2015年2月23日，美国食品和药物管理局（FDA）加速批准了Panobinostat（帕比司他，商品名FARYDAK，瑞士诺华制药公司生产）联合硼替佐米和地塞米松用于治疗已经接受过包括硼替佐米和免疫调节剂在内的至少两个方案治疗的多发骨髓瘤。帕比司他是一种组蛋白脱乙酰酶抑制剂。
这项批准是基于一项临床试验的有效结果，该临床试验评估了帕比司他或安慰剂 联合硼替佐米和地塞米松治疗的情况。该研究的主要疗效评估终点是无进展生存期（PFS）。中位PFS在含帕比司他组（帕比司他－ 硼替佐米－地塞米松）和对照组（安慰剂－硼替佐米－地塞米松）分别为10.6和5.8个月。总有效率在帕比司他组和安慰剂组分别为58.5％和41.4％。
在含帕比司他组的最常见不良反应（发生率> 20％）是腹泻、疲劳、恶心、外周水肿、食欲下降、发热和呕吐。严重不良反应包括肺炎、腹泻、血小板减少、疲劳和败血症。最常见的血液学异常包括血小板减少和白细胞减少;最常见的生化异常是低磷血症和低钾血症。64％的含帕比司他组和42％的对照组患者有心电图变化，包括新的T波的改变和ST段压低。帕比司他组相对于对照组发生心律失常的频率更高(12% vs. 5%)。
该药物对患者和医生做了黑框特别提醒：有可能引起严重和致命的心脏毒性和严重腹泻。出血和肝毒性的重要安全相关信息在注意事项部分都有特别提示。
帕比司他的推荐治疗方案
第一阶段治疗：第1－8个周期，每周期为3个星期（总时间为24周）
•帕比司他20mg口服，每日一次，每周三次，每周期使用两周休息一周。
•硼替佐米1.3mg /平米，每周两次静脉注射，每周期使用两周休息一周
•地塞米松20mg，口服，在用硼替佐米的当天和第二天
第二阶段治疗：第9－16个周期，每周期为3个星期（总时间为24周）
患者达到临床获益（评价标准为SD，PR，MR，nCR，或CR），没有严重的持续毒副反应，此时可考虑在修改剂量的基础上继续另外8个周期的治疗。
帕比司他20 mg口服，每日一次，每周三次，每周期使用两周休息一周。
•硼替佐米1.3 mg /平米，每周一次静脉注射，每周期使用两周休息一周
•地塞米松20 mg，口服，在用硼替佐米的当天和第二天

FARYDAK capsules are packaged in PVC/PCTFE blister packs.
10mg  Blister packs containing 6 capsules ………………………….…….NDC 0078-0650-06
15mg  Blister packs containing 6 capsules ………………………….…….NDC 0078-0651-06
20mg  Blister packs containing 6 capsules ………………………….…….NDC 0078-0652-06

FARYDAK Rx
Pharmacological Class:
Histone deacetylase (HDAC) inhibitor.

Active Ingredient(s):
Panobinostat 10mg, 15mg, 20mg; capsules.

Company
Novartis Pharmaceuticals Corp
Indication(s):
Multiple myeloma, in patients who have received at least two prior regimens (including bortezomib and an immunomodulatory agent), in combination with bortezomib and dexamethasone.

Pharmacology:
Panobinostat inhibits the enzymatic activity of HDACs at nanomolar concentrations which results in increased acetylation of histone proteins, leading to transcriptional activation. Accumulation of acetylated histones and other proteins induces cell cycle arrest and/or apoptosis of some transformed cells.

Clinical Trials:
The efficacy and safety of Farydak with bortezomib and dexamethasone was eva luated in a randomized, double-blind, placebo-controlled, multicenter study in 768 patients with relapsed multiple myeloma who had received 1–3 prior lines of therapy. Patients were randomized to bortezomib and dexamethasone with Farydak or placebo. The primary endpoint was progression-free survival (PFS). A prespecified subgroup analysis (n=193) showed the benefit:risk was greater in this heavily pretreated population than the overall trial population. The median PFS was 10.6 months in the Farydak arm vs. 5.8 months in the placebo arm (HR 0.52; [95% CI: 0.36, 0.76]).

For more clinical trial data, see full labeling.

Legal Classification:
Rx

Adults:
Swallow whole with water. Take at same time on scheduled days. Initially 20mg once every other day for 3 doses/wk in Weeks 1 and 2 of each 21-day cycle for up to 8 cycles. Consider 8 more cycles for patients with clinical benefit if no severe or significant toxicity; max 16 cycles (48 wks). Give with bortezomib inj and oral dexamethasone per scheduled day. Hepatic impairment: mild: initially 15mg; moderate: initially 10mg; severe: avoid. Concomitant strong CYP3A inhibitors: initially 10mg. Dose adjustments and modifications for toxicity: see full labeling.

Children:
Not established.

Warnings/Precautions:
Risk of severe diarrhea and cardiac toxicities. Monitor hydration and electrolytes at baseline, weekly during therapy, or more as indicated. Initiate antidiarrheals at onset of diarrhea; interrupt dose if 4–6 stools/day. Do not initiate if history of recent MI or unstable angina, QTcF >450msec, significant baseline ST-segment or T-wave abnormalities, active infections. Perform ECG prior to initiation and repeat during treatment as indicated. Correct electrolyte abnormalities prior to initiation and monitor; interrupt if QTcF ≥480msec; discontinue if QT prolongation does not resolve. Serious hemorrhage. Obtain CBC prior to initiation; monitor weekly during therapy or more as indicated. Monitor for infections; treat and consider interruption or discontinuation if diagnosed. Monitor liver function prior to and during treatment; consider dose adjustments if abnormal tests observed. ESRD or dialysis: not studied. Elderly: monitor for toxicity more frequently (esp. GI, myelosuppression, cardiac). Pregnancy: avoid. Obtain pregnancy test prior to and during treatment. Use effective contraception during and for ≥1 month after last dose; males: use condoms during and for ≥3 months after last dose. Nursing mothers: not recommended.

Interaction(s)
Potentiated by strong CYP3A inhibitors (eg, boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, others); see Adults. Avoid star fruit, pomegranate or grapefruit juice. Avoid concomitant strong CYP3A inducers. Avoid concomitant sensitive CYP2D6 substrates (eg, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine) or substrates with narrow therapeutic index (eg, thioridazine, pimozide); if unavoidable, monitor frequently. Concomitant antiarrhythmics or QT prolonging drugs: not recommended. Antiemetics that prolong QT interval (eg, dolasetron, ondansetron, tropisetron): monitor ECG frequently.

Adverse Reaction(s)
Diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia, vomiting, electrolyte imbalance, increased creatinine, thrombocytopenia, lymphopenia, leukopenia, neutropenia, anemia.

How Supplied:
Blister packs—6

LAST UPDATED:
6/12/2015