangrel therapy. It is likely unnecessary, though, to advise patients to avoid dietary sources of vitamin C. Consider therapy modification
Multivitamins/Minerals (with ADEK, Folate, Iron): May diminish the therapeutic effect of Sangrel. Management: Patients should avoid taking extra vitamin C supplements and vitamin C-containing multivitamins with Sangrel. It is probably unnecessary to restrict or limit vitamin C-containing foods/beverages. Consider therapy modification
Multivitamins/Minerals (with AE, No Iron): May diminish the therapeutic effect of Sangrel. Specifically, vitamin C may decrease Sangrel therapeutic effects. Management: Patients should avoid taking extra vitamin C supplements and vitamin C-containing multivitamins during their Sangrel therapy. It is likely unnecessary, though, to advise patients to avoid dietary sources of vitamin C. Consider therapy modification
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy
Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
St John's Wort: May decrease the serum concentration of Sangrel. Avoid combination
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
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 7 describes safety data from 340 patients with previously untreated multiple myeloma who received Sangrel (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 Sangrel in combination with melphalan/prednisone is consistent with the known safety profiles of both Sangrel and melphalan/prednisone.
Table 7: Most Commonly Reported Adverse Reactions (≥ 10% in the Sangrel, Melphalan and Prednisone arm) with Grades 3 and ≥ 4 Intensity in the Previously Untreated Multiple Myeloma Study
a Represents High Level Term Peripheral Neuropathies NEC
Sangrel, Melphalan and
Prednisone
(n=340)
Melphalan and Prednisone
(n=337)
Toxicity Grade, n (%)
Toxicity Grade, n (%)
System Organ Class
Preferred Term
Total n (%)
3
≥ 4
Total n (%)
3
≥ 4
Blood and lymphatic system disorders
Thrombocytopenia
164 (48)
60 (18)
57 (17)
140 (42)
48 (14)
39 (12)
Neutropenia
160 (47)
101 (30)
33 (10)
143 (42)
77 (23)
42 (12)
Anemia
109 (32)
41 (12)
4 (1)
156 (46)
61 (18)
18 (5)
Leukopenia
108 (32)
64 (19)
8 (2)
93 (28)
53 (16)
11 (3)
Lymphopenia
78 (23)
46 (14)
17 (5)
51 (15)
26 (8)
7 (2)
Gastrointestinal disorders
Nausea
134 (39)
10 (3)
0
70 (21)
1 (< 1)
0
Diarrhea
119 (35)
19 (6)
2 (1)
20 (6)
1 (< 1)
0
Vomiting
87 (26)
13 (4)
0
41 (12)
2 (1)
0
Constipation
77 (23)
2 (1)
0
14 (4)
0
0
Abdominal Pain Upper
34 (10)
1 (< 1)
0
20 (6)
0
0
Nervous system disorders
Peripheral Neuropathya
156 (46)
42 (12)
2 (1)
4 (1)
0
0
Neuralgia
117 (34)
27 (8)
2 (1)
1 (< 1)
0
0
Paresthesia
42 (12)
6 (2)
0
4 (1)
0
0
General disorders and administration site
conditions
Fatigue
85 (25)
19 (6)
2 (1)
48 (14)
4 (1)
0
Asthenia
54 (16)
18 (5)
0
23 (7)
3 (1)
0
Pyrexia
53 (16)
4 (1)
0
19 (6)
1 (< 1)
1 (< 1)
Infections and infestations
Herpes Zoster
39 (11)
11 (3)
0
9 (3)
4 (1)
0
Metabolism and nutrition disorders
Anorexia
64 (19)
6 (2)
0
19 (6)
0
0
Skin and subcutaneous tissue disorders
Rash
38 (11)
2 (1)
0
7 (2)
0
0
Psychiatric disorders
Insomnia
35 (10)
1 (< 1)
0
21 (6)
0
0
Relapsed Multiple Myeloma Randomized Study of Sangrel versus Dexamethasone
The safety data described below and in Table 8 reflect exposure to either Sangrel (n=331) or dexamethasone (n=332) in a study of patients with relapsed multiple myeloma. Sangrel 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 Sangrel-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 Sangrel-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 Sangrel 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 Sangrel 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 Sangrel 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 Sangrel treatment group and 61 (18%) of
332 patients in the dexamethasone treatment group were discontinued from treatment due to adverse reactions. Among the 331 Sangrel-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 Sangrel-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 Sangrel versus Dexamethasone
The most common adverse reactions from the relapsed multiple myeloma study are shown in Table 8. All adverse reactions with incidence ≥ 10% in the Sangrel arm are included.
Table 8: Most Commonly Reported Adverse Reactions (≥ 10% in Sangrel arm), with Grades 3 and 4 Intensity in the Relapsed Multiple Myeloma Study of Sangrel versus Dexamethasone (N=663)
a Represents High Level Term Peripheral Neuropathies NEC
Preferred Term
All
Sangrel
(N=331)
Grade 3
Grade 4
All
Dexamethasone
(N=332)
Grade 3
Grade 4
Adverse Reactions
324 (98)
193 (58)
28 (8)
297 (89)
110 (33)
29 (9)
Nausea
172 (52)
8 (2)
0
31 (9)
0
0
Diarrhea NOS
171 (52)
22 (7)
0
36 (11)
2 (< 1)
0
Fatigue
130 (39)
15 (5)
0
82 (25)
8 (2)
0
Peripheral neuropathiesa
115 (35)
23 (7)
2 (< 1)
14 (4)
0
1 (< 1)
Thrombocytopenia
109 (33)
80 (24)
12 (4)
11 (3)
5 (2)
1 (< 1)
Constipation
99 (30)
6 (2)
0
27 (8)
1 (< 1)
0
Vomiting NOS
96 (29)
8 (2)
0
10 (3)
1 (< 1)
0
Anorexia
68 (21)
8 (2)
0
8 (2)
1 (< 1)
0
Pyrexia
66 (20)
2 (< 1)
0
21 (6)
3 (< 1)
1 (< 1)
Paresthesia
64 (19)
5 (2)
0
24 (7)
0
0
Anemia NOS
63 (19)
20 (6)
1 (< 1)
21 (6)
8 (2)
0
Headache NOS
62 (19)
3 (< 1)
0
23 (7)
1 (< 1)
0
Neutropenia
58 (18)
37 (11)
8 (2)
1 (< 1)
1 (< 1)
0
Rash NOS
43 (13)
3 (< 1)
0
7 (2)
0
0
Appetite decreased NOS
36 (11)
0
0
12 (4)
0
0
Dyspnea NOS
35 (11)
11 (3)
1 (< 1)
37 (11)
7 (2)
1 (< 1)
Abdominal pain NOS
35 (11)
5 (2)
0
7 (2)
0
0
Weakness
34 (10)
10 (3)
0
28 (8)
8 (2)
0
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 Sangrel treatment. These patients were treated for a total of 5.3 to 23 months, including time on Sangrel in the prior Sangrel study.
Integrated Summary of Safety (Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma)
Safety data from phase 2 and 3 studies of single agent Sangrel 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1,163 patients with previously-treated multiple myeloma (N=1,008) 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 Sangrel subcutaneous versus intravenous in relapsed multiple myeloma. In the integrated studies, the safety profile of Sangrel 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 Sangrel administered intravenously, local skin irritation was reported in 5% of patients, but extravasation of Sangrel 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 adverse reactions included diarrhea, vomiting and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each) and pneumonia, dyspnea, peripheral neuropathies, and herpes zoster (1% each).
Adverse reactions leading to discontinuation occurred in 22% of patients. The reasons for discontinuation included peripheral neuropathy (8%), and fatigue, thrombocytopenia, and diarrhea (2% each).
In total, 2% of the patients died and the cause of death was considered by the investigator to be possibly related to study drug: including reports of cardiac arrest, congestive heart failure, respiratory failure, renal failure, pneumonia and sepsis.
Most Commonly Reported Adverse Reactions in the Integrated Summary of Safety
The most common adverse reactions are shown in Table 9. All adverse reactions occurring at ≥ 10% are included. In the absence of a randomized comparator arm, it is often not possible to distinguish between adverse events that are drug-caused and those that reflect the patient's underlying disease. Please see the discussion of specific adverse reactions that follows.
Table 9: Most Commonly Reported (≥ 10% Overall) Adverse Reactions in Integrated Analyses of Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma Studies using the 1.3 mg/m2 Dose (N=1,163)
a Represents High Level Term Peripheral Neuropathies NEC
All Patients
Multiple Myeloma
Mantle Cell Lymphoma
(N=1,163)
(N=1,008)
(N=155)
Preferred Term
All
≥ Grade 3
All
≥ Grade 3
All
≥ Grade 3
Nausea
567 (49)
36 (3)
511 (51)
32 (3)
56 (36)
4 (3)
Diarrhea NOS
530 (46)
83 (7)
470 (47)
72 (7)
60 (39)
11 (7)
Fatigue
477 (41)
86 (7)
396 (39)
71 (7)
81 (52)
15 (10)
Peripheral neuropathiesa
443 (38)
129 (11)
359 (36)
110 (11)
84 (54)
19 (12)
Thrombocytopenia
369 (32)
295 (25)
344 (34)
283 (28)
25 (16)
12 (8)
Vomiting NOS
321 (28)
44 (4)
286 (28)
40 (4)
35 (23)
4 (3)
Constipation
296 (25)
17 (1)
244 (24)
14 (1)
52 (34)
3 (2)
Pyrexia
249 (21)
16 (1)
233 (23)
15 (1)
16 (10)
1 (< 1)
Anorexia
227 (20)
19 (2)
205 (20)
16 (2)
22 (14)
3 (2)
Anemia NOS
209 (18)
65 (6)
190 (19)
63 (6)
19 (12)
2 (1)
Headache NOS
175 (15)
8 (< 1)
160 (16)
8 (< 1)
15 (10)
0
Neutropenia
172 (15)
121 (10)
164 (16)
117 (12)
8 (5)
4 (3)
Rash NOS
156 (13)
8 (< 1)
120 (12)
4 (< 1)
36 (23)
4 (3)
Paresthesia
147 (13)
9 (< 1)
136 (13)
8 (< 1)
11 (7)
1 (< 1)
Dizziness (excl vertigo)
129 (11)
13 (1)
101 (10)
9 (< 1)
28 (18)
4 (3)
Weakness
124 (11)
31 (3)
106 (11)
28 (3)
18 (12)
3 (2)
Description of Selected Adverse Reactions from the Integrated Phase 2 and 3 Relapsed Multiple Myeloma and Phase 2 Relapsed Mantle Cell Lymphoma Studies
Gastrointestinal Toxicity
A total of 75% of patients experienced at least one gastrointestinal disorder. The most common gastrointestinal disorders included nausea, diarrhea, constipation, vomiting, and appetite decreased. Other gastrointestinal disorders included dyspepsia and dysgeusia. Grade 3 adverse reactions occurred in 14% of patients; ≥ Grade 4 adverse reactions were ≤ 1%. Gastrointestinal adverse reactions were considered serious in 7% of patients. Four percent (4%) of patients discontinued due to a gastrointestinal adverse reaction. Nausea was reported more often in patients with multiple myeloma (51%) compared to patients with mantle cell lymphoma (36%).
Thrombocytopenia
Across the studies, Sangrel-associated thrombocytopenia was characterized by a decrease in platelet count during the dosing period (days 1 to 11) and a return toward baseline during the 10-day rest period during each treatment cycle. Overall, thrombocytopenia was reported in 32% of patients. Thrombocytopenia was Grade 3 in 22%, ≥ Grade 4 in 4%, and serious in 2% of patients, and the reaction resulted in Sangrel discontinuation in 2% of patients. Thrombocytopenia was reported more often in patients with multiple myeloma (34%) compared to patients with mantle cell lymphoma (16%). The incidence of ≥ Grade 3 thrombocytopenia also was higher in patients with multiple myeloma (28%) compared to patients with mantle cell lymphoma (8%).
Peripheral Neuropathy
Overall, peripheral neuropathies occurred in 38% of patients. Peripheral neuropathy was Grade 3 for 11% of patients and ≥ Grade 4 for < 1% of patients. Eight percent (8%) of patients discontinued Sangrel due to peripheral neuropathy. The incidence of peripheral neuropathy was higher among patients with mantle cell lymphoma (54%) compared to patients with multiple myeloma (36%).
In the Sangrel versus dexamethasone phase 3 relapsed multiple myeloma study, among the 62 Sangrel-treated patients who experienced ≥ Grade 2 peripheral neuropathy and had dose adjustments, 48% had improved or resolved with a median of 3.8 months from first onset.
In the phase 2 relapsed multiple myeloma studies, among the 30 patients who experienced Grade 2 peripheral neuropathy resulting in discontinuation or who experienced ≥ Grade 3 peripheral neuropathy, 73% reported improvement or resolution with a median time of 47 days to improvement of one Grade or more from the last dose of Sangrel.
Hypotension
The incidence of hypotension (postural, orthostatic and hypotension NOS) was 8% in patients treated with Sangrel. Hypotension was Grade 1 or 2 in the majority of patients and Grade 3 in 2% and ≥ Grade 4 in
< 1%. Two percent (2%) of patients had hypotension reported as a serious adverse reaction, and 1% discontinued due to hypotension. The incidence of hypotension was similar in patients with multiple myeloma (8%) and those with mantle cell lymphoma (9%). In addition, < 1% of patients experienced hypotension associated with a syncopal reaction.
Neutropenia
Neutrophil counts decreased during the Sangrel dosing period (days 1 to 11) and returned toward baseline during the 10-day rest period during each treatment cycle. Overall, neutropenia occurred in 15% of patients and was Grade 3 in 8% of patients and ≥ Grade 4 in 2%. Neutropenia was reported as a serious adverse reaction in < 1% of patients and < 1% of patients discontinued due to neutropenia. The incidence of neutropenia was higher in patients with multiple myeloma (16%) compared to patients with mantle cell lymphoma (5%). The incidence of ≥ Grade 3 neutropenia also was higher in patients with multiple myeloma (12%) compared to patients with mantle cell lymphoma (3%).
Asthenic conditions were reported in 54% of patients. Fatigue was reported as Grade 3 in 7% and ≥ Grade 4 in < 1% of patients. Asthenia was reported as Grade 3 in 2% and ≥ Grade 4 in < 1% of patients. Two percent (2%) of patients discontinued treatment due to fatigue and < 1% due to weakness and asthenia. Asthenic conditions were reported in 53% of patients with multiple myeloma and 59% of patients with mantle cell lymphoma.
Pyrexia
Pyrexia (> 38ºC) was reported as an adverse reaction for 21% of patients. The reaction was Grade 3 in 1% and ≥ Grade 4 in < 1%. Pyrexia was reported as a serious adverse reaction in 3% of patients and led to Sangrel discontinuation in < 1% of patients. The incidence of pyrexia was higher among patients with multiple myeloma (23%) compared to patients with mantle cell lymphoma (10%). The incidence of ≥ Grade 3 pyrexia was 1% in patients with multiple myeloma and < 1% in patients with mantle cell lymphoma.
Herpes Virus Infection
Consider using antiviral prophylaxis in subjects being treated with Sangrel. In the randomized studies in
previously untreated and relapsed multiple myeloma, herpes zoster reactivation was more common in subjects treated with Sangrel (ranging between 6 to 11%) than in the control groups (3 to 4%). Herpes simplex was seen in 1 to 3% in subjects treated with Sangrel and 1 to 3% in the control groups. In the previously untreated multiple myeloma study, herpes zoster virus reactivation in the Sangrel, melphalan and prednisone arm was less common in subjects receiving prophylactic antiviral therapy (3%) than in subjects who did not receive prophylactic antiviral therapy (17%).
Additional Adverse Reactions from Clinical Studies
The following clinically important serious adverse reactions that are not described above have been reported in clinical trials in patients treated with Sangrel administered as monotherapy or in combination with other chemotherapeutics. These studies were conducted in patients with hematological malignancies and in solid tumors.
Blood and lymphatic system disorders: Anemia, disseminated intravascular coagulation, febrile neutropenia, lymphopenia, leukopenia
General disorders and administration site conditions: Chills, edema, edema peripheral, injection site erythema, neuralgia, injection site pain, irritation, malaise, phlebitis
The following adverse reactions have been identified from the worldwide postmarketing experience with Sangrel. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:
Sangrel for Injection is contraindicated in patients with hypersensitivity (not including local reactions) to Sangrel, boron, boric acid or glycine. Reactions have included anaphylactic reactions.
Sangrel for Injection is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of Sangrel.
DailyMed. "BORTEZOMIB: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
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