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CARFILZOMIB

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Carfilzomib is a proteosome inhibitor for the treatment of multiple myeloma.

Specific Substances

    1) PR-171
    2) CAS 868540-17-4
    1.2.1) MOLECULAR FORMULA
    1) C40-H57-N5-O7 (Prod Info KYPROLIS(TM) intravenous injection, 2012)

Available Forms Sources

    A) FORMS
    1) Carfilzomib is available as 60 mg of lyophilized powder in a single-use vial, ready for reconstitution, for intravenous administration. The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    B) USES
    1) Carfilzomib is a proteosome inhibitor approved for the treatment of multiple myeloma in patients who have received at least 2 prior treatments including bortezomib and an immunomodulator and have demonstrated disease progression within 60 days from the completion of the last therapy (Prod Info KYPROLIS(TM) intravenous injection, 2012).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Carfilzomib is a proteosome inhibitor approved for the treatment of multiple myeloma in patients who have disease progression despite treatment with bortezomib and an immunomodulator.
    B) PHARMACOLOGY: Carfilzomib, a tetrapeptide epoxy ketone proteasome inhibitor, has antiproliferative and proapoptotic activities in solid and hematologic tumor cells by irreversibly binding to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse reactions (30% or more) are fatigue, nausea, diarrhea, anemia, thrombocytopenia, dyspnea, and pyrexia.
    2) LESS FREQUENT: Other adverse effects that have occurred less frequently include peripheral edema, hypertension, chest pain, congestive heart failure, hyperglycemia, electrolyte abnormalities (hypokalemia, hypomagnesemia, hypophosphatemia, hyponatremia), vomiting, constipation, anorexia, acute renal failure, lymphopenia, neutropenia, hepatic failure, back pain, arthralgia, muscle spasms, asthenia, headache, insomnia, peripheral neuropathy, dizziness, hypoesthesia, cough, upper respiratory infection, pulmonary hypertension, infusion reaction, and tumor lysis syndrome.
    E) WITH POISONING/EXPOSURE
    1) Toxicity following overdose has not been reported. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses and may include anemia, neutropenia, and thrombocytopenia.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever has been reported with therapeutic use.
    0.2.20) REPRODUCTIVE
    A) Although there are no adequate and well-controlled studies of carfilzomib use in pregnant women, embryo-fetal toxicity, including an increase in preimplantation loss, an increase in early resorptions and postimplantation loss, and a decrease in fetal weight, was reported in animals at doses lower than the recommended dose in humans.

Laboratory Monitoring

    A) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Following a therapeutic dose, platelet nadirs occur approximately day 8 of each 28-day cycle, with recovery to baseline by the start of the next 28-day cycle.
    B) Obtain baseline electrolytes and assess renal function and hepatic enzymes in patients with evidence of tumor lysis syndrome or after significant overdose. Monitor fluid balance.
    C) Monitor respiratory and cardiac function, ECG and cardiac rhythm in symptomatic patients. Cardiac complications, including cardiac arrest, congestive heart failure, and pulmonary edema, have been reported with therapeutic use.
    D) Monitor vital signs including temperature.
    E) Serum carfilzomib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.

Treatment Overview

    0.4.4) EYE EXPOSURE
    A) Irrigate eyes with 0.9% saline or water. Perform an eye exam, including slit lamp, if irritation persists.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Wash exposed skin well with soap and water and remove contaminated clothing.
    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Administer colony stimulating factors (filgrastim or sargramostim) in patients who develop severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or anemia. For severe hypertension with end organ effects, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives.
    C) INTRATHECAL INJECTION
    1) No clinical reports available, information derived from experience with other antineoplastics. After an overdose, keep the patient upright and immediately drain at least 20 mL of CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free saline). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 24 hours). Add fresh frozen plasma (25 mL FFP to 1 L NS or LR) or 5% albumin to the perfusate to enhance removal as carfilzomib is highly protein bound. Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.
    D) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; administered via the parenteral route. For dermal exposures, cleanse skin with soap and water, and for eye exposures, flush with water.
    E) AIRWAY MANAGEMENT
    1) Intubate if patient is unable to protect their airway.
    F) ANTIDOTE
    1) None
    G) MYELOSUPPRESSION
    1) Administer colony stimulating factors to patients who develop severe neutropenia following a significant overdose. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours OR 250 mcg/m(2)/day SubQ once daily. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or anemia. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    H) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
    I) FEBRILE NEUTROPENIA
    1) If fever (38.3 C) develops during neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
    J) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to be effective due to high protein binding (97%).
    K) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no role for home management.
    2) ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    4) TRANSFER CRITERIA: Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    L) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of carfilzomib. Some toxic effects of overdose may be delayed (ie, particularly myelosuppression), so reliable follow-up is imperative. Patients taking carfilzomib may have severe co-morbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression, cardiotoxicity).
    M) PHARMACOKINETICS
    1) Plasma protein binding is 97% and volume of distribution is 28 L. Carfilzomib is rapidly and extensively metabolized by hepatocytes into 2 inactive metabolites. Half-life was 1 hour or less following IV doses of 15 mg/m(2) or greater on day 1 of cycle 1.
    N) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULTS: The recommended dose is 20 mg/m(2)/day, based on actual BSA up to a maximum 2.2 m(2), as an IV infusion over 2 to 10 minutes on 2 consecutive days, each week for 3 weeks (days 1, 2, 8, 9, 15, and 16), followed by a 12 days of rest (days 17 to 28), in the first treatment cycle. If cycle 1 is tolerated, the carfilzomib dose should be escalated to 27 mg/m(2)/day beginning in cycle 2 and continued at 27 mg/m(2)/day in subsequent cycles. CHILDREN: Safety and efficacy have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Carfilzomib is a proteosome inhibitor approved for the treatment of multiple myeloma in patients who have disease progression despite treatment with bortezomib and an immunomodulator.
    B) PHARMACOLOGY: Carfilzomib, a tetrapeptide epoxy ketone proteasome inhibitor, has antiproliferative and proapoptotic activities in solid and hematologic tumor cells by irreversibly binding to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse reactions (30% or more) are fatigue, nausea, diarrhea, anemia, thrombocytopenia, dyspnea, and pyrexia.
    2) LESS FREQUENT: Other adverse effects that have occurred less frequently include peripheral edema, hypertension, chest pain, congestive heart failure, hyperglycemia, electrolyte abnormalities (hypokalemia, hypomagnesemia, hypophosphatemia, hyponatremia), vomiting, constipation, anorexia, acute renal failure, lymphopenia, neutropenia, hepatic failure, back pain, arthralgia, muscle spasms, asthenia, headache, insomnia, peripheral neuropathy, dizziness, hypoesthesia, cough, upper respiratory infection, pulmonary hypertension, infusion reaction, and tumor lysis syndrome.
    E) WITH POISONING/EXPOSURE
    1) Toxicity following overdose has not been reported. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses and may include anemia, neutropenia, and thrombocytopenia.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever has been reported with therapeutic use.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Pyrexia (all grades) occurred in 30.4% (160/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 or 4 pyrexia was reported in 1.3% and 0.4% of patients, respectively (Prod Info KYPROLIS(TM) intravenous injection, 2012).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) Peripheral edema (all grades) occurred in 24% (126/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 peripheral edema was reported in 0.6% of patients and none of the patients had Grade 4 peripheral edema (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    B) HYPERTENSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) Hypertension (all grades) occurred in 14.3% (75/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 or 4 hypertension was reported in 2.9% and 0.4% of patients, respectively (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    C) CHEST WALL PAIN
    1) WITH THERAPEUTIC USE
    a) Chest wall pain (all grades) occurred in 11.4% (60/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 chest wall pain was reported in 0.6% of patients and none of the patients had Grade 4 chest wall pain (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    D) CONGESTIVE HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) Congestive heart failure occurred in 3% of patients who received a median cumulative dose of carfilzomib 993.4 mg (n=526) for relapsed and/or refractory multiple myeloma during clinical trials. New onset or worsening of preexisting congestive heart failure with decreased left ventricular function or myocardial ischemia were also noted. Cardiac failure events (eg, congestive heart failure, pulmonary edema, decreased ejection fraction) were reported in 7% of patients (Prod Info KYPROLIS(TM) intravenous injection, 2012).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea (all grades) occurred in 34.6% (182/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 or 4 dyspnea was reported in 4.8% and 0.2% of patients, respectively. One death was reported (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    B) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) Upper respiratory infection (all grades) occurred in 28.3% (149/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 upper respiratory infection (URI) was reported in 3.2% of patients and none of the patients had Grade 4 URI (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    C) COUGH
    1) WITH THERAPEUTIC USE
    a) Cough (all grades) occurred in 26% (137/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 cough was reported in 0.2% of patients and none of the patients had Grade 4 cough (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    D) PNEUMONIA
    1) WITH THERAPEUTIC USE
    a) Pneumonia (all grades) occurred in 12.7% (67/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 or 4 pneumonia was reported in 9.9% and 0.6% of patients, respectively, and one patient died from pneumonia (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    E) PULMONARY HYPERTENSION
    1) WITH THERAPEUTIC USE
    a) Pulmonary arterial hypertension (all grades) occurred in 2% of patients who received a median cumulative dose of carfilzomib 993.4 mg (n=526) for relapsed and/or refractory multiple myeloma during clinical trials. Grade 3 or greater pulmonary hypertension was reported in less than 1% of patients (Prod Info KYPROLIS(TM) intravenous injection, 2012).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache (all grades) occurred in 27.6% (145/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 headache was reported in 1.3% of patients and none of the patients had Grade 4 headache (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    B) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia (all grades) occurred in 17.9% (94/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. None of the patients had Grade 3 or 4 insomnia (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    C) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness (all grades) occurred in 12.5% (66/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 or 4 dizziness was reported in 1% and 0.2% of patients, respectively (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    D) HYPESTHESIA
    1) WITH THERAPEUTIC USE
    a) Hypoesthesia (all grades) occurred in 12.2% (64/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 hypoesthesia was reported in 0.6% of patients and none of the patients had Grade 4 hypoesthesia (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    E) DISORDER OF THE PERIPHERAL NERVOUS SYSTEM
    1) WITH THERAPEUTIC USE
    a) Peripheral neuropathy, including peripheral sensory and motor neuropathy, was reported in 14% of patients who received a median cumulative dose of carfilzomib 993.4 mg (n=526) for relapsed and/or refractory multiple myeloma during clinical trials. Grade 3 or serious peripheral neuropathy occurred in 1% and less than 1% of patients, respectively (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    F) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) Asthenia (all grades) occurred in 13.9% (73/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 or 4 asthenia was reported in 2.3% and 0.2% of patients, respectively (Prod Info KYPROLIS(TM) intravenous injection, 2012).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea (all grades) occurred in 44.9% (236/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 nausea was reported in 1.3% of patients and none of the patients had Grade 4 nausea (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    b) Vomiting (all grades) occurred in 22.2% (117/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 vomiting was reported in 1% of patients and none of the patients had Grade 4 vomiting (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea (all grades) occurred in 32.7% (172/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 or 4 diarrhea was reported in 0.8% and 0.2% of patients, respectively (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    C) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation (all grades) occurred in 20.9% (110/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 constipation was reported in 0.2% of patients and none of the patients had Grade 4 constipation (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    D) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia (all grades) occurred in 12% (63/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 anorexia was reported in 0.2% of patients and none of the patients had Grade 4 anorexia (Prod Info KYPROLIS(TM) intravenous injection, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) Hepatic failure, including fatalities, was reported in less than 1% of patients who received a median cumulative dose of carfilzomib 993.4 mg (n=526) for relapsed and/or refractory multiple myeloma during clinical trials. Elevated serum transaminases and bilirubin were also noted (Prod Info KYPROLIS(TM) intravenous injection, 2012).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) Acute renal failure was reported in 4% of patients who received a median cumulative dose of carfilzomib 993.4 mg (n=526) for relapsed and/or refractory multiple myeloma during clinical trials, and one patient died from sepsis and worsening of renal function. Elevations in serum creatinine were also noted (Prod Info KYPROLIS(TM) intravenous injection, 2012).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia (all grades) occurred in 46.8% (246/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 or 4 anemia was reported in 21.1% and 1.3% of patients, respectively (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia (all grades) occurred in 36.3% (191/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 and 4 thrombocytopenia occurred in 13.1% and 10.3% of patients, respectively (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    C) LYMPHOCYTOPENIA
    1) WITH THERAPEUTIC USE
    a) Lymphopenia (all grades) occurred in 24% (126/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 or 4 lymphopenia was reported in 16% and 2.1% of patients, respectively (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    D) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) Neutropenia (all grades) occurred in 20.7% (109/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 and 4 neutropenia occurred in 9.5% and 0.8% of patients, respectively (Prod Info KYPROLIS(TM) intravenous injection, 2012).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) Back pain (all grades) occurred in 20.2% (106/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 back pain was reported in 2.9% of patients and none of the patients had Grade 4 back pain (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgia (all grades) occurred in 15.8% (83/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 arthralgia was reported in 1.3% of patients and none of the patients had Grade 4 arthralgia (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    C) SKELETAL MUSCLE SPASM
    1) WITH THERAPEUTIC USE
    a) Muscle spasms (all grades) occurred in 14.4% (76/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 muscle spasms were reported in 0.4% of patients and none of the patients had Grade 4 muscle spasms (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    D) PAIN IN LIMB
    1) WITH THERAPEUTIC USE
    a) Pain in an extremity (all grades) occurred in 13.3% (70/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 pain in an extremity was reported in 1.3% of patients and none of the patients had Grade 4 pain in an extremity (Prod Info KYPROLIS(TM) intravenous injection, 2012).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hyperglycemia (all grades) occurred in 11.8% (62/526) of patients with relapsed and/or refractory multiple myeloma who received a median cumulative dose of carfilzomib 993.4 mg during clinical trials. Grade 3 or 4 hyperglycemia was reported in 3% and 0.6% of patients, respectively (Prod Info KYPROLIS(TM) intravenous injection, 2012).

Reproductive

    3.20.1) SUMMARY
    A) Although there are no adequate and well-controlled studies of carfilzomib use in pregnant women, embryo-fetal toxicity, including an increase in preimplantation loss, an increase in early resorptions and postimplantation loss, and a decrease in fetal weight, was reported in animals at doses lower than the recommended dose in humans.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) During animal studies, there were no reports of teratogenicity with administration of IV carfilzomib during organogenesis at doses up to 2 mg/kg/day (Prod Info KYPROLIS(R) intravenous injection solution, 2016).
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) Consider the benefits versus the potential risks to the fetus before prescribing to pregnant females. Pregnancy should be avoided while taking carfilzomib. If pregnancy occurs, apprise patients of the potential hazard to the fetus (Prod Info KYPROLIS(R) intravenous injection solution, 2016).
    B) CONTRACEPTION
    1) Females of reproductive potential must use adequate contraception during treatment and for at least 30 days after discontinuation. Males of reproductive potential should use adequate contraception during treatment and for 90 days after completion (Prod Info KYPROLIS(R) intravenous injection solution, 2016).
    C) ANIMAL STUDIES
    1) During animal studies, an increase in preimplantation loss was reported with doses approximately 20% of the recommended human dose. Similarly, an increase in early resorption, postimplantation loss, and a decrease in fetal weight was reported at doses approximately 40% of the human recommended dose (Prod Info KYPROLIS(R) intravenous injection solution, 2016).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known whether carfilzomib is excreted into human breast milk; therefore, there is a potential for adverse reactions (Prod Info KYPROLIS(R) intravenous injection solution, 2016).
    B) BREAST MILK
    1) Use in lactating women only if potential benefit outweighs potential risk (Prod Info KYPROLIS(R) intravenous injection solution, 2016).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Fertility studies have not been conducted. There were no apparent effects on reproductive tissues during 28-day repeat-dose animal toxicity studies or in 6- and 9-month chronic toxicity studies (Prod Info KYPROLIS(R) intravenous injection solution, 2016).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, carcinogenicity studies have not been conducted (Prod Info KYPROLIS(TM) intravenous injection, 2012).

Genotoxicity

    A) Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral blood lymphocytes; however, it was not clastogenic in the in vivo mouse bone marrow micronucleus assay, nor was it mutagenic in the in vitro bacterial reverse mutation (Ames) test (Prod Info KYPROLIS(TM) intravenous injection, 2012).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Following a therapeutic dose, platelet nadirs occur approximately day 8 of each 28-day cycle, with recovery to baseline by the start of the next 28-day cycle.
    B) Obtain baseline electrolytes and assess renal function and hepatic enzymes in patients with evidence of tumor lysis syndrome or after significant overdose. Monitor fluid balance.
    C) Monitor respiratory and cardiac function, ECG and cardiac rhythm in symptomatic patients. Cardiac complications, including cardiac arrest, congestive heart failure, and pulmonary edema, have been reported with therapeutic use.
    D) Monitor vital signs including temperature.
    E) Serum carfilzomib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    4.1.2) SERUM/BLOOD
    A) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery.
    1) Following a therapeutic dose, platelet nadirs occur approximately day 8 of each 28-day cycle, with recovery to baseline by the start of the next 28-day cycle (Prod Info KYPROLIS(TM) intravenous injection, 2012).
    B) Obtain baseline electrolytes and assess renal function and hepatic enzymes in patients with evidence of tumor lysis syndrome or after significant overdose. Monitor fluid balance.
    C) Serum carfilzomib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs including temperature.
    b) Monitor respiratory and cardiac function, ECG and cardiac rhythm in symptomatic patients. Cardiac complications, including cardiac arrest, congestive heart failure, and pulmonary edema, have been reported with therapeutic use (Prod Info KYPROLIS(TM) intravenous injection, 2012).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no role for home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.

Monitoring

    A) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Following a therapeutic dose, platelet nadirs occur approximately day 8 of each 28-day cycle, with recovery to baseline by the start of the next 28-day cycle.
    B) Obtain baseline electrolytes and assess renal function and hepatic enzymes in patients with evidence of tumor lysis syndrome or after significant overdose. Monitor fluid balance.
    C) Monitor respiratory and cardiac function, ECG and cardiac rhythm in symptomatic patients. Cardiac complications, including cardiac arrest, congestive heart failure, and pulmonary edema, have been reported with therapeutic use.
    D) Monitor vital signs including temperature.
    E) Serum carfilzomib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is unlikely to be effective due to high protein binding (97%) (Prod Info KYPROLIS(TM) intravenous injection, 2012).

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULTS: The recommended dose is 20 mg/m(2)/day, based on actual BSA up to a maximum 2.2 m(2), as an IV infusion over 2 to 10 minutes on 2 consecutive days, each week for 3 weeks (days 1, 2, 8, 9, 15, and 16), followed by a 12 days of rest (days 17 to 28), in the first treatment cycle. If cycle 1 is tolerated, the carfilzomib dose should be escalated to 27 mg/m(2)/day beginning in cycle 2 and continued at 27 mg/m(2)/day in subsequent cycles. CHILDREN: Safety and efficacy have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) PREHYDRATION: 30 mL/kg orally at least 48 hours prior to dose 1; 250 to 500 mL of NS or other appropriate IV fluid prior to all cycle 1 doses; and an additional 250 to 500 mL after carfilzomib administration if needed. Continue IV hydration in subsequent cycles as indicated (Prod Info KYPROLIS(R) intravenous injection solution, 2016).
    B) PREMEDICATION: Administer dexamethasone dose 30 minutes to 4 hours as a premedication prior to all cycle 1 carfilzomib doses and reinstate thereafter should infusion reaction occur during subsequent cycles (Prod Info KYPROLIS(R) intravenous injection solution, 2016).
    C) COMBINATION WITH LENALIDOMIDE AND DEXAMETHASONE
    1) USUAL DOSAGE: 20 mg/m(2)/day IV (based on actual BSA up to a maximum 2.2 m(2)) over 10 minutes on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, and 16), given in combination with lenalidomide. If day 1 and 2 carfilzomib doses are tolerated in cycle 1, escalate dose to 27 mg/m(2)/day on day 8 of cycle 1; in cycle 13 and subsequently, omit day 8 and 9 carfilzomib doses. Continue carfilzomib for up to 18 cycles and lenalidomide with dexamethasone thereafter until disease progression or unacceptable toxicity (Prod Info KYPROLIS(R) intravenous injection solution, 2016).
    D) COMBINATION WITH DEXAMETHASONE
    1) USUAL DOSAGE: 20 mg/m(2)/day IV (based on actual BSA up to a maximum 2.2 m(2)) over 30 minutes on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, 16). If day 1 and 2 carfilzomib doses are tolerated in cycle 1, escalate dose to 56 mg/m(2)/day on day 8. Continue carfilzomib until disease progression or unacceptable toxicity (Prod Info KYPROLIS(R) intravenous injection solution, 2016).
    E) MONOTHERAPY
    1) 20/27 mg/m2 REGIMEN BY 10-MINUTE INFUSION: The recommended dose is 20 mg/m(2)/day, based on actual BSA up to a maximum 2.2 m(2), as an IV over 10 minutes on 2 consecutive days, each week for 3 weeks (days 1, 2, 8, 9, 15, and 16), followed by 12 days of rest (days 17 to 28), in the first treatment cycle. If days 1 and 2 carfilzomib doses are tolerated in cycle 1, escalate the dose to 27 mg/m(2) on day 8 of cycle 1; in cycle 13 and subsequent cycles thereafter, omit day 8 and 9 carfilzomib doses. Carfilzomib treatment may be continued until disease progression or unacceptable toxicity occurs (Prod Info KYPROLIS(R) intravenous injection solution, 2016).
    2) 20/56 mg/m2 REGIMEN BY 30-MINUTE INFUSION: The recommended dose is 20 mg/m(2)/day, based on actual BSA up to a maximum 2.2 m(2), as an IV infusion over 30 minutes on 2 consecutive days, each week for 3 weeks (days 1, 2, 8, 9, 15, and 16), followed by 12 days of rest (days 17 to 28), in the first treatment cycle. If days 1 and 2 carfilzomib doses are tolerated in cycle 1, escalate the dose to 56 mg/m(2) on day 8 of cycle 1; in cycle 13 and subsequent cycles thereafter, omit day 8 and 9 carfilzomib doses. Carfilzomib treatment may be continued until disease progression or unacceptable toxicity occurs (Prod Info KYPROLIS(R) intravenous injection solution, 2016).
    7.2.2) PEDIATRIC
    A) Safety and efficacy in pediatric patients have not been established (Prod Info KYPROLIS(R) intravenous injection solution, 2016).

Maximum Tolerated Exposure

    A) A specific toxic dose has not been established.

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Carfilzomib, a tetrapeptide epoxy ketone proteasome inhibitor, has antiproliferative and proapoptotic activities in solid and hematologic tumor cells by irreversibly binding to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome (Prod Info KYPROLIS(TM) intravenous injection, 2012).

Physicochemical

Physical Characteristics

    A) Carfilzomib is a crystalline substance that is practically insoluble in water and very slightly soluble in acidic conditions (Prod Info KYPROLIS(TM) intravenous injection, 2012).

Molecular Weight

    A) 719.9 (Prod Info KYPROLIS(TM) intravenous injection, 2012)

References

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