carfilzomib

carfilzomib

(car- fil-zoe- mib) ,

Kyprolis

(trade name)

Classification

Therapeutic: antineoplastics
Pharmacologic: proteasome inhibitors
Pregnancy Category: D

Indications

Treatment of multiple myeloma in patients whose disease has progressed despite previous therapy with bortezomib and immunotherapy in the previous 60 days.

Action

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

Therapeutic effects

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

Contraindications/Precautions

Contraindicated in: Obstetric: Pregnancy (may cause fetal harm); Lactation: Breast feeding should be avoided.
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 heart failure has not been established); Large tumor load (↑ risk of tumor lysis syndrome); Dehydration, diarrhea or electrolyte abnormalities (correct prior to treatment); Hepatic impairment (safe and effective use has not been established); End stage renal disease (dose should be administered following dialysis); Pediatric: Safe and effective use in children has not been established.

Adverse Reactions/Side Effects

Central nervous system

  • dizziness (most frequent)
  • fatigue (most frequent)
  • headache (most frequent)
  • insomnia (most frequent)
  • weakness (most frequent)

Respiratory

  • cough (most frequent)
  • dyspnea (most frequent)

Cardiovascular

  • heart failure (life-threatening)
  • hypertension (most frequent)
  • myocardial ischemia (life-threatening)
  • peripheral edema (most frequent)
  • pulmonary hypertension

Gastrointestinal

  • hepatic failure (life-threatening)
  • anorexia (most frequent)
  • constipation (most frequent)
  • diarrhea (most frequent)
  • hepatic toxicity
  • nausea

Genitourinary

  • renal failure

Endocrinologic

  • hypoglycemia (most frequent)

Fluid and Electrolyte

  • hypercalcemia (most frequent)
  • hypokalemia (most frequent)
  • hyponatremia (most frequent)
  • hypomagnesemia (most frequent)
  • hypophosphatemia (most frequent)

Hematologic

  • thrombocytopenia
  • anemia (most frequent)
  • leukopenia (most frequent)
  • lymphopenia

Musculoskeletal

  • back pain (most frequent)
  • chest wall pain (most frequent)
  • muscle spasms (most frequent)

Neurologic

  • hypoesthesia (most frequent)
  • peripheral neuropathy

Miscellaneous

  • tumor lysis syndrome (life-threatening)
  • fever/chills (most frequent)
  • infusion reactions

Interactions

Drug-Drug interaction

None noted.

Route/Dosage

Intravenous (Adults) Cycle 1—20 mg/m2 daily for 2 days weekly for 3 wk (days 1, 2, 8, 9, 15 and 16) followed by 12 day rest (days 17–28). Cycle 2 and subsequent cycles—If cycle 1 is tolerated dose should be increased to 27 mg/m2 and continued until unacceptable toxicity or disease progression. Dosa adjustments are required for hematologic, cardiac, pulmonary, renal, neurologic and hepatic toxicity.

Availability

Lyophilized powder for IV injection (requires reconstitution): 60 mg/vial

Nursing implications

Nursing assessment

  • Maintain hydration status throughout therapy. Monitor for dehydration and fluid overload.
  • Monitor for cardiac complications (new or worsening CHF, decreased left ventricular function, myocardial ischemia). Withhold dose for Grade 3 or 4 cardiac events until recovery. Consider restarting at a reduced dose. If tolerated, dose may be escalated to previous dose.
  • Assess for pulmonary hypertension with cardiac imaging. Withhold 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.
  • Assess for sensory and motor peripheral neuropathy periodically during therapy. If Grade 3 or 4 occurs, withhold dose until resolved or returned to baseline. Restart with prior or reduced dose, may escalate if tolerated.
  • Lab Test Considerations: 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. Withhold dose for Grade 4 thrombocytopenia or Grade 3 neutropenia. If recovered to baseline, continue with same dose. If recovered to Grade 3 thrombocytopenia or Grade 2 neutropenia, reduce dose by one dose level; may escalate if tolerated.
    • Monitor liver enzymes frequently during therapy. May cause ↑ serum transaminases and bilirubin. If Grade 3 or 4 ↑ of transaminases, bilirubin, or other liver abnormalities withhold 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, withhold dose until recovered to Grade 1 or to baseline. If renal function decline in attributed to therapy restart at a reduced dose; if not restart at prior dose. May escalate dose if tolerated.
    • May cause hyperglycemia, hypercalcemia, hypophosphatemia, and hyponatremia.

Potential Nursing Diagnoses

Activity intolerance

Implementation

  • Hydrate patient to reduce risk of renal toxicity and tumor lysis syndrome. Prior to each dose administer 250–500 mL IV of 0.9% NaCl or other appropriate fluid. Administer another 250–500 mL as needed following therapy.
    • Premedicate with dexamethasone 4 mg PO or IV prior to all doses of Cycle 1 and prior to all doses during first cycle of dose escalation. Reinstate if symptoms develop during subsequent cycles.
  • Intravenous Administration
  • Intermittent Infusion: Reconstitute each vial by injecting 29 mL Sterile Water for injection 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 shale. 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 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: Infuse over 2–10 min; do not administer as a bolus. Flush line with 0.9% NaCl or D5W 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 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 occur immediately or up to 24 hrs after administration.
  • 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.
  • 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.
  • Advise female patients to use effective contraception during therapy and to avoid breastfeeding.

Evaluation/Desired Outcomes

  • Slowed progression of multiple myeloma.
References in periodicals archive ?
Results from the final analysis of the Phase 3 ASPIRE trial published today in the Journal of Clinical Oncology are significant, as they further validate carfilzomib, lenalidomide and dexamethasone as a standard of care regimen for patients with relapsed or refractory multiple myeloma," said Keith Stewart, M.
Summary: Washington DC [USA], Dec 30 (ANI): A study has recently found that taking a higher dose of Carfilzomib, which is used for treating cancer, can increase the risk of hypertension, heart failure, and heart attacks in multiple myeloma patients.
Later in the year, Janssen entered into a master clinical trial collaboration and supply agreement with Onyx Pharmaceuticals, a subsidiary of Amgen, to evaluate the efficacy and safety of CD38-directed immunotherapy daratumumab (DARZALEX) in combination with a proteasome inhibitor (PI) carfilzomib (KYPROLIS) and dexamethasone.
Additionally, when I tried to search for a specific conference paper, "Phase I/II Study of the Combination of Panobinostat (PAN) and Carfilzomib (CFZ) in Patients (pts) with Relapsed or Relapsed/Refractory Multiple Myeloma (MM)" that was presented at the 2015 ASCO meeting, the search hit was not the paper from the ASCO meeting but a poster with the same title from another conference by the same author.
Carfilzomib for the Treatment of Multiple Myeloma: Systematic Review of the Literature and Colombian Experience Based on RIPS
Other new antineoplastics are the antiandrogen enzalutamide (Xtandi; prostate cancer but could be used for other cancers), the proteasome inhibitor carfilzomib (Kyprolis; multiple myeloma), and the protein synthesis inhibitor omacetaxine (Synribo; leukemia).
Several new agents have shown promising results in early phase clinical trials and are being explored as single agents or in combination with other agents in clinical trials like pomalidomide, (70) (a new IMiD) and carfilzomib, (71) (a second generation proteasome inhibitor).
2005: Proteolix enters into a Collaboration Agreement with Ligand (formerly CyDex Pharmaceuticals) for a Captisol-enabled IV formulation of carfilzomib to solve stability and solubility issues, and enable a reduced drug load
Carfilzomib, a second-generation proteasome inhibitor studied in patients with relapsed and refractory multiple myeloma, overcame concerns about cardiotoxicity to win a Food and Drug Administration advisory panel's support for accelerated approval.
A new last-ditch treatment for patients with the blood cancer multiple myeloma (MM) might be getting closer to market after clinical trials of the experimental drug carfilzomib found that it shrank tumors significantly in 24 percent of patients.
Onyx (ONXX) paid $276 million up front to acquire the privately held Proteolix to get to its multiple myeloma drug carfilzomib.