Kyprolis(carfilzomib)Injection - America[美国药品]

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Kyprolis(carfilzomib)Injection

2013-11-09 01:17:30 来源: 作者: 【大中小】浏览:772次评论:0条

Generic Name: carfilzomib
Dosage Form: injection, powder, lyophilized, for solution
Indications and Usage for Kyprolis
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.
Kyprolis Dosage and Administration

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%.

Table 1: Kyprolis Dosage Regimen for Patients with Multiple Myeloma
* If previous cycle dosage is tolerated.
Kyprolis (20 mg/m2):	Cycle 1
	Week 1		Week 2		Week 3		Week 4
	Day 1	Day 2	Days 3-7	Day 8	Day 9	Days 10-14	Day 15	Day 16	Days 17-21	Days 22-28
	20	20	No Dosing	20	20	No Dosing	20	20	No Dosing	No Dosing
Kyprolis (27 mg/m2):	Cycles 2 and Beyond*
	Week 1		Week 2		Week 3		Week 4
	Day 1	Day 2	Days 3-7	Day 8	Day 9	Days 10-14	Day 15	Day 16	Days 17-21	Days 22-28
	27	27	No Dosing	27	27	No Dosing	27	27	No Dosing	No Dosing

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.

Table 2: Dose Modifications for Toxicity* during Kyprolis Treatment
* National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0
Hematologic Toxicity	Recommended Action
Grade 3a or 4 Neutropenia Grade 4 Thrombocytopenia [see Warnings and Precautions (5.6)]	Withhold dose. If fully recovered before next scheduled dose, continue at same dose level. If recovered to Grade 2 neutropenia or Grade 3 thrombocytopenia, reduce dose by one dose level (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.
Non-Hematologic Toxicity	Recommended Action
Cardiac Toxicity Grade 3 or 4, new onset or worsening of: congestive heart failure; decreased left ventricular function; or myocardial ischemia [see Warnings and Precautions (5.1)]	Withhold until resolved or returned to baseline. After resolution, consider if restarting Kyprolis at a reduced dose is appropriate (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.
Pulmonary Hypertension [see Warnings and Precautions (5.2)]	Withhold until resolved or returned to baseline. Restart at the dose used prior to the event or reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2), at the discretion of the physician. If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.
Pulmonary Complications Grade 3 or 4 [see Warnings and Precautions (5.3)]	Withhold until resolved or returned to baseline. Consider restarting at the next scheduled treatment with one dose level reduction (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.
Hepatic Toxicity Grade 3 or 4 elevation of transaminases, bilirubin or other liver abnormalities [see Warnings and Precautions (5.7)]	Withhold until resolved or returned to baseline. After resolution, consider if restarting Kyprolis is appropriate; may be reinitiated at a reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2) with frequent monitoring of liver function. If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.
Renal Toxicity Serum creatinine equal to or greater than 2 × baseline [see Adverse Reactions (6.1)]	Withhold until renal function has recovered to Grade 1 or to baseline and monitor renal function. If attributable to Kyprolis, restart at the next scheduled treatment at a reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). If not attributable to Kyprolis, restart at the dose used prior to the event. If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.
Peripheral Neuropathy Grade 3 or 4 [see Adverse Reactions (6.1)]	Withhold until resolved or returned to baseline. Restart at the dose used prior to the event or reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2), at the discretion of the physician. If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.
Other Grade 3 or 4 non-hematological toxicities	Withhold until resolved or returned to baseline. Consider restarting at the next scheduled treatment with one dose level reduction (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

Administration Precautions

The quantity of Kyprolis contained in one single-use vial (60 mg carfilzomib) may exceed the required dose. Caution should be used in calculating the quantity delivered to prevent overdosing.

Do not mix Kyprolis with or administer as an infusion with other medicinal products.

The intravenous administration line should be flushed with normal saline or 5% Dextrose Injection, USP immediately before and after Kyprolis administration. Kyprolis should not be administered as a bolus. Kyprolis should be administered over 2 to 10 minutes.

Reconstitution and Preparation for Intravenous Administration

Kyprolis vials contain no antimicrobial preservatives and are intended only for single use. Unopened vials of Kyprolis are stable until the date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete preparation instructions prior to reconstitution.

Reconstitution/Preparation Steps:

Remove vial from refrigerator just prior to use.
Aseptically reconstitute each vial by slowly injecting 29 mL Sterile Water for Injection, USP, directing the solution onto the INSIDE WALL OF THE VIAL to minimize foaming.
Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution of any cake or powder occurs. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow solution to rest in vial for about 2 to 5 minutes, until foaming subsides.
After reconstitution, Kyprolis is ready for intravenous administration. The reconstituted product should be a clear, colorless solution. If any discoloration or particulate matter is observed, do not use the reconstituted product.
When administering in an intravenous bag, withdraw the calculated dose [see Dosage and Administration (2.1)] from the vial and dilute into 50 mL 5% Dextrose Injection, USP intravenous bag.
Immediately discard the vial containing the unused portion.

The stabilities of reconstituted Kyprolis under various temperature and container conditions are shown in Table 3.

Table 3: Stability of Reconstituted Kyprolis
* Total time from reconstitution to administration should not exceed 24 hours. † 5% Dextrose Injection, USP.
Storage Conditions of Reconstituted Kyprolis	Stability*per Container
Storage Conditions of Reconstituted Kyprolis	Vial	Syringe	IV Bag (D5W†)
Refrigerated (2°C to 8°C; 36°F to 46°F)	24 hours	24 hours	24 hours
Room Temperature (15°C to 30°C; 59°F to 86°F)	4 hours	4 hours	4 hours

Dosage Forms and Strengths

Kyprolis single-use vial contains 60 mg of carfilzomib as a sterile, white to off-white lyophilized cake or powder.

Contraindications

None.

Warnings and 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. eva luate 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)

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