Kyprolis

Generic Name: carfilzomib
Date of Approval: July 20, 2012
Company: Onyx Pharmaceuticals, Inc.
Treatment for: Multiple Myeloma

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FDA Approves Kyprolis

The U.S. Food and Drug Administration (FDA) has granted accelerated approval of Kyprolis (carfilzomib) for Injection, a proteasome inhibitor, 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. The indication for Kyprolis is based on response rate. Currently, no data are available for Kyprolis that demonstrate an improvement in progression-free survival or overall survival.

The approval was based on the results of the Phase 2b 003-A1 study, a single-arm, multicenter clinical trial that enrolled 266 patients with multiple myeloma who had received a median of five prior anti-myeloma regimens. The primary efficacy endpoint was overall response (ORR) and determined by an Independent Review Committee using the International Myeloma Working Group (IMWG) criteria. ORR was 22.9% and median response duration was 7.8 months.

Safety data were evaluated in 526 patients with relapsed and/or refractory multiple myeloma who received single-agent carfilzomib. There were 37 deaths on study, or 7% of patients. The most common causes of death, other than disease progression, were cardiac (5 patients), end-organ failure (4 patients), and infection (4 patients).

Important warnings and precautions include:

cardiac arrest
congestive heart failure
myocardial ischemia
pulmonary hypertension
pulmonary complications
infusion reactions
infusion reactions
tumor lysis syndrome
thrombocytopenia
hepatic toxicity
embryo-fetal toxicity.

The most common serious adverse reactions were pneumonia, acute renal failure, pyrexia, and congestive heart failure.

The most common adverse reactions (incidence of 30% or greater) observed in clinical trials of patients with multiple myeloma were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia.

Serious adverse reactions were reported in 45% of patients.

Important Safety Information Regarding Kyprolis (carfilzomib) for Injection

Death due to cardiac arrest has occurred within a day of Kyprolis administration. 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 arterial hypertension (PAH) was reported in 2% of patients treated with Kyprolis and was Grade 3 or greater in less than 1% of patients. 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.

Infusion reactions, 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 can occur immediately following or up to 24 hours after administration of Kyprolis. Administration of dexamethasone prior to Kyprolis reduces the incidence and severity of reactions. 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.

Thrombocytopenia following Kyprolis administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with Kyprolis in < 1% of patients.

Cases of hepatic failure, including fatal cases, have been reported (< 1%). Kyprolis can cause elevations of serum transaminases and bilirubin.

There are no adequate and well-controlled studies in pregnant women using Kyprolis. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with Kyprolis.

About Multiple Myeloma

Multiple myeloma is the second most common hematologic cancer and results from an abnormality of plasma cells, usually in the bone marrow. In the United States, more than 50,000 people are living with multiple myeloma and approximately 20,000 new cases are diagnosed annually.[i] Worldwide, more than 220,000 people are living with multiple myeloma and approximately 100,000 new cases are diagnosed annually.[ii]

About the Kyprolis (carfilzomib) for Injection Development Program

Kyprolis is approved by the U.S. Food and Drug Administration (FDA) 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. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Kyprolis is being studied in several clinical trials either as a single-agent or in combination with other therapies, including:

A global Phase 3 clinical trial, known as the ASPIRE trial, has completed enrollment and is evaluating the combination of lenalidomide and low-dose dexamethasone with or without Kyprolis in patients with relapsed multiple myeloma who have received one to three prior therapies. The company has an agreement with the FDA on a Special Protocol Assessment (SPA) and has received Scientific Advice from the European Medicines Agency (EMA) on the design and planned analysis of the trial.

A Phase 3 clinical trial, known as the FOCUS trial, is evaluating single-agent Kyprolis in patients with relapsed and refractory myeloma who have received three or more prior therapies. The trial is designed to facilitate regulatory approvals around the world.

A global head-to-head Phase 3 clinical trial, known as the ENDEAVOR trial, is evaluating the combination of Kyprolis and low-dose dexamethasone versus the combination of bortezomib and low-dose dexamethasone.

A Phase 1/2 study being conducted by Onyx's partner Ono Pharmaceutical Co., Ltd. is evaluating Kyprolis in Japanese patients with relapsed/refractory multiple myeloma.

Highlights of Kyprolis Prescribing Information

These highlights do not include all the information needed to use Kyprolis safely and effectively. See full prescribing information for Kyprolis.

Indications and Usage

Kyprolis is a proteasome inhibitor 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. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Dosage and Administration

Administer 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).
Recommended Cycle 1 dose is 20 mg/m2/day and if tolerated increase Cycle 2 dose and subsequent cycles doses to 27 mg/m2/day.
Hydrate patients prior to and following administration.
Pre-medicate with dexamethasone prior to all Cycle 1 doses, during the first cycle of dose escalation, and if infusion reaction symptoms develop or reappear.
Modify dosing based on toxicity.

Dosage Forms and Strengths

Single-use vial: 60 mg sterile lyophilized powder

Contraindications

None

Warnings and Precautions

Cardiac Adverse Reactions including heart failure and ischemia: Monitor for cardiac complications. Treat promptly and withhold Kyprolis.
Pulmonary Hypertension: Withhold dosing if suspected.
Pulmonary Complications: Monitor for and manage dyspnea immediately; interrupt Kyprolis until symptoms have resolved or returned to baseline.
Infusion Reactions: Pre-medicate with dexamethasone to prevent.
Advise patients to seek immediate medical attention if symptoms develop.
Tumor Lysis Syndrome (TLS): Hydrate patients to prevent. Monitor for TLS and treat promptly.
Thrombocytopenia: Monitor platelet counts; reduce or interrupt dosing as clinically indicated.
Hepatic Toxicity and Hepatic Failure: Monitor liver enzymes and withhold dosing if suspected.
Embryo-fetal Toxicity: Kyprolis can cause fetal harm. Females of reproductive potential should avoid becoming pregnant while being treated.

Use In Specific Populations

Patients on dialysis: Administer Kyprolis after the dialysis procedure.

Kyprolis side effects

Most commonly reported adverse reactions (incidence ≥ 30%) are fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia.

To report SUSPECTED ADVERSE REACTIONS, contact Onyx Pharmaceuticals, Inc. at 1-877-669-9121 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See also: Kyprolis side effects (in more detail)

Patient Counseling Information

Discuss the following with patients prior to treatment with Kyprolis:

Instruct patients to contact their physician if they develop any of the following symptoms: fever, chills, rigors, chest pain, cough, or swelling of the feet or legs.
Advise patients that Kyprolis may cause fatigue, dizziness, fainting, and/or drop in blood pressure. Advise patients not to drive or operate machinery if they experience any of these symptoms.
Advise patients that they may experience shortness of breath (dyspnea) during treatment with Kyprolis. This most commonly occurs within a day of dosing. Advise patients to contact their physicians if they experience shortness of breath.
Counsel patients to avoid dehydration, since patients receiving Kyprolis therapy may experience vomiting and/or diarrhea. Instruct patients to seek medical advice if they experience symptoms of dizziness, lightheadedness, or fainting spells.
Counsel females of reproductive potential to use effective contraceptive measures to prevent pregnancy during treatment with Kyprolis. Advise the patient that if she becomes pregnant during treatment, to contact her physician immediately.
Advise patients not to take Kyprolis treatment while pregnant or breastfeeding. If a patient wishes to restart breastfeeding after treatment, advise her to discuss the appropriate timing with her physician.
Advise patients to discuss with their physician any medication they are currently taking prior to starting treatment with Kyprolis, or prior to starting any new medication(s) during treatment with Kyprolis.