全球唯一的口服蛋白酶体抑制剂Ninlaro（ixazomib）获FDA批准用于治疗多发性骨髓瘤
2015年11月23日，美国FDA批准Ninlaro（ixazomib）与两款其它药物合并用于治疗既往至少接受过一种治疗的多发性骨髓瘤患者。多发性骨髓瘤是血液肿瘤的一种，它产生于骨髓中发现的抗感染浆细胞（一种白细胞）中。这些癌细胞增殖并产生一种异常蛋白，其可将其它健康血细胞从骨髓中排挤出去。该疾病可以导致免疫系统变弱，引起其它骨骼及肾脏问题。美国国家癌症研究所预测，今年美国将有2.685万新确诊多发性骨髓瘤病例，将有1.124万人因此而死亡。
“随着我们对多发性骨髓瘤潜在生物学的更多了解，我们深受鼓舞地看到治疗这一疾病新方法的发展，”FDA药物评价与研究中心血液及肿瘤产品办公室主任、医学博士Pazdur称。“今天的批准是今年获批用于多发性骨髓瘤的第三款药物，此次批准为患者提供了一款新型口服治疗药物，当其它治疗药物失败时，它可以延缓疾病的进展。”FDA在今年2月份批准了帕比司他，11月初批准了Darzalex（daratumumab）。
Ninlaro是一类蛋白酶体抑制剂抗癌药物，它通过阻断多发性骨髓瘤细胞的酶，阻碍多发性骨髓瘤细胞增长与生存而发挥作用。Ninlaro是第一款口服蛋白酶体抑制剂，其被批准与其它FDA批准的多发性骨髓治疗药物来那度胺及地塞米松（一种糖皮质激素）合并使用。
Ninlaro的安全性及有效性在一项国际的、随机、双盲临床临床试验中得到证实，该试验的受试者为722名经先前治疗后多发性骨髓瘤复发或对先前治疗不响应的患者。研究受试者在试验中接受Ninlaro+来那度胺+地塞米松或安慰剂+来那度胺+地塞米松进行治疗。那些使用Ninlaro的受试者与使用安慰剂方案的受试者相比，其在疾病未恶化的情况下生存更久，两组的平均无进展生存期分别为20.6个月与14.7个月。
Ninlaro最常见的副作用有腹泻、便秘、低血小板计数(血小板减少症)、周围神经病变(神经损伤导致的麻木和疼痛，通常是手和脚)、恶心、外周性水肿(皮肤下流体导致的肿胀)、呕吐和背部疼痛。
FDA授予了Ninlaro优先审评与孤儿药资格。优先审评资格授予那些如果获得批准将在严重疾病治疗中对安全性或有效性有明显改善的药物申请。孤儿药资格可以提供激励措施，如税收抵免、申请者费用豁免及孤儿药独占权资格，以此鼓励用于罕见病药物的开发。
Ninlaro由日本大阪的武田制药上市销售。帕比司他由新泽西东汉诺威的诺华制药上市。Darzalex由宾夕法尼亚州霍舍姆的杨森生物科技上市。来那度胺由新泽西萨米特的塞尔基因公司上市。

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use NINLARO safely and effectively. See full prescribing information for NINLARO.
NINLARO ® (ixazomib) capsules, for oral use
Initial U.S. Approval: 2015
INDICATIONS AND USAGE
NINLARO is a proteasome inhibitor indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. (1)
DOSAGE AND ADMINISTRATION
Recommended starting dose of 4 mg taken orally on Days 1, 8, and 15 of a 28-day cycle. (2.1)
Dose should be taken at least one hour before or at least two hours after food. (2.1)
DOSAGE FORMS AND STRENGTHS
Capsules: 4 mg, 3 mg, and 2.3 mg (3)
CONTRAINDICATIONS
None. (4)
WARNINGS AND PRECAUTIONS
Thrombocytopenia: Monitor platelet counts at least monthly during treatment and adjust dosing, as needed. (2.2, 5.1)
Gastrointestinal Toxicities: Adjust dosing for severe diarrhea, constipation, nausea, and vomiting, as needed. (2.2, 5.2)
Peripheral Neuropathy: Monitor patients for symptoms of peripheral neuropathy and adjust dosing, as needed. (2.2, 5.3)
Peripheral Edema: Monitor for fluid retention. Investigate for underlying causes, when appropriate. Adjust dosing, as needed. (2.2, 5.4)
Cutaneous Reactions: Monitor patients for rash and adjust dosing, as needed. (2.2, 5.5)
Hepatotoxicity: Monitor hepatic enzymes during treatment. (5.6)
Embryo-Fetal Toxicity: NINLARO can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. (5.7, 8.1)
ADVERSE REACTIONS
The most common adverse reactions (≥ 20%) are diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting, and back pain. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals America, Inc. at 1-844-617-6468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Strong CYP3A inducers: Avoid concomitant use with NINLARO. (7.1, 12.3)
USE IN SPECIFIC POPULATIONS
Hepatic Impairment: Reduce the NINLARO starting dose to 3 mg in patients with moderate or severe hepatic impairment. (2.3, 8.6)
Renal Impairment: Reduce the NINLARO starting dose to 3 mg in patients with severe renal impairment or end-stage renal disease requiring dialysis. (2.4, 8.7)
Lactation: Discontinue nursing. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 11/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
NINLARO is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.
2 DOSAGE AND ADMINISTRATION
2.1 Dosing and Administration Guidelines
NINLARO in combination with lenalidomide and dexamethasone
The recommended starting dose of NINLARO is 4 mg administered orally once a week on Days 1, 8, and 15 of a 28-day treatment cycle.
The recommended starting dose of lenalidomide is 25 mg administered daily on Days 1 through 21 of a 28-day treatment cycle.
The recommended starting dose of dexamethasone is 40 mg administered on Days 1, 8, 15, and 22 of a 28-day treatment cycle.
Table 1: Dosing Schedule for NINLARO taken with Lenalidomide and Dexamethasone ✔ Take  medicine

28-Day Cycle (a 4-week cycle)
	Week 1		Week 2		Week 3		Week 4
	Day 1	Days 2-7	Day 8	Days 9-14	Day 15	Days 16-21	Day 22	Days 23-28
NINLARO	✔		✔		✔
Lenalidomide	✔	✔ Daily	✔	✔ Daily	✔	✔ Daily
Dexamethasone	✔		✔		✔		✔

For additional information regarding lenalidomide and dexamethasone, refer to their prescribing information.
NINLARO should be taken once a week on the same day and at approximately the same time for the first three weeks of a four week cycle. NINLARO should be taken at least one hour before or at least two hours after food [see Clinical Pharmacology (12.3)]. The whole capsule should be swallowed with water. The capsule should not be crushed, chewed or opened [see How Supplied/Storage and Handling (16.3)].
If a NINLARO dose is delayed or missed, the dose should be taken only if the next scheduled dose is ≥ 72 hours away. A missed dose should not be taken within 72 hours of the next scheduled dose. A double dose should not be taken to make up for the missed dose.
If vomiting occurs after taking a dose, the patient should not repeat the dose. The patient should resume dosing at the time of the next scheduled dose.
Prior to initiating a new cycle of therapy:
Absolute neutrophil count should be at least 1,000/mm3
Platelet count should be at least 75,000/mm3
Non-hematologic toxicities should, at the physician's discretion, generally be recovered to patient's baseline condition or Grade 1 or lower
Treatment should be continued until disease progression or unacceptable toxicity.
2.2 Dose Modification Guidelines
The NINLARO dose reduction steps are presented in Table 2 and the dose modification guidelines are provided in Table 3.
Table 2: NINLARO Dose Reductions due to Adverse Reactions 

Recommended starting dose*	First reduction to	Second reduction to	Discontinue
4 mg	3 mg	2.3 mg

Recommended starting dose of 3 mg in patients with moderate or severe hepatic impairment, severe renal impairment or end-stage renal disease requiring dialysis [ see Dosage and Administration (2.3, 2.4)].
An alternating dose modification approach is recommended for NINLARO and lenalidomide for thrombocytopenia, neutropenia, and rash as described in Table 3. Refer to the lenalidomide prescribing information if dose reduction is needed for lenalidomide.
Table 3: Dose Modifications Guidelines for NINLARO in Combination with Lenalidomide and Dexamethasone

Hematological Toxicities	Recommended Actions
Thrombocytopenia (Platelet Count)
Platelet count less than 30,000/mm3	Withhold NINLARO and lenalidomide until platelet count is at least 30,000/mm3. Following recovery, resume lenalidomide at the next lower dose according to its prescribing information and resume NINLARO at its most recent dose. If platelet count falls to less than 30,000/mm3 again, withhold NINLARO and lenalidomide until platelet count is at least 30,000/mm3. Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose.*
Neutropenia (Absolute Neutrophil Count)
Absolute neutrophil count less than 500/mm3	Withhold NINLARO and lenalidomide until absolute neutrophil count is at least 500/mm3. Consider adding G-CSF as per clinical guidelines. Following recovery, resume lenalidomide at the next lower dose according to its prescribing information and resume NINLARO at its most recent dose. If absolute neutrophil count falls to less than 500/mm3 again, withhold NINLARO and lenalidomide until absolute neutrophil count is at least 500/mm3. Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose.*
Non-Hematological Toxicities	Recommended Actions
Rash
Grade† 2 or 3	Withhold lenalidomide until rash recovers to Grade 1 or lower. Following recovery, resume lenalidomide at the next lower dose according to its prescribing information. If Grade 2 or 3 rash occurs again, withhold NINLARO and lenalidomide until rash recovers to Grade 1 or lower. Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose.*
Grade 4	Discontinue treatment regimen.
Peripheral Neuropathy
Grade 1 Peripheral Neuropathy with Pain or Grade 2 Peripheral Neuropathy	Withhold NINLARO until peripheral neuropathy recovers to Grade 1 or lower without pain or patient's baseline. Following recovery, resume NINLARO at its most recent dose.
Grade 2 Peripheral Neuropathy with Pain or Grade 3 Peripheral Neuropathy	Withhold NINLARO. Toxicities should, at the physician's discretion, generally recover to patient's baseline condition or Grade 1 or lower prior to resuming NINLARO. Following recovery, resume NINLARO at the next lower dose.
Grade 4 Peripheral Neuropathy	Discontinue treatment regimen.
Other Non-Hematological Toxicities
Other Grade 3 or 4 Non-Hematological Toxicities	Withhold NINLARO. Toxicities should, at the physician's discretion, generally recover to patient's baseline condition or Grade 1 or lower prior to resuming NINLARO. If attributable to NINLARO, resume NINLARO at the next lower dose following recovery.

For additional occurrences, alternate dose modification of lenalidomide and NINLARO
Grading based on National Cancer Institute Common Terminology Criteria (CTCAE) Version 4.03
2.3 Dosage in Patients with Hepatic Impairment
Reduce the starting dose of NINLARO to 3 mg in patients with moderate (total bilirubin greater than 1.5-3 × ULN) or severe (total bilirubin greater than 3 × ULN) hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
2.4 Dosage in Patients with Renal Impairment
Reduce the starting dose of NINLARO to 3 mg in patients with severe renal impairment (creatinine clearance less than 30 mL/min) or end-stage renal disease (ESRD) requiring dialysis. NINLARO is not dialyzable and therefore can be administered without regard to the timing of dialysis [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
Refer to the lenalidomide prescribing information for dosing recommendations in patients with renal impairment.
3 DOSAGE FORMS AND STRENGTHS
NINLARO is available in the following capsule strengths:
4 mg: Light orange gelatin capsule imprinted with "Takeda" on the cap and "4.0 mg" on the body in black ink. NINLARO 4 mg capsules contain 4 mg of ixazomib equivalent to 5.7 mg of ixazomib citrate.
3 mg: Light grey gelatin capsule imprinted with "Takeda" on the cap and "3.0 mg" on the body in black ink. NINLARO 3 mg capsules contain 3 mg of ixazomib equivalent to 4.3 mg of ixazomib citrate.
2.3 mg: Light pink gelatin capsule imprinted with "Takeda" on the cap and "2.3 mg" on the body in black ink. NINLARO 2.3 mg capsules contain 2.3 mg of ixazomib equivalent to 3.3 mg of ixazomib citrate.
4 CONTRAINDICATIONS(What is this?)
None.
5 WARNINGS AND PRECAUTIONS
5.1 Thrombocytopenia
Thrombocytopenia has been reported with NINLARO with platelet nadirs typically occurring between Days 14-21 of each 28-day cycle and recovery to baseline by the start of the next cycle. Three percent of patients in the NINLARO regimen and 1% of patients in the placebo regimen had a platelet count ≤ 10,000/mm3 during treatment. Less than 1% of patients in both regimens had a platelet count ≤ 5000/mm3 during treatment. Discontinuations due to thrombocytopenia were similar in both regimens (< 1% of patients in the NINLARO regimen and 2% of patients in the placebo regimen discontinued one or more of the three drugs).The rate of platelet transfusions was 6% in the NINLARO regimen and 5% in the placebo regimen.
Monitor platelet counts at least monthly during treatment with NINLARO. Consider more frequent monitoring during the first three cycles. Manage thrombocytopenia with dose modifications [see Dosage and Administration (2.2)] and platelet transfusions as per standard medical guidelines.
5.2 Gastrointestinal Toxicities
Diarrhea, constipation, nausea, and vomiting, have been reported with NINLARO, occasionally requiring use of antidiarrheal and antiemetic medications, and supportive care. Diarrhea was reported in 42% of patients in the NINLARO regimen and 36% in the placebo regimen, constipation in 34% and 25%, respectively, nausea in 26% and 21%, respectively, and vomiting in 22% and 11%, respectively. Diarrhea resulted in discontinuation of one or more of the three drugs in 1% of patients in the NINLARO regimen and < 1% of patients in the placebo regimen. Adjust dosing for Grade 3 or 4 symptoms [see Dosage and Administration (2.2)].
5.3 Peripheral Neuropathy
The majority of peripheral neuropathy adverse reactions were Grade 1 (18% in the NINLARO regimen and 14% in the placebo regimen) and Grade 2 (8% in the NINLARO regimen and 5% in the placebo regimen). Grade 3 adverse reactions of peripheral neuropathy were reported at 2% in both regimens; there were no Grade 4 or serious adverse reactions.
The most commonly reported reaction was peripheral sensory neuropathy (19% and 14% in the NINLARO and placebo regimen, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (< 1%). Peripheral neuropathy resulted in discontinuation of one or more of the three drugs in 1% of patients in both regimens. Patients should be monitored for symptoms of neuropathy. Patients experiencing new or worsening peripheral neuropathy may require dose modification [see Dosage and Administration (2.2)].
5.4 Peripheral Edema
Peripheral edema was reported in 25% and 18% of patients in the NINLARO and placebo regimens, respectively. The majority of peripheral edema adverse reactions were Grade 1 (16% in the NINLARO regimen and 13% in the placebo regimen) and Grade 2 (7% in the NINLARO regimen and 4% in the placebo regimen).
Grade 3 peripheral edema was reported in 2% and 1% of patients in the NINLARO and placebo regimens, respectively. There was no Grade 4 peripheral edema reported. There were no discontinuations reported due to peripheral edema. Evaluate for underlying causes and provide supportive care, as necessary. Adjust dosing of dexamethasone per its prescribing information or NINLARO for Grade 3 or 4 symptoms [see Dosage and Administration (2.2)].
5.5 Cutaneous Reactions
Rash was reported in 19% of patients in the NINLARO regimen and 11% of patients in the placebo regimen. The majority of the rash adverse reactions were Grade 1 (10% in the NINLARO regimen and 7% in the placebo regimen) or Grade 2 (6% in the NINLARO regimen and 3% in the placebo regimen). Grade 3 rash was reported in 3% of patients in the NINLARO regimen and 1% of patients in the placebo regimen. There were no Grade 4 or serious adverse reactions of rash reported. The most common type of rash reported in both regimens included maculo-papular and macular rash. Rash resulted in discontinuation of one or more of the three drugs in < 1% of patients in both regimens. Manage rash with supportive care or with dose modification if Grade 2 or higher [see Dosage and Administration (2.2)].
5.6 Hepatotoxicity
Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have each been reported in < 1% of patients treated with NINLARO. Events of liver impairment have been reported (6% in the NINLARO regimen and 5% in the placebo regimen). Monitor hepatic enzymes regularly and adjust dosing for Grade 3 or 4 symptoms [see Dosage and Administration (2.2)].
5.7 Embryo-Fetal Toxicity
NINLARO can cause fetal harm when administered to a pregnant woman based on the mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using NINLARO. Ixazomib caused embryo-fetal toxicity in pregnant rats and rabbits at doses resulting in exposures that were slightly higher than those observed in patients receiving the recommended dose.
Females of reproductive potential should be advised to avoid becoming pregnant while being treated with NINLARO. If NINLARO is used during pregnancy or if the patient becomes pregnant while taking NINLARO, the patient should be apprised of the potential hazard to the fetus. Advise females of reproductive potential that they must use effective contraception during treatment with NINLARO and for 90 days following the final dose [see Use in Specific Populations (8.1, 8.3) and Nonclinical Toxicology (13.1)].
6 ADVERSE REACTIONS
The following adverse reactions are described in detail in other sections of the prescribing information:
Thrombocytopenia [see Warnings and Precautions (5.1)]
Gastrointestinal Toxicities [see Warnings and Precautions (5.2)]
Peripheral Neuropathy [see Warnings and Precautions (5.3)]
Peripheral Edema [see Warnings and Precautions (5.4)]
Cutaneous Reactions [see Warnings and Precautions (5.5)]
Hepatotoxicity [see Warnings and Precautions (5.6)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety population from the randomized, double-blind, placebo-controlled clinical study included 720 patients with relapsed and/or refractory multiple myeloma, who received NINLARO in combination with lenalidomide and dexamethasone (NINLARO regimen; N=360) or placebo in combination with lenalidomide and dexamethasone (placebo regimen; N=360).
The most frequently reported adverse reactions (≥ 20%) in the NINLARO regimen and greater than the placebo regimen were diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting, and back pain. Serious adverse reactions reported in ≥ 2% of patients included thrombocytopenia (2%) and diarrhea (2%). For each adverse reaction, one or more of the three drugs was discontinued in ≤ 1% of patients in the NINLARO regimen.
Table 4 summarizes the adverse reactions occurring in at least 5% of patients with at least a 5% difference between the NINLARO regimen and the placebo regimen.
Table 4: Non-Hematologic Adverse Reactions Occurring in ≥ 5% of Patients with a ≥ 5% Difference Between the NINLARO Regimen and the Placebo Regimen (All Grades, Grade 3 and Grade 4)

NINLARO + Lenalidomide and Dexamethasone N=360			Placebo + Lenalidomide and Dexamethasone N=360
System Organ Class / Preferred Term	N (%)			N (%)
	All	Grade 3	Grade 4	All	Grade 3	Grade 4
Note: Adverse reactions included as preferred terms are based on MedDRA version 16.0.
Represents a pooling of preferred terms
Infections and infestations
Upper respiratory tract infection	69 (19)	1 (< 1)	0	52 (14)	2 (< 1)	0
Nervous system disorders
Peripheral neuropathies*	100 (28)	7 (2)	0	77 (21)	7 (2)	0
Gastrointestinal disorders
Diarrhea	151 (42)	22 (6)	0	130 (36)	8 (2)	0
Constipation	122 (34)	1 (< 1)	0	90 (25)	1 (< 1)	0
Nausea	92 (26)	6 (2)	0	74 (21)	0	0
Vomiting	79 (22)	4 (1)	0	38 (11)	2 (< 1)	0
Skin and subcutaneous tissue disorders
Rash*	68 (19)	9 (3)	0	38 (11)	5 (1)	0
Musculoskeletal and connective tissue disorders
Back pain	74 (21)	2 (< 1)	0	57 (16)	9 (3)	0
General disorders and administration site conditions
Edema peripheral	91 (25)	8 (2)	0	66 (18)	4 (1)	0

Table 5 represents pooled information from adverse event and laboratory data.
Table 5: Thrombocytopenia and Neutropenia 

NINLARO + Lenalidomide and Dexamethasone N=360		Placebo + Lenalidomide and Dexamethasone N=360
	N (%)		N (%)
	Any Grade	Grade 3-4	Any Grade	Grade 3-4
Thrombocytopenia	281 (78)	93 (26)	196 (54)	39 (11)
Neutropenia	240 (67)	93 (26)	239 (66)	107 (30)

Eye Disorders
Eye disorders were reported with many different preferred terms but in aggregate, the frequency was 26% in patients in the NINLARO regimen and 16% of patients in the placebo regimen. The most common adverse reactions were blurred vision (6% in the NINLARO regimen and 3% in the placebo regimen), dry eye (5% in the NINLARO regimen and 1% in the placebo regimen), and conjunctivitis (6% in the NINLARO regimen and 1% in the placebo regimen). Grade 3 adverse reactions were reported in 2% of patients in the NINLARO regimen and 1% in the placebo regimen.
Adverse Reactions Reported Outside of the Randomized Controlled Trial
The following serious adverse reactions have each been reported at a frequency of < 1%: acute febrile neutrophilic dermatosis (Sweet's syndrome), Stevens-Johnson syndrome, transverse myelitis, posterior reversible encephalopathy syndrome, tumor lysis syndrome, and thrombotic thrombocytopenic purpura.
7 DRUG INTERACTIONS
7.1 Strong CYP3A Inducers
Avoid concomitant administration of NINLARO with strong CYP3A inducers (such as rifampin, phenytoin, carbamazepine, and St. John's Wort) [see Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Women should avoid becoming pregnant while being treated with NINLARO.
Risk Summary
NINLARO can cause fetal harm when administered to a pregnant woman. There are no human data available regarding the potential effect of NINLARO on pregnancy or development of the embryo or fetus. Ixazomib caused embryo-fetal toxicity in pregnant rats and rabbits at doses resulting in exposures that were slightly higher then those observed in patients receiving the recommended dose [see Data]. Advise women of the potential risk to a fetus and to avoid becoming pregnant while being treated with NINLARO.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
In an embryo-fetal development study in pregnant rabbits there were increases in fetal skeletal variations/abnormalities (fused caudal vertebrae, number of lumbar vertebrae, and full supernumerary ribs) at doses that were also maternally toxic (≥ 0.3 mg/kg). Exposures in the rabbit at 0.3 mg/kg were 1.9 times the clinical time averaged exposures at the recommended dose of 4 mg. In a rat dose range-finding embryo-fetal development study, at doses that were maternally toxic, there were decreases in fetal weights, a trend towards decreased fetal viability, and increased post-implantation losses at 0.6 mg/kg. Exposures in rats at the dose of 0.6 mg/kg was 2.5 times the clinical time averaged exposures at the recommended dose of 4 mg.
8.2 Lactation
Risk Summary
It is not known whether NINLARO or its metabolites are present in human milk. Many drugs are present in human milk and as a result, there could be a potential for adverse events in nursing infants. Advise women to discontinue nursing.
8.3 Females and Males of Reproductive Potential
Contraception
Male and female patients of childbearing potential must use effective contraceptive measures during and for 90 days following treatment.
Infertility
Fertility studies were not conducted with NINLARO; however there were no effects on reproductive organs in either males or females in nonclinical studies in rats and dogs [see Nonclinical Toxicology (13.1)].
8.4 Pediatric Use
Safety and effectiveness have not been established in pediatric patients.
8.5 Geriatric Use
Of the total number of subjects in clinical studies of NINLARO, 55% were 65 and over, while 17% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
8.6 Hepatic Impairment
In patients with moderate or severe hepatic impairment, the mean AUC increased by 20% when compared to patients with normal hepatic function. Reduce the starting dose of NINLARO in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].
8.7 Renal Impairment
In patients with severe renal impairment or ESRD requiring dialysis, the mean AUC increased by 39% when compared to patients with normal renal function. Reduce the starting dose of NINLARO in patients with severe renal impairment or ESRD requiring dialysis. NINLARO is not dialyzable and therefore can be administered without regard to the timing of dialysis [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
10 OVERDOSAGE
There is no known specific antidote for NINLARO overdose. In the event of an overdose, monitor the patient for adverse reactions [see Adverse Reactions (6.1)] and provide appropriate supportive care.
11 DESCRIPTION
NINLARO (ixazomib) is an antineoplastic agent. Ixazomib citrate, a prodrug, rapidly hydrolyzes under physiological conditions to its biologically active form, ixazomib. The chemical name of ixazomib citrate is 1,3,2-dioxaborolane-4,4-diacetic acid, 2-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-5-oxo- and the structural formula is:

The molecular formula for ixazomib citrate is C20H23BCl2N2O9 and its molecular weight is 517.12. Ixazomib citrate has one chiral center and is the R-stereoisomer. The solubility of ixazomib citrate in 0.1N HCl (pH 1.2) at 37°C is 0.61 mg/mL (reported as ixazomib). The solubility increases as the pH increases.
NINLARO (ixazomib) capsules for oral use contain 4, 3 or 2.3 mg of ixazomib equivalent to 5.7, 4.3 or 3.3 mg of ixazomib citrate, respectively. Inactive ingredients include microcrystalline cellulose, magnesium stearate, and talc. Capsule shells contain gelatin and titanium dioxide. The 4 mg capsule shell contains red and yellow iron oxide, the 3 mg capsule shell contains black iron oxide and the 2.3 mg capsule shell contains red iron oxide. The printing ink contains shellac, propylene glycol, potassium hydroxide, and black iron oxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ixazomib is a reversible proteasome inhibitor. Ixazomib preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome.
Ixazomib induced apoptosis of multiple myeloma cell lines in vitro. Ixazomib demonstrated in vitro cytotoxicity against myeloma cells from patients who had relapsed after multiple prior therapies, including bortezomib, lenalidomide, and dexamethasone. The combination of ixazomib and lenalidomide demonstrated synergistic cytotoxic effects in multiple myeloma cell lines. In vivo, ixazomib demonstrated antitumor activity in a mouse multiple myeloma tumor xenograft model.
12.2 Pharmacodynamics
Cardiac Electrophysiology
NINLARO did not prolong the QTc interval at clinically relevant exposures based on pharmacokinetic-pharmacodynamic analysis of data from 245 patients.
12.3 Pharmacokinetics
Absorption
After oral administration, the median time to achieve peak ixazomib plasma concentrations was one hour. The mean absolute oral bioavailability was 58%, based on population PK analysis. Ixazomib AUC increases in a dose proportional manner over a dose range of 0.2 to 10.6 mg.
A food effect study conducted in patients with a single 4 mg dose of ixazomib showed that a high-fat meal decreased ixazomib AUC by 28% and Cmax by 69% [see Dosage and Administration (2.1)].
Distribution
Ixazomib is 99% bound to plasma proteins and distributes into red blood cells with a blood-to-plasma ratio of 10. The steady-state volume of distribution is 543 L.
Elimination
Based on a population PK analysis, systemic clearance was approximately 1.9 L/hr with inter-individual variability of 44%. The terminal half-life (t1/2) of ixazomib was 9.5 days. Following weekly oral dosing, the accumulation ratio was determined to be 2-fold.
Metabolism
After oral administration of a radiolabeled dose, ixazomib represented 70% of total drug-related material in plasma. Metabolism by multiple CYP enzymes and non-CYP proteins is expected to be the major clearance mechanism for ixazomib. At clinically relevant ixazomib concentrations, in vitro studies using human cDNA-expressed cytochrome P450 isozymes showed that no specific CYP isozyme predominantly contributes to ixazomib metabolism. At higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms with estimated relative contributions of 3A4 (42%), 1A2 (26%), 2B6 (16%), 2C8 (6%), 2D6 (5%), 2C19 (5%) and 2C9 (< 1%).
Excretion
After administration of a single oral dose of 14C-ixazomib to 5 patients with advanced cancer, 62% of the administered radioactivity was excreted in urine and 22% in the feces. Unchanged ixazomib accounted for < 3.5% of the administered dose recovered in urine.
Specific Populations
Age, Sex, Race
There was no clinically meaningful effect of age (range 23-91 years), sex, body surface area (range 1.2-2.7 m2), or race on the clearance of ixazomib based on population PK analysis.
Hepatic Impairment
The PK of ixazomib was similar in patients with normal hepatic function and in patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1-1.5 × ULN and any AST) based on population PK analysis.
The PK of ixazomib was characterized in patients with normal hepatic function at 4 mg (N=12), moderate hepatic impairment at 2.3 mg (total bilirubin > 1.5-3 × ULN, N=13) or severe hepatic impairment at 1.5 mg (total bilirubin > 3 × ULN, N=18). Dose-normalized mean AUC was 20% higher in patients with moderate or severe hepatic impairment as compared to patients with normal hepatic function [see Dosage and Administration (2.3)].
Renal Impairment
The PK of ixazomib was similar in patients with normal renal function and in patients with mild or moderate renal impairment (creatinine clearance ≥ 30 mL/min) based on population PK analysis.
The PK of ixazomib was characterized at a dose of 3 mg in patients with normal renal function (creatinine clearance ≥ 90 mL/min, N=18), severe renal impairment (creatinine clearance < 30 mL/min, N=14), or ESRD requiring dialysis (N=6). Mean AUC was 39% higher in patients with severe renal impairment or ESRD requiring dialysis as compared to patients with normal renal function. Pre- and post-dialyzer concentrations of ixazomib measured during the hemodialysis session were similar, suggesting that ixazomib is not dialyzable [see Dosage and Administration (2.4)].
Drug Interactions
Effect of Other Drugs on NINLARO
Strong CYP3A Inducers
Co-administration of NINLARO with rifampin decreased ixazomib Cmax by 54% and AUC by 74% [see Drug Interactions (7.1)].
Strong CYP3A Inhibitors
Co-administration of NINLARO with clarithromycin did not result in a clinically meaningful change in the systemic exposure of ixazomib.
Strong CYP1A2 Inhibitors
Co-administration of NINLARO with strong CYP1A2 inhibitors did not result in a clinically meaningful change in the systemic exposure of ixazomib based on a population PK analysis.
Effect of NINLARO on Other Drugs
Ixazomib is neither a reversible nor a time-dependent inhibitor of CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Ixazomib did not induce CYP1A2, CYP2B6, and CYP3A4/5 activity or corresponding immunoreactive protein levels. NINLARO is not expected to produce drug-drug interactions via CYP inhibition or induction.
Transporter-Based Interactions
Ixazomib is a low affinity substrate of P-gp. Ixazomib is not a substrate of BCRP, MRP2 or hepatic OATPs. Ixazomib is not an inhibitor of P-gp, BCRP, MRP2, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2-K. NINLARO is not expected to cause transporter-mediated drug-drug interactions.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Ixazomib was not mutagenic in a bacterial reverse mutation assay (Ames assay). Ixazomib was considered positive in an in vitro clastogenicity test in human peripheral blood lymphocytes. However, in vivo, ixazomib was not clastogenic in a bone marrow micronucleus assay in mice and was negative in an in vivo comet assay in mice, as assessed in the stomach and liver. No carcinogenicity studies have been performed with ixazomib.
Developmental toxicity studies in rats and rabbits did not show direct embryo-fetal toxicity below maternally toxic doses of ixazomib. Studies of fertility and early embryonic development and pre- and postnatal toxicology were not conducted with ixazomib, but evaluation of reproductive tissues was conducted in the general toxicity studies. There were no effects due to ixazomib treatment on male or female reproductive organs in studies up to 6-months duration in rats and up to 9-months duration in dogs.
14 CLINICAL STUDIES
The efficacy and safety of NINLARO in combination with lenalidomide and dexamethasone was evaluated in a randomized, double-blind, placebo-controlled, multicenter study in patients with relapsed and/or refractory multiple myeloma who had received at least one prior line of therapy. Patients who were refractory to lenalidomide or proteasome inhibitors were excluded from the study.
A total of 722 patients were randomized in a 1:1 ratio to receive either the combination of NINLARO, lenalidomide and dexamethasone (N=360; NINLARO regimen) or the combination of placebo, lenalidomide and dexamethasone (N=362; placebo regimen) until disease progression or unacceptable toxicity. Randomization was stratified according to number of prior lines of therapy (1 versus 2 or 3), myeloma International Staging System (ISS) (stage I or II versus III), and previous therapy with a proteasome inhibitor (exposed or naïve). Twenty three percent (N=166) of the patients had light chain disease and 12% (N=87) of patients had free light chain-measurable only disease.
Thromboprophylaxis was recommended for all patients in both treatment groups according to the lenalidomide prescribing information. Antiemetics were used in 19% of patients in the NINLARO regimen and 12% of patients in the placebo regimen; antivirals in 64% and 60%, respectively, and antihistamines in 27% and 19%, respectively. These medications were given to patients at the physician's discretion as prophylaxis and/or management of symptoms.
Patients received NINLARO 4 mg or placebo on Days 1, 8, and 15 plus lenalidomide (25 mg) on Days 1 through 21 and dexamethasone (40 mg) on Days 1, 8, 15, and 22 of a 28-day cycle. Patients with renal impairment received a starting dose of lenalidomide according to its prescribing information. Treatment continued until disease progression or unacceptable toxicities.
Table 6 summarizes the baseline patient and disease characteristics in the study. The baseline demographics and disease characteristics were balanced and comparable between the study regimens.
Table 6: Baseline Patient and Disease Characteristics

NINLARO + Lenalidomide and Dexamethasone (N = 360)	Placebo + Lenalidomide and Dexamethasone (N = 362)
Primary refractory, defined as best response of stable disease or disease progression on all prior lines of therapy, was documented in 7% and 6% of patients in the NINLARO regimen and placebo regimens, respectively.
Patient Characteristics
Median age in years (range)	66 (38, 91)	66 (30, 89)
Gender (%) Male/ Female	58/42	56/44
Age Group (% [< 65/ ≥ 65 years])	41/59	43/57
Race n (%)
White	310 (86)	301 (83)
Black	7 (2)	6 (2)
Asian	30 (8)	34 (9)
Other or Not Specified	13 (4)	21 (6)
ECOG performance status, n (%)
0 or 1	336 (93)	334 (92)
2	18 (5)	24 (7)
Missing	6 (2)	4 (1)
Creatinine clearance, n (%)
< 30 mL/min	5 (1)	5 (1)
30-59 mL/min	74 (21)	95 (26)
≥ 60 mL/min	281 (78)	261 (72)
Disease Characteristics
Myeloma ISS stage, n (%)
Stage I or II	315 (87)	320 (88)
Stage III	45 (13)	42 (12)
Prior line therapies n (%)
Median (range)	1 (1, 3)	1 (1,3)
1	224 (62)	217 (60)
2 or 3	136 (38)	145 (40)
Status at Baseline n (%)
Relapsed	276 (77)	280 (77)
Refractory*	42 (12)	40 (11)
Relapsed and Refractory	41 (11)	42 (12)
Type of Prior Therapy n (%)
Bortezomib containing	248 (69)	250 (69)
Carfilzomib containing	1 (<1)	4 (1)
Thalidomide containing	157 (44)	170 (47)
Lenalidomide containing	44 (12)	44 (12)
Melphalan containing	293 (81)	291 (80)
Stem cell transplantation	212 (59)	199 (55)
High risk (deletion (del) 17, t(4:14) and/or t(14:16)	75 (21)	62 (17)
deletion del (17)	36 (10)	33 (9)

The efficacy of NINLARO was evaluated by progression-free survival (PFS) according to the 2011 International Myeloma Working Group (IMWG) Consensus Uniform Response Criteria as assessed by a blinded independent review committee (IRC) based on central lab results. Response was assessed every four weeks until disease progression.
The approval of NINLARO was based upon a statistically significant improvement in PFS of the NINLARO regimen compared to the placebo regimen. PFS results are summarized in Table 7 and shown in Figure 1.
Table 7: Progression-Free Survival and Response Rate 

NINLARO + Lenalidomide and Dexamethasone (N = 360)	Placebo + Lenalidomide and Dexamethasone (N = 362)
NE: Not evaluable.
Hazard ratio is based on a stratified Cox's proportional hazard regression model. A hazard ratio less than 1 indicates an advantage for the NINLARO regimen. P-value is based on the stratified log-rank test.
Progression-free Survival
PFS Events, n (%)	129 (36)	157 (43)
Median (months) (95% CI)	20.6 (17.0, NE)	14.7 (12.9, 17.6)
Hazard Ratio* (95% CI)	0.74 (0.59, 0.94)
p-value†	0.012
Response Rate
Overall Response Rate, n (%)	282 (78)	259 (72)
Complete Response	42 (12)	24 (7)
Very Good Partial Response	131 (36)	117 (32)
Partial Response	109 (30)	118 (33)

The median time to response was 1.1 months in the NINLARO regimen and 1.9 months in the placebo regimen. The median duration of response was 20.5 months in the NINLARO regimen and 15 months in the placebo regimen for responders in the response evaluable population.
Figure 1: Kaplan-Meier Plot of Progression-Free Survival

A non-inferential PFS analysis was conducted at a median follow up of 23 months with 372 PFS events. Hazard ratio of PFS was 0.82 (95% confidence interval [0.67, 1.0]) for NINLARO regimen versus placebo regimen, and estimated median PFS was 20 months in the NINLARO regimen and 15.9 months in the placebo regimen. At the same time, a planned interim OS analysis was conducted with 35% of the required number of deaths for final OS analysis; there were 81 deaths in the NINLARO regimen and 90 deaths in the placebo regimen. An OS benefit was not demonstrated.
15 REFERENCES
1.OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
NINLARO is supplied as:
4 mg gelatin capsule: Light orange, size 3, imprinted with "Takeda" on the cap and "4.0 mg" on the body in black ink. NINLARO 4 mg capsules contain 4 mg of ixazomib equivalent to 5.7 mg of ixazomib citrate.
One 4 mg capsule in a single blister pack (NDC 63020-080-01)
Three 4 mg single packs in a carton (NDC 63020-080-02)
3.0 mg gelatin capsule: Light grey, size 4, imprinted with "Takeda" on the cap and "3.0 mg" on the body in black ink. NINLARO 3 mg capsules contain 3 mg of ixazomib equivalent to 4.3 mg of ixazomib citrate.
One 3 mg capsule in a single blister pack (NDC 63020-079-01)
Three 3 mg single packs in a carton (NDC 63020-079-02)
2.3 mg gelatin capsule: Light pink, size 4, imprinted with "Takeda" on the cap and "2.3 mg" on the body in black ink. NINLARO 2.3 mg capsules contain 2.3 mg of ixazomib equivalent to 3.3 mg of ixazomib citrate.
One 2.3 mg capsule in a single blister pack (NDC 63020-078-01)
Three 2.3 mg single packs in a carton (NDC 63020-078-02)
Capsules are individually packaged in a PVC-Aluminum/Aluminum blister.
16.2 Storage
NINLARO may be stored at room temperature. Do not store above 30°C (86°F). Do not freeze.
Store capsules in original packaging until immediately prior to use.
16.3 Handling and Disposal
NINLARO is cytotoxic1. Capsules should not be opened or crushed. Direct contact with the capsule contents should be avoided. In case of capsule breakage, avoid direct contact of capsule contents with the skin or eyes. If contact occurs with the skin, wash thoroughly with soap and water. If contact occurs with the eyes, flush thoroughly with water.
Any unused medicinal product or waste material should be disposed in accordance with local requirements.
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fcef9088-ebab-4bd8-933f-c35f9c8bd50b&audience=consumer

美国FDA核准武田首个也是唯一的口服蛋白酶体抑制剂NINLARO(ixazomib)用于治疗多发性骨髓瘤
NINLARO可为先前至少用过一种药物的多发性骨髓瘤患者提供新的选择
马萨诸塞州剑桥和日本大阪-武田药品工业株式会社(TSE: 4502)今天宣布，美国食品药品管理局(FDA)已核准首个且唯一的口服蛋白酶体抑制剂NINLARO(ixazomib)胶囊联合来那度胺和地塞米松用于治疗先前至少用过一种药物的多发性骨髓瘤患者。NINLARO胶囊为每周一次给药。
武田于2015年7月向FDA递交NINLARO的新药申请，于9月获得优先审理，PDUFA（处方药使用者费用法）排期为2016年3月10日，这体现了多发性骨髓瘤这一致残性、复发性、难以治愈的罕见癌症对新治疗药物有深切而持续的未获满足的需求。
Dana-Farber癌症研究所Jerome Lipper多发性骨髓瘤中心临床项目负责人兼临床研究总监、TOURMALINE-MM1（今天的核准就是以这项枢纽性3期试验为依据的）研究者Paul Richardson, M.D.说：“随着NINLARO的核准，我们现在能够为患者提供每周一次口服的蛋白酶体抑制剂，作为具有高度活性的三药联合治疗的一员。
作为TOURMALINE-MM1试验的研究者，我们认为，对下列患者组合开展一项全面的‘真实世界’评估是至关重要的，包括复发/难治多发性骨髓瘤最常见患者类型中的一部分，例如老龄患者、中度肾功能损害患者、轻链病和高危细胞遗传学特质。此外，我们对患者的治疗持续至疾病进展，以确定NINLARO 治疗复发/难治疾病的可持续性。TOURMALINE-MM1数据令人信服地表明，口服基于NINLARO的三药治疗可有效延长无进展生存期，临床收益优于来那度胺和地塞米松，安全性在可耐受范围。”
武田首席医学和科学官Andy Plump, M.D.博士说：“约20年前，我们在临床研究中推出了治疗多发性骨髓瘤的首个蛋白酶体抑制剂VELCADE。从那时起，我们对这一罕见癌症的科学了解取得了显著的进展，导致了NINLARO的推出。NINLARO是一个全新的蛋白酶体抑制剂分子，可每周一次口服，给药方便，在提供有效性的同时，其安全性也在可耐受范围。武田很高兴将这一重大创新带给今日的多发性骨髓瘤患者，同时我们会通过扎实的临床开发项目不断探寻NINLARO的潜力。”
国际多发性骨髓瘤基金会主席Brian Durie博士说：“IMF很高兴ixazomib获得核准。此举为基于全口服蛋白酶体抑制剂的三药联合治疗敞开了大门。我在多发性骨髓瘤领域工作了数十载，虽然见证过重大进展，但该领域依然存在未获满足的巨大需求。随着今天的核准，我们现在拥有了一个吸引众多多发性骨髓瘤患者的新选择。”
FDA核准NINLARO的依据是TOURMALINE-MM1 3期临床试验的结果，该试验是首个双盲、安慰剂对照蛋白酶体抑制剂试验。TOURMALINE-MM1是5项进行中的3期临床试验中第一项得出研究结果的试验。TOURMALINE项目迄今已在40个国家募集了约3,000例患者。NINLARO 3期 TOURMALINE-MM1枢纽性试验的数据即将在2015年12月召开的美国血液学会第57届年会上呈报。
多发性骨髓瘤研究基金会(MMRF)创始人、执行董事长Kathy Giusti说：“ixazomib 获得核准为多发性骨髓瘤治疗领域提供了一个翘首以待的新选择。它属于帮助我们更好地理解该疾病并为患者提供持续希望的进展。今天的癌症诊断与刚过去的几年就有不同，见证不断的进步是令人激动的。作为一名患者，我理解人们迫切需要通过能够带来新治疗选择的伙伴关系来促进研究，正如我们与武田合作完成的那样。”
武田肿瘤部总裁Christophe Bianchi, M.D.解释道：“NINLARO属于同类中首个的创新，得到全球性开发项目的支持，这对我们武田肿瘤部是前所未有的，我们希望对所有参研患者难以置信的力量和无价参与表达我们衷心的感谢。NINLARO的问世标志着前进了重要的一步 ，因为它的有效性和安全性——加上它是全口服给药——有望减轻一部分服药负担，并帮助患者获得这一可持续治疗的全部收益。作为武田20年不懈承诺的一部分，我们将为了这些患者而不断追求进展，并期待在世界其他市场推出NINLARO并拓展获取途径。”
关于TOURMALINE-MM1试验
TOURMALINE-MM1是国际性、随机、双盲、安慰剂对照临床试验，受试者为 722例，旨在评估NINLARO联合来那度胺和地塞米松治疗复发和/或难治多发性骨髓瘤成人患者是否优于安慰剂联合来那度胺和地塞米松。结果显示，NINLARO可有效延长无进展生存期(PFS)，安全性可控。该试验达到其主要终点，本次分析中显示PFS的延长有临床意义和统计学意义，分析显示，NINLARO治疗组患者疾病无恶化的生存时间显著长于对照组患者。该试验中，患者持续治疗直至进展，并评估长期转归指标。
TOURMALINE-MM1试验中，接受NINLARO的患者最常见的不良反应(≥20%)包括腹泻、便秘、血小板减少、周围神经病变、恶心、外周水肿、呕吐和背痛。报告率≥2%的严重不良反应包括血小板减少(2%)和腹泻(2%)。
独立数据监测委员会(IDMC)对有效性和安全性数据进行复核后，建议该研究继续按盲态进行，以待长期转归指标的进一步成熟，包括总生存(OS)和长期安全性。
关于NINLARO(ixazomib)胶囊
NINLARO (ixazomib)是首个也是唯一的口服蛋白酶体抑制剂，其适应证是联合来那度胺和地塞米松用于治疗先前至少用过一种药物的多发性骨髓瘤患者。NINLARO每周一次口服，分别在28天周期的第1、8、15、28天给药。NINLARO目前正在欧洲药品管理局(EMA)审批中，并已获得人用药品委员会(CHMP)的加快评审。2014年，NINLARO还被美国FDA认可为用于复发或难治全身性轻链(AL)淀粉样变（一种相关的超级孤儿病）的突破性治疗药物。
TOURMALINE临床开发项目进一步巩固了武田为全球多发性骨髓瘤患者和治疗这些患者的医疗卫生专业人士开发创新治疗药物的不懈承诺。5项全球性3期试验正在进行中：
·TOURMALINE-MM1研究ixazomib 联合来那度胺和地塞米松与安慰剂对照用于复发和/或难治多发性骨髓瘤
·TOURMALINE-MM2研究ixazomib联合来那度胺和地塞米松与安慰剂对照用于新诊断的多发性骨髓瘤患者
·TOURMALINE-MM3研究ixazomib与安慰剂对照用于新诊断的多发性骨髓瘤患者在诱导治疗和自体干细胞移植(ASCT)后的维持治疗
·TOURMALINE-MM4研究ixazomib与安慰剂对照用于尚未接受ASCT的新诊断的多发性骨髓瘤患者的维持治疗
·TOURMALINE-AL1研究ixazomib联合地塞米松与医师选用的治疗方案对照用于复发或难治AL淀粉样变
除了TOURMALINE研究，大量研究者发起的研究正在全球范围内评估ixazomib用于患者。
有关进行中的3期研究的进一步信息，请访问www.clinicaltrials.gov。欲了解有关NINLARO的更多信息，请访问www.NINLARO.com或致电1-844-N1POINT (1-844-617-6468)。
重要安全性信息
警示与注意事项
血小板减少：NINLARO用药期间已有报道。治疗期间应监测血小板计数，每月至少一次，在最初3个治疗周期中可考虑更频繁的监测。必要时可调整剂量。血小板计数最低点发生于每28天治疗周期的第14-21天期间，在下一轮周期开始前恢复至基线水平。
胃肠道毒性（包括腹泻、便秘、恶心和呕吐）：NINLARO用药期间已有报道，偶而可能需要使用止泻药和镇吐药，并给予支持性治疗。对于重度症状，应调整剂量。
周围神经病变（主要是感觉神经）：NINLARO用药期间已有报道。应监测患者的周围神经病变症状，必要时可调整剂量。
外周水肿：NINLARO用药期间已有报道。应监测体液潴留。必要时应调查基础病因，并提供支持性治疗。必要时可调整剂量。
皮肤反应（皮疹、最常见为斑丘疹和斑疹）：NINLARO用药期间已有报道。皮疹的处治可采用支持性治疗或调整剂量。
肝脏毒性：NINLARO用药期间已有报道。治疗期间应定期监测肝酶，必要时可调整剂量。
胚胎-胎儿毒性：NINLARO可导致胚胎损害。应告知女性该药对胚胎的潜在风险，以避免妊娠，并在NINLARO治疗期间及末次给药后90天内采取避孕措施。
不良反应
NINLARO治疗患者中发生率?20%的最常见不良反应有：腹泻、便秘、血小板减少、周围神经病变、恶心、外周水肿、呕吐和背痛。
特殊人群
肝功能损害：中度或重度肝功能损害患者可降低NINLARO 起始剂量至3毫克。
肾功能损害：需要透析的重度肾功能损害或终末期肾病患者可降低NINLARO 起始剂量至3毫克。NINLARO无法经透析清除。
哺乳：建议乳母在NINLARO用药期间停止哺乳。
药物相互作用：应避免NINLARO与CYP3A强诱导剂合并使用。
适应证
NINLARO (ixazomib)的适应证是联合来那度胺和地塞米松用于治疗先前至少用过一种药物的多发性骨髓瘤患者。
请参阅伴随的NINLARO完整处方信息。
关于多发性骨髓瘤
多发性骨髓瘤是一种浆细胞癌，见于骨髓。多发性骨髓瘤中，一组浆细胞（或骨髓瘤细胞）转化为癌细胞并增生，使浆细胞的数目高于正常水平。由于浆细胞在体内广泛游走，有可能累及体内多数骨骼，可能导致压缩性骨折、骨溶解性病灶和相关疼痛。多发性骨髓瘤可导致若干严重健康问题，累及骨骼、免疫系统、肾脏和个体的红细胞计数，部分较常见症状包括骨骼疼痛和疲乏，疲乏是贫血的症状。多发性骨髓瘤属罕见癌症，每年新发病例在美国超过26,000人、全球约为114,000人。