carfilzomib

General

Pronunciation:
car- fil-zoe- mib


Trade Name(s)

  • Kyprolis

Ther. Class.
antineoplastics

Pharm. Class.
proteasome inhibitors

Indications

  • Treatment of multiple myeloma in patients whose disease has relapsed or is refractory despite receiving ≥1 previous drug therapies (as monotherapy).
  • Treatment of multiple myeloma in patients whose disease has relapsed or is refractory despite receiving 1–3 previous drug therapies (in combination with dexamethasone or lenalidomide + dexamethasone).

Action

Acts as a proteasome inhibitor by binding to sites on the 20s proteasome. Has antiproliferative and proapoptotic activity.

Therapeutic Effect(s):

Delayed progression of multiple myeloma.

Pharmacokinetics

Absorption: IV administration results in complete bioavailability.

Distribution: Unknown.

Metabolism and Excretion: Rapidly and extensively metabolized by extrahepatic enzymes. Metabolites have no antineoplastic activity.

Half-life: Unknown.

TIME/ACTION PROFILE (proteasome inhibition)

ROUTEONSETPEAKDURATION
IVwithin 1 hrunknown>48 hr

Contraindication/Precautions

Contraindicated in:

  • Severe hepatic impairment;
  • Concurrent use with melphalan and prednisone in newly diagnosed patients ineligible for transplant (↑ risk of serious/fatal adverse reactions);
  • OB:  Pregnancy (may cause fetal harm)
  • Lactation.

Use Cautiously in:

  • History of cardiovascular disease (may ↑ risk of adverse cardiovascular reactions, safe and effective use in patients with New York Heart Association Class III and IV HF, recent MI, or conduction abnormalities has not been established)
  • Large tumor load (↑ risk of tumor lysis syndrome)
  • Dehydration, diarrhea or electrolyte abnormalities (correct prior to treatment)
  • Mild or moderate hepatic impairment (↓ dose)
  • Renal impairment (↑ risk of acute renal failure)
  • Rep:  Women of reproductive potential and men with female sexual partners of reproductive potential;
  • Pedi:  Safety and effectiveness not established in children
  • Geri:  ↑ risk of cardiovascular events in older adults.

Adverse Reactions/Side Effects

CNS: POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES), dizziness, fatigue, headache, insomnia, weakness

CV: HF, MYOCARDIAL ISCHEMIA/INFARCTION, SUDDEN CARDIAC DEATH, VENOUS THROMBOEMBOLISM, hypertension, peripheral edema

Endo: hypoglycemia

F and E: hypercalcemia, hypokalemia, hyponatremia, hypomagnesemia, hypophosphatemia

GI: HEPATIC FAILURE, anorexia, constipation, diarrhea, hepatic toxicity, nausea

GU: ACUTE RENAL FAILURE

Hemat: THROMBOCYTOPENIA, THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP)/HEMOLYTIC UREMIC SYNDROME (HUS), anemia, leukopenia, lymphopenia

MS: back pain, chest wall pain, muscle spasms

Neuro: hypoesthesia, peripheral neuropathy

Resp: ACUTE RESPIRATORY DISTRESS SYNDROME, INTERSTITIAL LUNG DISEASE, PNEUMONITIS, cough, dyspnea, pulmonary edema, pulmonary hypertension

Misc: INFUSION REACTIONS, TUMOR LYSIS SYNDROME, fever/chills

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

None reported.

Route/Dosage

Combination Therapy with Lenalidomide + Dexamethasone

IV (Adults):  Cycle 1– 20 mg/m2  daily for 2 days (Days 1 and 2); if tolerated, ↑ dose to 27 mg/m2 on Days 8, 9, 15, and 16 of a 28-day treatment cycle.  Cycles 2–12– 27 mg/m2  on Days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle;  Cycles 13–18– 27 mg/m2  on Days 1, 2, 15, and 16 of a 28-day treatment cycle.  Cycles 19 and subsequent cycles– Continue lenalidomide and dexamethasone (without carfilzomib) until unacceptable toxicity or disease progression.

Combination Therapy with Dexamethasone

Twice Weekly Regimen

IV (Adults):  Cycle 1– 20 mg/m2  daily for 2 days (Days 1 and 2); if tolerated, ↑ dose to 56 mg/m2 on Days 8, 9, 15, and 16 of a 28-day treatment cycle.  Cycle 2 and subsequent cycles– 56 mg/m2  on Days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle. Continue both carfilzomib and dexamethasone until unacceptable toxicity or disease progression.

Once Weekly Regimen

IV (Adults):  Cycle 1– 20 mg/m2  on Day 1; if tolerated, ↑ dose to 70 mg/m2 on Days 8 and 15 of a 28-day treatment cycle.  Cycle 2 and subsequent cycles– 70 mg/m2  on Days 1, 8, and 15 of a 28-day treatment cycle. Continue both carfilzomib and dexamethasone until unacceptable toxicity or disease progression.

Monotherapy

20/27 mg/m2  Regimen

IV (Adults):  Cycle 1– 20 mg/m2  daily for 2 days (Days 1 and 2); if tolerated, ↑ dose to 27 mg/m2 on Days 8, 9, 15, and 16 of a 28-day treatment cycle.  Cycles 2–12– 27 mg/m2  on Days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle;  Cycle 13 and subsequent cycles– 27 mg/m2  on Days 1, 2, 15, and 16 of a 28-day treatment cycle. Continue carfilzomib until unacceptable toxicity or disease progression.

20/56 mg/m2  Regimen

IV (Adults):  Cycle 1– 20 mg/m2  daily for 2 days (Days 1 and 2); if tolerated, ↑ dose to 56 mg/m2 on Days 8, 9, 15, and 16 of a 28-day treatment cycle.  Cycles 2–12– 56 mg/m2  on Days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle;  Cycle 13 and subsequent cycles– 56 mg/m2  on Days 1, 2, 15, and 16 of a 28-day treatment cycle. Continue carfilzomib until unacceptable toxicity or disease progression.

Renal Impairment 
IV (Adults):  Hemodialysis– Administer dose after hemodialysis.

Hepatic Impairment 
IV (Adults):  Mild or moderate hepatic impairment– ↓ dose by 25%.

Availability (generic available)

Lyophilized powder for injection: 10 mg/vial, 30 mg/vial, 60 mg/vial

Assessment

  • Maintain hydration status throughout therapy. Monitor for dehydration and fluid overload, especially in patients with or at risk for HF.
  • Monitor for cardiac complications (BP, new or worsening HF, decreased left ventricular function, myocardial ischemia). Hold dose for Grade 3 or 4 cardiac events until recovery. Consider restarting at a reduced dose. If tolerated, may escalate to previous dose.
  • Assess for pulmonary hypertension with cardiac imaging. Hold dose until resolved or returned to baseline. Consider restarting based on risk/benefit ratio. May use a reduced dose and escalate as tolerated.
  • Monitor for dyspnea frequently during therapy. Interrupt therapy until symptoms resolved; consider restarting with one dose level reduction and increase as tolerated. If drug-induced pulmonary toxicity occurs, discontinue carfilzomib.
  • Assess for sensory and motor peripheral neuropathy periodically during therapy. If Grade 3 or 4 occurs, hold dose until resolved or returned to baseline. Restart with prior or reduced dose, may escalate if tolerated.
  • Monitor for signs and symptoms of tumor lysis syndrome (hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia) during therapy. Consider uric acid lowering drugs in patients at risk. Manage promptly; may require discontinuation.
  • Monitor for signs/symptoms of infusion reactions (fever, chills, arthralgia, myalgia, facial flushing, facial edema, laryngeal edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness). May occur immediately or up to 24 hrs after administration. Premedicate with dexamethasone prophylactically.
  • Assess for signs and symptoms of thrombotic thrombocytopenic purpura /hemolytic uremic syndrome (weakness, confusion or coma, abdominal pain, nausea, vomiting, diarrhea, arrhythmias). Discontinue therapy if symptoms occur.
  • Monitor for signs and symptoms of PRES (seizure, headache, lethargy, confusion, blindness, altered consciousness, other visual and neurological disturbances, hypertension). Determined with MRI. Discontinue if symptoms occur.

Lab Test Considerations:

Obtain a negative pregnancy test before starting therapy.

Monitor CBC and platelet count frequently during therapy. Nadir of thrombocytopenia occurs around Day 8 of 28–day cycle and recovery to baseline by start of next 28–day cycle.  If ANC <0.5 x 109 /L,  hold dose. If recovered to ≥0.5 x 109 /L, continue at same dose. For subsequent drops to <0.5 x 109 /L, follow recommendations above and consider 1 dose level reduction when restarting carfilzomib.  If ANC <0.5 x 109 /L and an oral temperature >38.5°C. or two consecutive readings of >38.0° for more than 2 hrs,  hold dose. If ANC returns to baseline and fever resolves, resume therapy at same dose.  If platelets <10 x 109 /L or evidence of bleeding with thrombocytopenia,  hold dose. If recovered to ≥10 x 109 /L and/or bleeding is controlled, continue at same dose. For subsequent drops to <10 x 109 /L, follow recommendations above and consider 1 dose level reduction when restarting carfilzomib.
  • Monitor liver enzymes frequently during therapy. May cause ↑ serum transaminases and bilirubin. If Grade 3 or 4 ↑ of transaminases, bilirubin, or other liver abnormalities, hold dose until resolved or return to baseline. May be restarted at a reduced dose with frequently liver function monitoring; may escalate dose if tolerated.
  • Monitor renal function frequently during therapy.  If serum creatinine ≥2 times baseline or CCr <15 mL/min, or CCr ↓ ≤50% of baseline, or need for dialysis, hold dose and continue monitoring. If ↓ renal function due to carfilzomib, resume when renal function has recovered to within 25% of baseline; start at 1 dose level reduction. If not due to carfilzomib, dosing may be resumed at discretion of physician. For patients on dialysis receiving carfilzomib, administer dose after dialysis procedure.
  • Monitor serum potassium periodically during therapy. May cause hyperglycemia, hypercalcemia, hypophosphatemia, and hyponatremia.

Potential Diagnoses

Implementation

  • Hydrate patient to reduce risk of renal toxicity and tumor lysis syndrome. At least 48 hrs before Cycle 1, Day 1, administer oral fluids (30 mL per kg) and IV fluids (250 mL to 500 mL of IV fluid prior to each dose in Cycle 1). Give an additional 250 mL to 500 mL of IV fluids following administration, if needed. Continue oral and/or IV hydration, as needed, in subsequent cycles. Monitor for fluid overload and adjust hydration to patient needs.
    •  For monotherapy,  premedicate with dexamethasone 4 mg PO or IV at least 30 minutes but no >4 hrs prior to all doses during Cycle 1 to reduce the incidence and severity of infusion reactions.  For combination with lenalidomide,  premedicate with dexamethasone 40 mg PO or IV at least 30 minutes but no >4 hrs before doses on Days 1, 8, 15, and 22 during each cycle to reduce incidence and severity of infusion reactions. Continue hydration as needed during subsequent cycles.
  • Thromboprophylaxis regimen should be used with combination therapy of carfilzomib with dexamethasone, with or without lenalidomide.
  • Use antiviral prophylaxis to decrease risk of herpes zoster reactivation.

IV Administration

  • Intermittent Infusion:  Using a 21-gauge needle, reconstitute each 10 mg vial by injecting 5 mL, each 30 mg vial by injecting 15 mL, or each 60 mg vial by injecting 29 mL Sterile Water for injection respectively, directed onto inside wall of vial to minimize foaming. Swirl gently or invert slowly for 1 min or until complete dissolution of powder; do not shake. If foaming occurs, allow solution to rest for 2–5 min until foaming subsides. Solution should be clear and colorless; do not administer solutions that are discolored or contain particulate matter. Diluent:  Withdraw calculated dose from vial and dilute in 50 or 100 mL D5W. Vial may exceed required dose; calculate dose carefully to prevent overdosing. Reconstituted solution is stable at room temperature for 4 hrs and 24 hrs if refrigerated. Discard unused portion.
  • Rate:  For carfilzomib in combination with lenalidomide and dexamethasone , infuse over 10 min.  For carflizomib in combination with dexamethasone,  infuse over 30 min.  For monotherapy with 20/27 mg/m2  regimen,  infuse over 10 min.  For monotherapy with 20/27 mg/m2  regimen,  infuse over 30 min. Do not administer as a bolus. Flush line with 0.9% NaCl or D5W immediately prior to and following administration.
  • Y-Site Incompatibility: Do not mix with or infuse with other medications.

Patient/Family Teaching

  • Explain purpose of medication to patient.
  • Advise patient to notify health care professional immediately if infusion reactions (fever, chills, rigors, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, chest pain, cough, swelling of feet or legs) occur.
  • May cause fatigue, dizziness, fainting, and drop in BP. Caution patient to avoid driving or other activities requiring alertness until response to medication is known.
  • Advise patient to maintain hydration status during therapy; may cause vomiting and/or diarrhea.
  • Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
  • Rep:  Advise female patients of reproductive potential to use effective contraception during therapy and for 6 mo following last dose of therapy and to avoid breastfeeding during and for 2 wk after last dose. Avoid hormonal contraceptives during combination therapy to prevent increased risk of thrombosis. Advise male patients with female partners of reproductive potential to use effective contraception during and for 3 mo after last dose. May impair fertility in male and female patients.

Evaluation/Desired Outcomes

Slowed progression of multiple myeloma.

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