Carfilzomib: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
No edit summary
No edit summary
Line 46: Line 46:
=====Condition1=====
=====Condition1=====


* Dosing Information
*KYPROLIS is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.
 
:* Dosage


=====Condition2=====
*Dosing Guidelines
:*KYPROLIS is administered intravenously over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17 to 28). Each 28-day period is considered one treatment cycle (Table 1).
:*In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, the dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequent cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs [see Dosage and Administration (2.4)].
:*The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a body surface are of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%.


* Dosing Information
T1


:* Dosage
*Hydration and Fluid Monitoring
:*Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome (TLS) with KYPROLIS treatment [see Warnings and Precautions (5.5)]. Maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid. Give an additional 250 mL to 500 mL of intravenous fluids as needed following KYPROLIS administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor patients during this period for fluid overload [see Warnings and Precautions (5.1)].


=====Condition3=====
*Dexamethasone Premedication
:*Pre-medicate with dexamethasone 4 mg orally or intravenously prior to all doses of KYPROLIS during Cycle 1 and prior to all KYPROLIS doses during the first cycle of dose escalation to 27 mg/m2 to reduce the incidence and severity of infusion reactions [see Warnings and Precautions (5.4)]. Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or reappear during subsequent cycles.


* Dosing Information
*Dose Modifications Based on Toxicities
:*Recommended actions and dose modifications are presented in Table 2.


:* Dosage
T2
 
=====Condition4=====
 
* Dosing Information
 
:* Dosage


<!--Off-Label Use and Dosage (Adult)-->
<!--Off-Label Use and Dosage (Adult)-->
Line 160: Line 158:
|contraindications=
|contraindications=


* Condition1
*None.


<!--Warnings-->
<!--Warnings-->


|warnings=
|warnings=
* Description


====Precautions====
====Precautions====


* Description
* Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia
:*Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre-existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment[see Dosage and Administration (2.4)]. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications.


<!--Adverse Reactions-->
*Pulmonary Hypertension
:*Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration (2.4)].


<!--Clinical Trials Experience-->
*Pulmonary Complications
:*Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline [see Dosage and Administration (2.4) and Adverse Reactions (6.1)].


|clinicalTrials=
*Infusion Reactions
:*Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions [see Dosage and Administration (2.3)]. Inform patients of the risk and symptoms and to contact physician if symptoms of an infusion reaction occur [see Patient Counseling Information (17)].


There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.
*Tumor Lysis Syndrome
:*Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated [see Dosage and Administration (2.2)]. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved [see Dosage and Administration (2.4)].


=====Body as a Whole=====
*Thrombocytopenia
:*KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28-day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated [see Dosage and Administration (2.4)].


*Hepatic Toxicity and Hepatic Failure
:*Cases of hepatic failure, including fatal cases, have been reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently [see Dosage and Administration (2.4) and Adverse Reactions (6.1)].


*Embryo-fetal Toxicity
:*KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose.
:*Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus[see Use in Specific Populations (8.1)].


<!--Adverse Reactions-->


=====Cardiovascular=====
<!--Clinical Trials Experience-->
 
 
 
 
=====Digestive=====
 


|clinicalTrials=


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


=====Endocrine=====
*A total of 526 patients with relapsed and/or refractory multiple myeloma received KYPROLIS as monotherapy or with pre-dose dexamethasone. Patients received a median of four treatment cycles with a median cumulative KYPROLIS dose of 993.4 mg.


*Deaths due to all causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not attributed to disease progression were cardiac in 5 patients (acute coronary syndrome, cardiac arrest, cardiac disorder), end-organ failure in 4 patients (multi-organ failure, hepatic failure, renal failure), infection in 4 patients (sepsis, pneumonia, respiratory tract bacterial infection), dyspnea and intracranial hemorrhage in 1 patient each, and 1 patient found dead of unknown causes.


*Serious adverse reactions were reported in 45% patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each).


*Adverse reactions occurring at a rate of 10% or greater are presented in Table 4.


=====Hematologic and Lymphatic=====
T4


*Renal Events
:*The most common renal adverse reactions were increase in blood creatinine (24%) and renal failure (9%), which were mostly Grade 1 or Grade 2 in severity. Grade 3 renal adverse reactions occurred in 6% of patients and Grade 4 events occurred in 1%. Discontinuations due to increased blood creatinine and acute renal failure were 1% each. In one patient, death occurred with concurrent sepsis and worsening renal function [see Dosage and Administration (2.4)].


*Peripheral Neuropathy
:*Peripheral neuropathy (including all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% of patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended [see Dosage and Administration (2.4)].


 
*Herpes Virus Infection
=====Metabolic and Nutritional=====
:*Herpes zoster reactivation was reported in 2% of patients. Consider antiviral prophylaxis for patients who have a history of herpes zoster infection.
 
 
 
 
=====Musculoskeletal=====
 
 
 
 
=====Neurologic=====
 
 
 
 
=====Respiratory=====
 
 
 
 
=====Skin and Hypersensitivy Reactions=====
 
 
 
 
=====Special Senses=====
 
 
 
 
=====Urogenital=====
 
 
 
 
=====Miscellaneous=====
 
 


<!--Postmarketing Experience-->
<!--Postmarketing Experience-->
Line 249: Line 223:


There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
=====Body as a Whole=====
=====Cardiovascular=====
=====Digestive=====
=====Endocrine=====
=====Hematologic and Lymphatic=====
=====Metabolic and Nutritional=====
=====Musculoskeletal=====
=====Neurologic=====
=====Respiratory=====
=====Skin and Hypersensitivy Reactions=====
=====Special Senses=====
=====Urogenital=====
=====Miscellaneous=====


<!--Drug Interactions-->
<!--Drug Interactions-->
Line 306: Line 228:
|drugInteractions=
|drugInteractions=


* Drug
*Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected to influence exposure of other drugs [see Clinical Pharmacology (12.3)].
:* Description


<!--Use in Specific Populations-->
<!--Use in Specific Populations-->


|useInPregnancyFDA=
|useInPregnancyFDA=
* '''Pregnancy Category'''
* '''Pregnancy Category D'''
 
*Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. Based on its mechanism of action and findings in animals, KYPROLIS can cause fetal harm when administered to a pregnant woman. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. If KYPROLIS is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
 
*Carfilzomib was administered intravenously to pregnant rats and rabbits during the period of organogenesis at doses of 0.5, 1, and 2 mg/kg/day in rats and 0.2, 0.4, and 0.8 mg/kg/day in rabbits. Carfilzomib was not teratogenic at any dose tested. In rabbits, there was an increase in pre-implantation loss at ≥ 0.4 mg/kg/day and an increase in early resorptions and post-implantation loss and a decrease in fetal weight at the maternally toxic dose of 0.8 mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are approximately 20% and 40%, respectively, of the recommended dose in humans of 27 mg/m2 based on body surface area.


|useInPregnancyAUS=
|useInPregnancyAUS=
Line 323: Line 248:


|useInNursing=
|useInNursing=
There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.
 
*It is not known whether KYPROLIS is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from KYPROLIS, 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.


|useInPed=
|useInPed=
There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.
 
*The safety and effectiveness of KYPROLIS in pediatric patients have not been established.


|useInGeri=
|useInGeri=
There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.
 
*In studies of KYPROLIS there were no clinically significant differences observed in safety and efficacy between patients less than 65 years of age and patients 65 years of age and older.  


|useInGender=
|useInGender=
Line 338: Line 266:


|useInRenalImpair=
|useInRenalImpair=
There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.
 
*The pharmacokinetics and safety of KYPROLIS were evaluated in a Phase 2 trial in patients with normal renal function and those with mild, moderate, and severe renal impairment and patients on chronic dialysis. On average, patients were treated for 5.5 cycles using KYPROLIS doses of 15 mg/m2 on Cycle 1, 20 mg/m2 on Cycle 2, and 27 mg/m2 on Cycles 3 and beyond. The pharmacokinetics and safety of KYPROLIS were not influenced by the degree of baseline renal impairment, including the patients on dialysis. Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure [see Clinical Pharmacology (12.3)].  


|useInHepaticImpair=
|useInHepaticImpair=
There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.
 
*The safety, efficacy and pharmacokinetics of KYPROLIS have not been evaluated in patients with baseline hepatic impairment. Patients with the following laboratory values were excluded from the KYPROLIS clinical trials: ALT/AST ≥ 3 × upper limit of normal (ULN) and bilirubin ≥ 2 × ULN [see Clinical Pharmacology (12.3)].


|useInReproPotential=
|useInReproPotential=
Line 352: Line 282:


|administration=
|administration=
* Oral


* Intravenous
* Intravenous
Line 360: Line 288:


There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.
There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.
* Description


<!--IV Compatibility-->
<!--IV Compatibility-->
Line 372: Line 298:


|overdose=
|overdose=
===Acute Overdose===
====Signs and Symptoms====
* Description
====Management====
* Description


===Chronic Overdose===
===Chronic Overdose===
Line 393: Line 309:
|drugBox=
|drugBox=


{{Drugbox2
| drug_name        =
| IUPAC_name        = (''S'')-4-Methyl-''N''-((''S'')-1-(((''S'')-4-methyl-1-((''R'')-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((''S'')-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide
| image            = Carfilzomib00.png
| alt              =
| caption          =
<!-- Clinical data -->
| tradename        = Kyprolis
| Drugs.com        =
| MedlinePlus      =
| licence_US        = Carfilzomib
| pregnancy_AU      = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US      = D
| pregnancy_category=
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM -->
| legal_US = Rx-only
| legal_status      =
| routes_of_administration = Intravenous


<!-- Pharmacokinetic data -->
| bioavailability  =
| protein_bound    =
| metabolism        =
| elimination_half-life =
| excretion        =
<!-- Identifiers -->
| CAS_number        = 868540-17-4
| ATC_prefix        = L01
| ATC_suffix        = XX45
| PubChem          = 11556711
| DrugBank          =
| ChemSpiderID      = 9731489
| ChEMBL = 451887
| UNII              =
| KEGG              = D08880
| synonyms          = PX-171-007
<!-- Chemical data -->
| chemical_formula  =
|  C=40 | H=57 | N=5 | O=7
| molecular_weight  = 719.91 g mol
| smiles            = O=C(N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)[C@@]1(OC1)C)CC(C)C)Cc2ccccc2)CC(C)C)CCc3ccccc3)CN4CCOCC4
| StdInChI=1S/C40H57N5O7/c1-27(2)22-32(36(47)40(5)26-52-40)42-39(50)34(24-30-14-10-7-11-15-30)44-38(49)33(23-28(3)4)43-37(48)31(17-16-29-12-8-6-9-13-29)41-35(46)25-45-18-20-51-21-19-45/h6-15,27-28,31-34H,16-26H2,1-5H3,(H,41,46)(H,42,50)(H,43,48)(H,44,49)/t31-,32-,33-,34-,40+/m0/s1
| StdInChIKey = StdInChI
}}


<!--Mechanism of Action-->
<!--Mechanism of Action-->
Line 399: Line 363:
|mechAction=
|mechAction=


*  
* Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib had antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumor growth in models of multiple myeloma, hematologic, and solid tumors.


<!--Structure-->
<!--Structure-->
Line 405: Line 369:
|structure=
|structure=


*  
* KYPROLIS (carfilzomib) for Injection is an antineoplastic agent available for intravenous use only. KYPROLIS is a sterile, white to off-white lyophilized powder and is available as a single-use vial. Each vial of KYPROLIS contains 60 mg of carfilzomib, 3000 mg sulfobutylether beta-cyclodextrin, 57.7 mg citric acid, and sodium hydroxide for pH adjustment (target pH 3.5).
 
*Carfilzomib is a modified tetrapeptidyl epoxide, isolated as the crystalline free base. The chemical name for carfilzomib is (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide. Carfilzomib has the following structure:


: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
*Carfilzomib is a crystalline substance with a molecular weight of 719.9. The molecular formula is C40H57N5O7. Carfilzomib is practically insoluble in water, and very slightly soluble in acidic conditions.


<!--Pharmacodynamics-->
<!--Pharmacodynamics-->

Revision as of 20:31, 23 January 2015

Carfilzomib
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]

Disclaimer

WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.

Overview

Carfilzomib is a proteasome inhibitor that is FDA approved for the {{{indicationType}}} of multiple myeloma. Common adverse reactions include fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Condition1
  • KYPROLIS is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.
  • Dosing Guidelines
  • KYPROLIS is administered intravenously over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17 to 28). Each 28-day period is considered one treatment cycle (Table 1).
  • In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, the dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequent cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs [see Dosage and Administration (2.4)].
  • The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a body surface are of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%.

T1

  • Hydration and Fluid Monitoring
  • Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome (TLS) with KYPROLIS treatment [see Warnings and Precautions (5.5)]. Maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid. Give an additional 250 mL to 500 mL of intravenous fluids as needed following KYPROLIS administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor patients during this period for fluid overload [see Warnings and Precautions (5.1)].
  • Dexamethasone Premedication
  • Pre-medicate with dexamethasone 4 mg orally or intravenously prior to all doses of KYPROLIS during Cycle 1 and prior to all KYPROLIS doses during the first cycle of dose escalation to 27 mg/m2 to reduce the incidence and severity of infusion reactions [see Warnings and Precautions (5.4)]. Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or reappear during subsequent cycles.
  • Dose Modifications Based on Toxicities
  • Recommended actions and dose modifications are presented in Table 2.

T2

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Condition1
  • Developed by:
  • Class of Recommendation:
  • Strength of Evidence:
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Carfilzomib in adult patients.

Non–Guideline-Supported Use

Condition1
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Carfilzomib in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Condition1
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding FDA-Labeled Use of Carfilzomib in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition1
  • Developed by:
  • Class of Recommendation:
  • Strength of Evidence:
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Carfilzomib in pediatric patients.

Non–Guideline-Supported Use

Condition1
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Carfilzomib in pediatric patients.

Contraindications

  • None.

Warnings

Precautions

  • Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia
  • Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre-existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment[see Dosage and Administration (2.4)]. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications.
  • Pulmonary Hypertension
  • Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration (2.4)].
  • Pulmonary Complications
  • Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline [see Dosage and Administration (2.4) and Adverse Reactions (6.1)].
  • Infusion Reactions
  • Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions [see Dosage and Administration (2.3)]. Inform patients of the risk and symptoms and to contact physician if symptoms of an infusion reaction occur [see Patient Counseling Information (17)].
  • Tumor Lysis Syndrome
  • Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated [see Dosage and Administration (2.2)]. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved [see Dosage and Administration (2.4)].
  • Thrombocytopenia
  • KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28-day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated [see Dosage and Administration (2.4)].
  • Hepatic Toxicity and Hepatic Failure
  • Cases of hepatic failure, including fatal cases, have been reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently [see Dosage and Administration (2.4) and Adverse Reactions (6.1)].
  • Embryo-fetal Toxicity
  • KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose.
  • Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus[see Use in Specific Populations (8.1)].

Adverse Reactions

Clinical Trials 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 with rates in the clinical trials of another drug, and may not reflect the rates observed in medical practice.
  • A total of 526 patients with relapsed and/or refractory multiple myeloma received KYPROLIS as monotherapy or with pre-dose dexamethasone. Patients received a median of four treatment cycles with a median cumulative KYPROLIS dose of 993.4 mg.
  • Deaths due to all causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not attributed to disease progression were cardiac in 5 patients (acute coronary syndrome, cardiac arrest, cardiac disorder), end-organ failure in 4 patients (multi-organ failure, hepatic failure, renal failure), infection in 4 patients (sepsis, pneumonia, respiratory tract bacterial infection), dyspnea and intracranial hemorrhage in 1 patient each, and 1 patient found dead of unknown causes.
  • Serious adverse reactions were reported in 45% patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each).
  • Adverse reactions occurring at a rate of 10% or greater are presented in Table 4.

T4

  • Renal Events
  • The most common renal adverse reactions were increase in blood creatinine (24%) and renal failure (9%), which were mostly Grade 1 or Grade 2 in severity. Grade 3 renal adverse reactions occurred in 6% of patients and Grade 4 events occurred in 1%. Discontinuations due to increased blood creatinine and acute renal failure were 1% each. In one patient, death occurred with concurrent sepsis and worsening renal function [see Dosage and Administration (2.4)].
  • Peripheral Neuropathy
  • Peripheral neuropathy (including all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% of patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended [see Dosage and Administration (2.4)].
  • Herpes Virus Infection
  • Herpes zoster reactivation was reported in 2% of patients. Consider antiviral prophylaxis for patients who have a history of herpes zoster infection.

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Carfilzomib in the drug label.

Drug Interactions

  • Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected to influence exposure of other drugs [see Clinical Pharmacology (12.3)].

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

  • Pregnancy Category D
  • Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. Based on its mechanism of action and findings in animals, KYPROLIS can cause fetal harm when administered to a pregnant woman. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. If KYPROLIS is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
  • Carfilzomib was administered intravenously to pregnant rats and rabbits during the period of organogenesis at doses of 0.5, 1, and 2 mg/kg/day in rats and 0.2, 0.4, and 0.8 mg/kg/day in rabbits. Carfilzomib was not teratogenic at any dose tested. In rabbits, there was an increase in pre-implantation loss at ≥ 0.4 mg/kg/day and an increase in early resorptions and post-implantation loss and a decrease in fetal weight at the maternally toxic dose of 0.8 mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are approximately 20% and 40%, respectively, of the recommended dose in humans of 27 mg/m2 based on body surface area.


Pregnancy Category (AUS):

  • Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Carfilzomib in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Carfilzomib during labor and delivery.

Nursing Mothers

  • It is not known whether KYPROLIS is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from KYPROLIS, 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 safety and effectiveness of KYPROLIS in pediatric patients have not been established.

Geriatic Use

  • In studies of KYPROLIS there were no clinically significant differences observed in safety and efficacy between patients less than 65 years of age and patients 65 years of age and older.

Gender

There is no FDA guidance on the use of Carfilzomib with respect to specific gender populations.

Race

There is no FDA guidance on the use of Carfilzomib with respect to specific racial populations.

Renal Impairment

  • The pharmacokinetics and safety of KYPROLIS were evaluated in a Phase 2 trial in patients with normal renal function and those with mild, moderate, and severe renal impairment and patients on chronic dialysis. On average, patients were treated for 5.5 cycles using KYPROLIS doses of 15 mg/m2 on Cycle 1, 20 mg/m2 on Cycle 2, and 27 mg/m2 on Cycles 3 and beyond. The pharmacokinetics and safety of KYPROLIS were not influenced by the degree of baseline renal impairment, including the patients on dialysis. Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure [see Clinical Pharmacology (12.3)].

Hepatic Impairment

  • The safety, efficacy and pharmacokinetics of KYPROLIS have not been evaluated in patients with baseline hepatic impairment. Patients with the following laboratory values were excluded from the KYPROLIS clinical trials: ALT/AST ≥ 3 × upper limit of normal (ULN) and bilirubin ≥ 2 × ULN [see Clinical Pharmacology (12.3)].

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Carfilzomib in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Carfilzomib in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Intravenous

Monitoring

There is limited information regarding Monitoring of Carfilzomib in the drug label.

IV Compatibility

There is limited information regarding IV Compatibility of Carfilzomib in the drug label.

Overdosage

Chronic Overdose

There is limited information regarding Chronic Overdose of Carfilzomib in the drug label.

Pharmacology

Template:Px
Carfilzomib
Systematic (IUPAC) name
(S)-4-Methyl-N-((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide
Identifiers
CAS number 868540-17-4
ATC code L01XX45
PubChem 11556711
Chemical data
Formula Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox 
Mol. mass 719.91 g mol
SMILES eMolecules & PubChem
Synonyms PX-171-007
Pharmacokinetic data
Bioavailability ?
Metabolism ?
Half life ?
Excretion ?
Therapeutic considerations
Licence data

US

Pregnancy cat.

D(US)

Legal status

[[Prescription drug|Template:Unicode-only]](US)

Routes Intravenous

Mechanism of Action

  • Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib had antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumor growth in models of multiple myeloma, hematologic, and solid tumors.

Structure

  • KYPROLIS (carfilzomib) for Injection is an antineoplastic agent available for intravenous use only. KYPROLIS is a sterile, white to off-white lyophilized powder and is available as a single-use vial. Each vial of KYPROLIS contains 60 mg of carfilzomib, 3000 mg sulfobutylether beta-cyclodextrin, 57.7 mg citric acid, and sodium hydroxide for pH adjustment (target pH 3.5).
  • Carfilzomib is a modified tetrapeptidyl epoxide, isolated as the crystalline free base. The chemical name for carfilzomib is (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide. Carfilzomib has the following structure:
This image is provided by the National Library of Medicine.
  • Carfilzomib is a crystalline substance with a molecular weight of 719.9. The molecular formula is C40H57N5O7. Carfilzomib is practically insoluble in water, and very slightly soluble in acidic conditions.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Carfilzomib in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Carfilzomib in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Carfilzomib in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Carfilzomib in the drug label.

How Supplied

Storage

There is limited information regarding Carfilzomib Storage in the drug label.

Images

Drug Images

{{#ask: Page Name::Carfilzomib |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

{{#ask: Label Page::Carfilzomib |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

There is limited information regarding Patient Counseling Information of Carfilzomib in the drug label.

Precautions with Alcohol

  • Alcohol-Carfilzomib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. ↑ Empty citation (help)
  2. ↑ "http://www.ismp.org". External link in |title= (help)


{{#subobject: 

 |Page Name=Carfilzomib
 |Pill Name=No image.jpg
 |Drug Name=
 |Pill Ingred=|+sep=;
 |Pill Imprint=
 |Pill Dosage=
 |Pill Color=|+sep=;
 |Pill Shape=
 |Pill Size (mm)=
 |Pill Scoring=
 |Pill Image=
 |Drug Author=
 |NDC=

}}


{{#subobject: 

 |Label Page=Carfilzomib
 |Label Name=Carfilzomib11.png

}}


{{#subobject: 

 |Label Page=Carfilzomib
 |Label Name=Carfilzomib11.png

}}

Retrieved from "https://www.wikidoc.org/index.php?title=Carfilzomib&oldid=1059351"