2015年11月4日，美国食品药品监督管理局批准Onivyde（伊立替康脂质体注射液）联合氟尿嘧啶和亚叶酸治疗使用吉西他滨后化疗不佳的晚期胰腺癌患者。
美国国家癌症研究所表示，截止到2015年，美国新增胰腺癌确诊病例数预计到达48960人，死亡病例数与之接近（40560）。早期胰腺癌很难被诊断，且治疗手段有限。当癌症扩散到身体其他部位后，将不再可能手术切除肿瘤。
FDA药品评价研究中心血液及肿瘤产品办公室主任Richard Pazdur博士表示:“许多审批药品的FDA官员都是临床医生，他们特别鼓励那些可满足患者的新治疗方案。此次通过对Onivyde优先审批，患者可更早获得药物来延长寿命。”
FDA同时批准了对Onivyde的优先审查和孤儿药资格认定。优先审查旨在通过那些能显著提高严重疾病治疗的安全性和高效性的药物申请。孤儿药资格认定给药企带来许多激励政策，包括税收抵免、患者使用费豁免、孤儿药专营权以支持鼓励罕见病药物的开发。
Onivyde的疗效证实是基于一个由417名转移性胰腺癌患者组成的随机非盲三臂临床试验。该试验的胰腺癌患者虽然接受了以吉西他滨为基础的化疗，但肿瘤快速生长。该实验目的在于研究接受Onivyde联合氟尿嘧啶/亚叶酸或是单独使用Onivyde的患者寿命是否长于仅仅使用氟尿嘧啶/亚叶酸的患者寿命。研究人员发现，接受Onivyde联合氟尿嘧啶/亚叶酸的患者平均生存时间为6.1个月，接受氟尿嘧啶/亚叶酸治疗的患者只有4.2个月。但是单独使用Onivyde与使用氟尿嘧啶/亚叶酸患者的生存时间没有差异。
此外,相比于仅接受氟尿嘧啶/亚叶酸治疗的患者,接受氟尿嘧啶/亚叶酸联合Onivyde治疗的患者其肿瘤生长较慢。接受氟尿嘧啶/亚叶酸联合Onivyde治疗的患者其肿瘤生长平均时间为3.1个月，而仅接受氟尿嘧啶/亚叶酸治疗的患者为1.5个月。
通过对398名分别接受了氟尿嘧啶/亚叶酸联合Onivyde、氟尿嘧啶/亚叶酸、或Onivyde单独治疗中的患者，我们借此评估了Onivyde的安全性。使用Onivyde治疗最常见的副作用为腹泻、乏力、呕吐、恶心、食欲减退、口腔炎和发热。同时也有发现Onivyde会导致抗炎细胞（淋巴细胞和中性粒细胞）的减少。Onivyde治疗导致患者死亡的原因主要是中性粒细胞减少引发的败血症。
Onivyde的标签上标有黑框警告，告诫卫生保健人员该药物可能会引起严重的中性粒细胞减少和腹泻风险。不推荐单独使用Onivyde来治疗胰腺癌转移。该药由马萨诸塞州剑桥的Merrimack制药公司销售。
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ONIVYDE™ safely and effectively. See full prescribing information for ONIVYDE™
ONIVYDE™ (irinotecan liposome injection) , for intravenous use
Initial U.S. Approval: 1996
WARNING: SEVERE NEUTROPENIA AND SEVERE DIARRHEA
See full prescribing information for complete boxed warning
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Fatal neutropenic sepsis occurred in 0.8% of patients receiving ONIVYDE. Severe or life-threatening neutropenic fever or sepsis occurred in 3% and severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE in combination with fluorouracil and leucovorin. Withhold ONIVYDE for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment (2.2), (5.1).
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Severe diarrhea occurred in 13% of patients receiving ONIVYDE in combination with fluorouracil and leucovorin. Do not administer ONIVYDE to patients with bowel obstruction. Withhold ONIVYDE for diarrhea of Grade 2-4 severity. Administer loperamide for late diarrhea of any severity. Administer atropine, if not contraindicated, for early diarrhea of any severity (2.2), (5.2).
INDICATIONS AND USAGE
ONIVYDE is a topoisomerase inhibitor indicated, in combination with fluorouracil and leucovorin, for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. ( 1)
Limitation of Use: ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas. ( 1)
DOSAGE AND ADMINISTRATION
Do not substitute ONIVYDE for other drugs containing irinotecan HCl. (2.1)
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Recommended dose of ONIVYDE is 70 mg/m 2 intravenous infusion over 90 minutes every two weeks. ( 2.2)
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Recommended starting dose of ONIVYDE in patients homozygous for UGT1A1*28 is 50 mg/m 2 every two weeks. ( 2.2)
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There is no recommended dose of ONIVYDE for patients with serum bilirubin above the upper limit of normal.
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Premedicate with a corticosteroid and an anti-emetic. 30 minutes prior to ONIVYDE. ( 2.2)
DOSAGE FORMS AND STRENGTHS
Injection: 43 mg/10 mL single dose vial (3)
CONTRAINDICATIONS
Severe hypersensitivity reaction to ONIVYDE or irinotecan HCl. ( 4, 5.4)
WARNINGS AND PRECAUTIONS
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Interstitial lung disease (ILD): Fatal ILD has occurred in patients receiving irinotecan HCl. Discontinue ONIVYDE if ILD is diagnosed. ( 5.3)
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Severe hypersensitivity reaction: Permanently discontinue ONIVYDE for severe hypersensitivity reactions. ( 5.4, 4)
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Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.5, 8.1, 8.3)
ADVERSE REACTIONS
The most common adverse reactions (≥ 20%) of ONIVYDE: diarrhea, fatigue/asthenia, vomiting, nausea, decreased appetite, stomatitis, and pyrexia. The most common laboratory abnormalities (≥ 10% Grade 3 or 4) were lymphopenia and neutropenia. ( 6)
To report SUSPECTED ADVERSE REACTIONS, contact Merrimack Pharmaceuticals, Inc. at 1-844-441-6225 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
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Strong CYP3A4 Inducers: Avoid the use of strong CYP3A4 inducers if possible. Substitute non-enzyme inducing therapies at least 2 weeks prior to initiation of ONIVYDE. ( 7.1)
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Strong CYP3A4 Inhibitors: Avoid the use of strong CYP3A4 or UGT1A1 inhibitors, if possible; discontinue strong CYP3A4 inhibitors at least 1 week prior to starting therapy. ( 7.2)
USE IN SPECIFIC POPULATIONS
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Lactation: Do not breastfeed. ( 8.2)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 10/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
ONIVYDE ™ is indicated, in combination with fluorouracil and leucovorin, for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy.
Limitation of Use: ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas [see Clinical Studies (14)].
2 DOSAGE AND ADMINISTRATION
2.1 Important Use Information
DO NOT SUBSTITUTE ONIVYDE for other drugs containing irinotecan HCl.
2.2 Recommended Dose
Administer ONIVYDE prior to leucovorin and fluorouracil [see Clinical Studies (14)].
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The recommended dose of ONIVYDE is 70 mg/m 2 administered by intravenous infusion over 90 minutes every 2 weeks.
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The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m 2 administered by intravenous infusion over 90 minutes. Increase the dose of ONIVYDE to 70 mg/m 2 as tolerated in subsequent cycles.
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There is no recommended dose of ONIVYDE for patients with serum bilirubin above the upper limit of normal [see Adverse Reactions (6.1) and Clinical Studies (14)].
Premedication
Administer a corticosteroid and an anti-emetic 30 minutes prior to ONIVYDE infusion.
2.3 Dose Modifications for Adverse Reactions
For recommended dose modifications of fluorouracil (5-FU) or leucovorin (LV), refer to the Full Prescribing Information; refer to Clinical Studies ( 14).
2.4 Preparation and Administration
ONIVYDE is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1
Preparation
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Withdraw the calculated volume of ONIVYDE from the vial. Dilute ONIVYDE in
500 mL 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP and mix diluted solution by gentle inversion.
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Protect diluted solution from light.
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Administer diluted solution within 4 hours of preparation when stored at room temperature or within 24 hours of preparation when stored under refrigerated conditions [2ºC to 8ºC (36ºF to 46ºF)]. Allow diluted solution to come to room temperature prior to administration.
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Do NOT freeze.
Administration
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Infuse diluted solution intravenously over 90 minutes. Do not use in-line filters. Discard unused portion.
3 DOSAGE FORMS AND STRENGTHS
Injection: 43 mg/10 mL irinotecan free base as a white to slightly yellow, opaque, liposomal dispersion in a single-dose vial.
4 CONTRAINDICATIONS
ONIVYDE is contraindicated in patients who have experienced a severe hypersensitivity reaction to ONIVYDE or irinotecan HCl.
5 WARNINGS AND PRECAUTIONS
5.1 Severe Neutropenia
ONIVYDE can cause severe or life-threatening neutropenia and fatal neutropenic sepsis. In Study 1, the incidence of fatal neutropenic sepsis was 0.8% among patients receiving ONIVYDE, occurring in one of 117 patients in the ONIVYDE plus fluorouracil/leucovorin (ONIVYDE/5-FU/LV) arm and one of 147 patients receiving ONIVYDE as a single agent. Severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE/5-FU/LV compared to 2% of patients receiving fluorouracil/leucovorin alone (5-FU/LV). Grade 3 or 4 neutropenic fever/neutropenic sepsis occurred in 3% of patients receiving ONIVYDE/5-FU/LV, and did not occur in patients receiving 5-FU/LV.
In patients receiving ONIVYDE/5-FU/LV, the incidence of Grade 3 or 4 neutropenia was higher among Asian patients [18 of 33 (55%)] compared to White patients [13 of 73 (18%)]. Neutropenic fever/neutropenic sepsis was reported in 6% of Asian patients compared to 1% of White patients [see Clinical Pharmacology (12.3)].
Monitor complete blood cell counts on Days 1 and 8 of every cycle and more frequently if clinically indicated. Withhold ONIVYDE if the absolute neutrophil count (ANC) is below 1500/mm 3 or if neutropenic fever occurs. Resume ONIVYDE when the ANC is 1500/mm 3 or above. Reduce ONIVYDE dose for Grade 3-4 neutropenia or neutropenic fever following recovery in subsequent cycles [see Dosage and Administration (2.2)].
5.2 Severe Diarrhea
ONIVYDE can cause severe and life-threatening diarrhea. Do not administer ONIVYDE to patients with bowel obstruction.
Severe or life-threatening diarrhea followed one of two patterns: late onset diarrhea (onset more than 24 hours following chemotherapy) and early onset diarrhea (onset within 24 hours of chemotherapy, sometimes occurring with other symptoms of cholinergic reaction) [see Cholinergic Reactions (6.1)]. An individual patient may experience both early and late-onset diarrhea.
In Study 1, Grade 3 or 4 diarrhea occurred in 13% receiving ONIVYDE/5-FU/LV compared to 4% receiving 5-FU/LV. The incidence of Grade 3 or 4 late onset diarrhea was 9% in patients receiving ONIVYDE/5-FU/LV, compared to 4% in patients receiving 5-FU/LV. The incidence of Grade 3 or 4 early onset diarrhea was 3% in patients receiving ONIVYDE/5-FU/LV, compared to no Grade 3 or 4 early onset diarrhea in patients receiving 5-FU/LV. Of patients receiving ONIVYDE/5-FU/LV in Study 1, 34% received loperamide for late-onset diarrhea and 26% received atropine for early-onset diarrhea. Withhold ONIVYDE for Grade 2-4 diarrhea. Initiate loperamide for late onset diarrhea of any severity. Administer intravenous or subcutaneous atropine 0.25 to 1 mg (unless clinically contraindicated) for early onset diarrhea of any severity. Following recovery to Grade 1 diarrhea, resume ONIVYDE at a reduced dose [see Dosage and Administration (2.2)].
5.3 Interstitial Lung Disease
Irinotecan HCl can cause severe and fatal interstitial lung disease (ILD). Withhold ONIVYDE in patients with new or progressive dyspnea, cough, and fever, pending diagnostic eva luation. Discontinue ONIVYDE in patients with a confirmed diagnosis of ILD.
5.4 Severe Hypersensitivity Reaction
Irinotecan HCl can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction.
5.5 Embryo-Fetal Toxicity
Based on animal data with irinotecan HCl and the mechanism of action of ONIVYDE, ONIVYDE can cause fetal harm when administered to a pregnant woman. Embryotoxicity and teratogenicity were observed following treatment with irinotecan HCl, at doses resulting in irinotecan exposures lower than those achieved with ONIVYDE 70 mg/m 2 in humans, administered to pregnant rats and rabbits during organogenesis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ONIVYDE and for one month following the final dose [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].
6 ADVERSE REACTIONS
The following adverse drug reactions are discussed in greater detail in other sections of the label:
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of ONIVYDE cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice.
The safety data described below are derived from patients with metastatic adenocarcinoma of the pancreas previously treated with gemcitabine-based therapy who received any part of protocol-specified therapy in Study 1, an international, randomized, active-controlled, open-label trial. Protocol-specified therapy consisted of ONIVYDE 70 mg/m 2 with leucovorin 400 mg/m 2 and fluorouracil 2400 mg/m 2 over 46 hours every 2 weeks (ONIVYDE/5-FU/LV; N=117), ONIVYDE 100 mg/m 2 every 3 weeks (N=147), or leucovorin 200 mg/m 2 and fluorouracil 2000 mg/m 2 over 24 hours weekly for 4 weeks followed by 2 week rest (5-FU/LV; N=134) [see Clinical Studies (14)]. Serum bilirubin within the institutional normal range, albumin ≥ 3 g/dL, and Karnofsky Performance Status (KPS) ≥ 70 were required for study entry. The median duration of exposure was 9 weeks in the ONIVYDE/5-FU/LV arm, 9 weeks in the ONIVYDE monotherapy arm, and 6 weeks in the 5-FU/LV arm.
The most common adverse reactions (≥ 20%) of ONIVYDE were diarrhea, fatigue/asthenia, vomiting, nausea, decreased appetite, stomatitis, and pyrexia. The most common, severe laboratory abnormalities (≥ 10% Grade 3 or 4) were lymphopenia and neutropenia. The most common serious adverse reactions (≥ 2%) of ONIVYDE were diarrhea, vomiting, neutropenic fever or neutropenic sepsis, nausea, pyrexia, sepsis, dehydration, septic shock, pneumonia, acute renal failure, and thrombocytopenia.
Adverse reactions led to permanent discontinuation of ONIVYDE in 11% of patients receiving ONIVYDE/5-FU/LV; the most frequent adverse reactions resulting in discontinuation of ONIVYDE were diarrhea, vomiting, and sepsis. Dose reductions of ONIVYDE for adverse reactions occurred in 33% of patients receiving ONIVYDE/5-FU/LV; the most frequent adverse reactions requiring dose reductions were neutropenia, diarrhea, nausea, and anemia. ONIVYDE was withheld or delayed for adverse reactions in 62% of patients receiving ONIVYDE/5-FU/LV; the most frequent adverse reactions requiring interruption or delays were neutropenia, diarrhea, fatigue, vomiting, and thrombocytopenia.
Table 2 provides the frequency and severity of adverse reactions in Study 1 that occurred with higher incidence (≥5% difference for Grades 1-4 or ≥2% difference for Grades 3-4) in patients who received ONIVYDE/5-FU/LV compared to patients who received 5-FU/LV.
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