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新型抗癌药IBRANCE(PALBOCICLIB CAPSULE 帕博西尼胶囊) 获-FDA加速批准首个细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂与来曲唑联合应用转移性乳腺癌的一线治疗
2015年2月3日,FDA加速批准辉瑞公司上市的抗癌新药IBRANCE（palbociclib）联合来曲唑作为内分泌基础的一线疗法，治疗绝经期女性雌激素受体2阴性的晚期乳腺癌患者。
Palbociclib较来曲唑可使乳腺癌无进展生存期延长一倍，是乳腺癌患者的新希望，疗效获得突破,完全可以取代来曲唑的临床用药。
Palbociclib是全球首个CDK4/6激酶抑制剂上市，palbociclib是一种实验性、口服、靶向性CDK4/6抑制剂，能够选择性抑制细胞周期蛋白依赖性激酶4和6（CDK4/6），恢复细胞周期控制，阻断肿瘤细胞增殖。
细胞周期失控是癌症的一个标志性特征，CDK4/6在许多癌症中均过度活.
（1）新作用机制:palbociclib是一种口服、靶向性CDK4/6抑制剂，能够选择性抑制细胞周期蛋白依赖性激酶4和6（CDK4/6），恢复细胞周期控制，阻断肿瘤细胞增殖。细胞周期失控是癌症的一个标志性特征，CDK4/6 在许多癌症中均过度活。
（2）临床疗效好:palbociclib较来曲唑可使乳腺癌无进展生存期延长一倍，是乳腺癌患者的新希望，疗效获得突破。
（3）不良反应发生率低:palbociclib是胶囊剂，口服即可，与注射剂相比，安全性高，便于患者服用，提高患者依从性。此外这种药并没有传统化疗的副作用，如骨髓抑制和肠道反应等较轻微 。
（4）靶向性强:由于肿瘤细胞Cyclin D水平升高，能够增加细胞对药物的敏感性，增加药物的靶向性的疗效优异。
常规给药：Ibrance的推荐剂量为125毫克每日口服一次，连续服用21天，停药7天，总共28天一周期。Ibrance应与食物共同服用，并联合来曲唑2.5毫克，每日一次。
Ibrance 100mg-Kapseln-PFIZER LABORATORIES DIVISION-USA-Vereinigte Staaten von Amerika
Ibrance 125mg-Kapseln-PFIZER LABORATORIES DIVISION-USA-Vereinigte Staaten von Amerika
Ibrance 75mg-Kapseln-PFIZER LABORATORIES DIVISION-USA-Vereinigte
IBRANCE(palbociclib) Capsules
Generic Name: palbociclib
Date of Approval: February 3, 2015
Company: Pfizer Inc.
Treatment for: Breast Cancer
IBRANCE Rx
Generic Name and Formulations:
Palbociclib 75mg, 100mg, 125mg; capsules.
Company:
Pfizer Inc.
Indications for IBRANCE:
In combination with letrozole, for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for metastatic disease.
Adult:
Swallow whole. Take with food. 125mg once daily for 21 days followed by 7 days off to complete a 28-day cycle, in combination with letrozole 2.5mg once daily continuously throughout the 28-day cycle. Dose modification for adverse reactions: First reduction: 100mg/day; Second dose reduction: 75mg/day; discontinue if <75mg/day required. Dose modification for hematologic or non-hematologic toxicities: see full labeling. Concomitant strong CYP3A inhibitors: avoid and consider alternative drug; if use necessary, reduce palbociclib dose to 75mg.
Children:
Not evaluated.
Pharmacological Class:
Kinase inhibitor.
Warnings/Precautions:
Monitor CBC prior to initiation and at start of each cycle, as well as Day 14 of first 2 cycles, and as clinically indicated. Interrupt, reduce dose, or delay starting treatment cycles if Grade 3 or 4 neutropenia develops. Monitor for signs/symptoms of infection and pulmonary embolism; treat appropriately if develop. Moderate or severe hepatic impairment. Severe renal impairment. Pregnancy: avoid. Use effective contraception during therapy and for at least 2 weeks after last dose. Lactation: discontinue nursing.
Interactions:
Avoid concomitant strong CYP3A inhibitors (eg, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole), grapefruit or grapefruit juice; if unavoidable, reduce dose (see Adults). Avoid concomitant strong CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St. John’s wort) or moderate CYP3A inducers (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin). May potentiate midazolam or other CYP3A substrates with narrow therapeutic index (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, tacrolimus); reduce dose of these drugs.
Adverse Reactions:
Neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, epistaxis.
How Supplied:
Caps—21
IBRANCE® (palbociclib) Receives Approval in European Union for the Treatment of Women with HR+/HER2- Metastatic Breast Cancer
Pfizer Inc. (NYSE:PFE) today announced that the European Commission (EC) has approved IBRANCE® (palbociclib) for the treatment of women with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) locally advanced or metastatic breast cancer. The approval is for IBRANCE to be used in combination with an aromatase inhibitor. The approval also covers the use of IBRANCE in combination with fulvestrant in women who have received prior endocrine therapy.
IBRANCE is the first medicine to be approved in Europe that works by inhibiting cyclin-dependent kinases and 6 (CDK 4/6). It also is the first new medicine approved for the treatment of women with this type of metastatic breast cancer in the first-line setting in nearly 10 years. Women with HR+/HER2- metastatic breast cancer represent about 60 percent of all metastatic breast cancer cases.
“Today’s approval of IBRANCE in the European Union (EU) brings an innovative and much-needed new treatment option to tens of thousands of women with HR+/HER2- metastatic breast cancer,” said Andreas Penk, M.D., regional president, International Developed Markets, Pfizer Oncology. “With strong and consistent data in three pivotal clinical studies and rapid adoption as a standard of care in the U.S., IBRANCE represents a potential new benchmark for the treatment of HR+/HER2- metastatic breast cancer in Europe.”
The EC approval is based on a robust submission package including results from the Phase 2 PALOMA-1 trial in postmenopausal women with estrogen receptor-positive (ER+)/HER2- metastatic breast cancer who had not received prior systemic therapy for their advanced disease, the Phase 3 PALOMA-2 trial in the same population and the Phase 3 PALOMA-3 trial in women with HR+/HER2- metastatic breast cancer who had progressed on prior endocrine therapy. All three randomized trials demonstrated that IBRANCE in combination with an endocrine therapy significantly prolonged progression-free survival (PFS) compared to endocrine therapy alone or endocrine therapy with placebo.
Breast cancer is the most common invasive cancer among women in Europe, with more than 464,200 new cases and 131,260 deaths per year.2 Up to 30 percent of women diagnosed with and treated for early breast cancer will go on to develop metastatic breast cancer,3,4 which occurs when the cancer spreads beyond the breast to other parts of the body.5 There is no cure for metastatic breast cancer,6 and patients are in need of new treatment options that help keep their cancer from worsening, manage symptoms and help them maintain quality of life for as long as possible.3,5
“Palbociclib is an exciting advance in the management of women with hormone receptor-positive breast cancer. Patients with this type of breast cancer are usually treated with hormone therapy but many will progress or relapse – and as a result require chemotherapy, which often comes with life-limiting side-effects,” said Nicholas Turner, M.D., Ph.D., team leader at The Institute of Cancer Research, London, and consultant medical oncologist at The Royal Marsden NHS Foundation Trust, as well as principal investigator of the PALOMA-3 trial. “Palbociclib, when used in combination with standard hormone therapy, increases the duration of tumor control and is well tolerated by most women – and could delay the need for women with this type of advanced breast cancer to start chemotherapy.”
“Metastatic breast cancer patients in Europe need new treatment options available to them,” said Kathi Apostolidis, two-time breast cancer survivor and vice president of the European Cancer Patient Coalition. “Metastatic breast cancer places a heavy burden on cancer patients and their families, but patients hope that novel treatments may have the potential to provide better quality of life and outcomes.”
About the IBRANCE Pivotal Trials
PALOMA-1
The Phase 2 PALOMA-1 trial evaluated IBRANCE in combination with letrozole compared with letrozole alone as a first-line, or initial, therapy in 165 postmenopausal women with ER+/HER2- advanced breast cancer who had not received previous systemic treatment for their advanced disease. The combination of IBRANCE plus letrozole significantly prolonged PFS compared to letrozole alone (HR=0.488 [95% CI: 0.319–0.748]), with the median PFS of 20.2 months (95% CI: 13.8–27.5) in the IBRANCE arm compared to 10.2 months (95% CI: 5.7–12.6) in women who received letrozole alone. The most common adverse events (≥20%) of any grade reported in patients treated with IBRANCE plus letrozole versus letrozole alone included neutropenia (75% vs 5%), leukopenia (43% vs 3%), fatigue (41% vs 23%), anemia (35% vs 7%), upper respiratory infection (31% vs 18%), nausea (25% vs 13%), stomatitis (25% vs 7%), alopecia (22% vs 3%) and diarrhea (21% vs 10%).7
PALOMA-2
The Phase 3 PALOMA-2 trial evaluated IBRANCE in combination with letrozole compared with letrozole plus placebo as a first-line treatment in 666 postmenopausal women with ER+/HER2- metastatic breast cancer, the same patient population as PALOMA-1. The combination of IBRANCE plus letrozole resulted in a statistically significant improvement in PFS (HR=0.58 [95% CI: 0.46–0.72], P<0.000001), with a median PFS of 24.8 months compared to 14.5 months for those who were treated with letrozole plus placebo. The most common adverse events (≥20%) of any grade reported in patients treated with IBRANCE plus letrozole versus letrozole plus placebo included neutropenia (79.5% vs 6.3%), fatigue (37.4% vs 27.5%), nausea (35.1% vs 26.1%), arthralgia (33.3% vs 33.8%) and alopecia (32.9% vs 15.8%).8
PALOMA-3
The Phase 3 PALOMA-3 trial evaluated IBRANCE in combination with fulvestrant compared with placebo plus fulvestrant in 521 women with HR+/HER2- metastatic breast cancer, regardless of menopausal status, whose disease progressed on or after prior endocrine therapy. The combination of IBRANCE plus fulvestrant substantially improved PFS compared to fulvestrant plus placebo (HR=0.461 [95% CI: 0.360–0.591), P<0.0001), with a median PFS of 9.5 months (95% CI: 9.2–11.0) in the IBRANCE arm compared to 4.6 months (95% CI: 3.5–5.6) in women who received placebo plus fulvestrant. The most common adverse events (≥20%) of any grade reported in PALOMA-3 of IBRANCE plus fulvestrant versus placebo plus fulvestrant included neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), headache (26% vs 20%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%) and constipation (20% vs 16%).7
About IBRANCE® (palbociclib)
IBRANCE is an oral inhibitor of cyclin-dependent kinases 4 and 6,7 which are key regulators of the cell cycle that trigger cellular progression.9,10 With this latest regulatory milestone, IBRANCE now is approved in more than 50 countries.
IBRANCE® (palbociclib) INDICATIONS AND IMPORTANT SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION
IBRANCE is indicated in the U.S. for the treatment of HR+, HER2- advanced or metastatic breast cancer in combination with letrozole as initial endocrine based therapy in postmenopausal women, or fulvestrant in women with disease progression following endocrine therapy. The indication in combination with letrozole is approved under accelerated approval based on PFS. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Neutropenia was the most frequently reported adverse reaction in PALOMA-1 (75%) and PALOMA-3 (83%). In PALOMA-1, Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In PALOMA-3, Grade 3 (56%) or Grade 4 (11%) decreased neutrophil counts were reported in patients receiving IBRANCE plus fulvestrant. Febrile neutropenia has been reported in about 1% of patients exposed to IBRANCE. One death due to neutropenic sepsis was observed in PALOMA-3. Inform patients to promptly report any fever.
Monitor complete blood count prior to starting IBRANCE, at the beginning of each cycle, on Day 14 of first 2 cycles, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.
Pulmonary embolism (PE) has been reported at a higher rate in patients treated with IBRANCE plus letrozole in PALOMA-1 (5%) and in patients treated with IBRANCE plus fulvestrant in PALOMA-3 (1%) compared with no cases in patients treated either with letrozole alone or fulvestrant plus placebo. Monitor for signs and symptoms of PE and treat as medically appropriate.
Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females of reproductive potential to use effective contraception during IBRANCE treatment and for at least 3 weeks after the last dose. IBRANCE may impair fertility in males and has the potential to cause genotoxicity. Advise male patients with female partners of reproductive potential to use effective contraception during IBRANCE treatment and for 3 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise women not to breastfeed during IBRANCE treatment and for 3 weeks after the last dose because of the potential for serious adverse reactions in nursing infants.
The most common adverse reactions (≥10%) of any grade reported in PALOMA-1 of IBRANCE plus letrozole vs letrozole alone included neutropenia (75% vs 5%), leukopenia (43% vs 3%), fatigue (41% vs 23%), anemia (35% vs 7%), upper respiratory infection (31% vs 18%), nausea (25% vs 13%), stomatitis (25% vs 7%), alopecia (22% vs 3%), diarrhea (21% vs 10%), thrombocytopenia (17% vs 1%), decreased appetite (16% vs 7%), vomiting (15% vs 4%), asthenia (13% vs 4%), peripheral neuropathy (13% vs 5%), and epistaxis (11% vs 1%).
Grade 3/4 adverse reactions (≥10%) in PALOMA-1 reported at a higher incidence in the IBRANCE plus letrozole group vs the letrozole alone group included neutropenia (54% vs 1%) and leukopenia (19% vs 0%). The most frequently reported serious adverse events in patients receiving IBRANCE plus letrozole were pulmonary embolism (4%) and diarrhea (2%).
Lab abnormalities occurring in PALOMA-1 (all grades, IBRANCE plus letrozole vs letrozole alone) were decreased WBC (95% vs 26%), decreased neutrophils (94% vs 17%), decreased lymphocytes (81% vs 35%), decreased hemoglobin (83% vs 40%), and decreased platelets (61% vs 16%).
The most common adverse reactions (≥10%) of any grade reported in PALOMA-3 of IBRANCE plus fulvestrant vs fulvestrant plus placebo included neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), headache (26% vs 20%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), constipation (20% vs 16%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%).
Grade 3/4 adverse reactions (≥10%) in PALOMA-3 reported at a higher incidence in the IBRANCE plus fulvestrant group vs the fulvestrant plus placebo group included neutropenia (66% vs 1%) and leukopenia (31% vs 2%). The most frequently reported serious adverse reactions in patients receiving IBRANCE plus fulvestrant were infections (3%), pyrexia (1%), neutropenia (1%), and pulmonary embolism (1%).
Lab abnormalities occurring in PALOMA-3 (all grades, IBRANCE plus fulvestrant vs fulvestrant plus placebo) were decreased WBC (99% vs 26%), decreased neutrophils (96% vs 14%), anemia (78% vs 40%), and decreased platelets (62% vs 10%).
Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg/day. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided. Avoid concomitant use of strong CYP3A inducers. The dose of sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure.
IBRANCE has not been studied in patients with moderate to severe hepatic impairment or in patients with severe renal impairment (CrCl <30 mL/min).
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