英文药名：Farydak(panobinostat capsules) 中文药名：帕比司他胶囊 生产厂家：诺华制药 药品介绍 2015年2月23日，首个治疗多发性骨髓瘤的HDAC抑制剂帕比司他(Panobinostat；商品名Farydak)获美国FDA批准上市 Farydak是一种新型、广谱组蛋白脱乙酰酶（HDAC）抑制剂，具有一种新的作用机制，通过阻断组蛋白脱乙酰酶（HDAC）发挥作用，该药能够对癌细胞施以严重的应激直至其死亡，而健康细胞则不受影响。用于既往接受至少2种治疗方案（包括Velcade和一种免疫调节（IMiD）药物）治疗失败的多发性骨髓瘤（myltiple myeloma，MM）患者群体。 商品名称：Farydak 通用名称：panobinostat 中文名称：帕比司他 给药途径：口服 美国初次批准：2015年 适应证和用途 Farydak（panobinostat）联合Velcade（bortezomib，硼替佐米）和地塞米松（dexamethasone）用于既往接受至少2种治疗方案（包括Velcade和一种免疫调节（IMiD）药物）治疗失败的多发性骨髓瘤（myltiple myeloma，MM）患者群体。 Farydak（panobinostat）是一种新型、广谱组蛋白脱乙酰酶（HDAC）抑制剂，具有一种新的作用机制，通过阻断组蛋白脱乙酰酶（HDAC）发挥作用，该药能够对癌细胞施以严重的应激直至其死亡，而健康细胞则不受影响。 剂量和给药方法 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: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1.3 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 剂型和规格 胶囊：10mg，15mg，20mg 禁忌证 无 警告和注意事项 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。 不良反应 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%)。 临床试验 在193例临床试验多发性骨髓瘤参加者，接受至少两次以前治疗包括硼替佐米和一种免疫调节剂，证实Farydak与硼替佐米和地塞米松联用的安全性和疗效。参加者被随机地赋予接受一种Farydak，硼替佐米和地塞米松联用，或单独硼替佐米和地塞米松。 研究结果显示参加者接受Farydak组合见到其疾病进展延缓(无进展生存)共约10.6个月，与之比较用单独硼替佐米和地塞米松治疗参加者至5.8个月。此外，59 %的Farydak-治疗参加者见到治疗后其癌皱缩或消失(反应率)，相比接受硼替佐米和地塞米松参加者为41%。 在特殊人群中使用 肝损害：减少轻度或中度肝损害患者farydak的剂量，避免严重肝功能损害的患者使用。 贮存和处置 储存在20°～25°，允许在15°C和30°C之间的偏移。在原包装盒中储存水泡包，以防光照。 Farydak胶囊不应分离、粉碎或咀嚼，避免皮肤或粘膜与farydak胶囊粉直接接触。如果有接触发生，应当彻底清洗。应避免接触破碎的胶囊。 Farydak (panobinostat) for the Treatment of Multiple Myeloma Farydak (panobinostat, previously known as LBH589) is a histone deacetylase (HDAC) inhibitor indicated for the treatment of patients with multiple myeloma. The drug was discovered and developed by Novartis. 2015, Novartis received approval from US Food and Drug Administration (FDA) for Farydak in combination with bortezomib and dexamethasone for the treatment of multiple myeloma patients who previously received at least two regimens including bortezomib and an immunomodulatory (IMiD) agent. Multiple myeloma Multiple myeloma, also known as plasma cell myeloma, is the second most common blood cancer, which emanates in the plasma cells in bone marrow. It results in plasma cells producing antibodies and also restrains production of normal blood cells. It is estimated that one to five in every 100,000 people worldwide are affected by multiple myeloma. The National Cancer Institute estimates that approximately 21,700 people in the US are diagnosed with multiple myeloma every year, of which 10,710 die from the disease. Farydak's mechanism of action Farydak contains a histone deacetylase (HDAC) inhibitor that restrains the enzymatic activity of HDACs at nanomolar concentrations. The drug shows more cytotoxicity towards tumour cells compared to normal cells. It is available in 20mg dosed capsules for oral administration. Clinical trials on Farydak Marketing approval for Farydak by the FDA was based on results obtained from a Phase III clinical trial. The randomised, double blind, placebo-controlled, multicentre clinical study enrolled 768 patients with relapsed multiple myeloma that received one to three prior lines of therapy. Patients were administered with either bortezomib, dexamethasone in addition to Farydak 20mg, or placebo plus bortezomib and dexamethasone. The treatment was continued for a maximum of 16 cycles (48 weeks). The primary endpoint of the study was progression-free survival (PFS), which was assessed through modified European Bone Marrow Transplant Group (EBMT) criteria. Results of the study demonstrated the median PFS in the Farydak, bortezomib, dexamethasone treatment arm was 12 months, whereas it was 8.1 months in the placebo plus bortezomib and dexamethasone arm. Farydak's safety and efficacy were evaluated in a prespecified subgroup analysis of 193 patients who received prior treatment with both bortezomib and an immunomodulatory agent and a median of two prior therapies. Results of the study showed the median PFS was 10.6 months in the patients treated with Farydak, bortezomib, and dexamethasone and 5.8 months in the placebo plus bortezomib and dexamethasone arm. Adverse effects associated with the use of Farydak in the clinical study included diarrhoea, fatigue, nausea, peripheral oedema, decreased appetite, pyrexia and vomiting. Farydak Description FARYDAK (panobinostat lactate) is a histone deacetylase inhibitor. FARYDAK capsules contain 10 mg, 15 mg, or 20 mg panobinostat free base. The inactive ingredients are magnesium stearate, mannitol, microcrystalline cellulose and pregelatinized starch. The capsules contain gelatin, FD&C Blue 1 (10 mg capsules), yellow iron oxide (10 mg and 15 mg capsules), red iron oxide (15 mg and 20 mg capsules) and titanium dioxide. WARNING: FATAL AND SERIOUS TOXICITIES: SEVERE DIARRHEA AND CARDIAC TOXICITIES Severe diarrhea occurred in 25% of panobinostat treated patients. Monitor for symptoms, institute antidiarrheal treatment, interrupt panobinostat and then reduce dose or discontinue panobinostat. (5.1) Severe and fatal cardiac ischemic events, severe arrhythmias, and ECG changes have occurred in patients receiving panobinostat. Arrhythmias may be exacerbated by electrolyte abnormalities. Obtain ECG and electrolytes at baseline and periodically during treatment as clinically indicated. (5.2) 1. DESCRIPTION  Panobinostat lactate is a histone deacetylase inhibitor. The chemical name of panobinostat lactate is 2-Hydroxypropanoic acid, compd. with 2-(E)-N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide (1:1). The structural formula is: Empirical formula: C21H23N3O2•C3H6O3 - Molecular weight: 439.51 (as a lactate), equivalent to 349.43 (free base) Panobinostat lactate anhydrous is a white to slightly yellowish or brownish powder. Panobinostat lactate anhydrous is light sensitive. Panobinostat lactate anhydrous is both chemically and thermodynamically a stable crystalline form with no polymorphic behavior. Panobinostat free base is not chiral and shows no specific optical rotation. Panobinostat lactate anhydrous is slightly soluble in water. Solubility of panobinostat lactate anhydrous is pH-dependent, with the highest solubility in buffer pH 3.0 (citrate). Panobinostat capsules contain 10 mg, 15 mg, or 20 mg panobinostat free base. The inactive ingredients are magnesium stearate, mannitol, microcrystalline cellulose and pregelatinized starch. The capsules contain gelatin, FD&C Blue 1 (10 mg capsules), yellow iron oxide (10 mg and 15 mg capsules), red iron oxide (15 mg and 20 mg capsules) and titanium dioxide. 2. INDICATIONS AND USAGE  Panobinostat, a histone deacetylase inhibitor, in combination with bortezomib and dexamethasone, is indicated for the treatment of patients with multiple myeloma who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent. This indication is approved under accelerated approval based on progression free survival [see Clinical Studies]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. 3. DOSAGE AND ADMINISTRATION  3.1 Recommended Dosing The recommended starting dose of panobinostat is 20 mg, taken orally once every other day for 3 doses per week in Weeks 1 and 2 of each 21-day cycle for up to 8 cycles. Consider continuing treatment for an additional 8 cycles for patients with clinical benefit who do not experience unresolved severe or medically significant toxicity. The total duration of treatment may be up to 16 cycles (48 weeks). Panobinostat is administered in combination with bortezomib and dexamethasone as shown in Table 1 and Table 2. The recommended dose of bortezomib is 1.3 mg/m2 given as an injection. The recommended dose of dexamethasone is 20 mg taken orally per scheduled day, on a full stomach. Table 1: Recommended Dosing Schedule of Panobinostat in Combination with Bortezomib and Dexamethasone During Cycles 1 to 8 Table 2: Recommended Dosing Schedule of Panobinostat in Combination with Bortezomib and Dexamethasone During Cycles 9 to 16 3.2 Administration and Monitoring Instructions Panobinostat should be taken orally once on each scheduled day at about the same time, either with or without food [see Clinical Pharmacology]. Panobinostat capsules should be swallowed whole with a cup of water. Do not open, crush, or chew the capsules [see How Supplied/Storage and Handling (13)]. If a dose is missed it can be taken up to 12 hours after the specified dose time. If vomiting occurs the patient should not repeat the dose, but should take the next usual scheduled dose. Counsel patients on the correct dosing schedule, technique of administration of panobinostat, and when to take panobinostat if dosing adjustments are made. Prior to the start of panobinostat treatment and during treatment, monitoring should include: • Complete Blood Count (CBC): Obtain a CBC before initiating treatment. Verify that the baseline platelet count is at least 100 x 109/L and the baseline absolute neutrophil count (ANC) is at least 1.5 x 109/L. Monitor the CBC weekly (or more often as clinically indicated) during treatment. [see Warnings and Precautions (5.4) Adverse Reactions (6.1)]. • ECG: Perform an ECG prior to the start of therapy and repeat periodically during treatment as clinically indicated. Verify that the QTcF is less than 450 msec prior to initiation of treatment with panobinostat. If during treatment with panobinostat, the QTcF increases to ≥480 msec, interrupt treatment. Correct any electrolyte abnormalities. If QT prolongation does not resolve, permanently discontinue treatment with panobinostat [see Warnings and Precautions (5.2), Adverse Reactions (6.1)]. During the clinical trial, ECGs were performed at baseline and prior to initiation of each cycle for the first 8 cycles. • Serum Electrolytes: Obtain electrolytes, including potassium and magnesium, at baseline and monitor during therapy. Correct abnormal electrolyte values before treatment [see Warnings and Precautions (5.2), Adverse Reactions (6.1)]. During the trial, monitoring was conducted prior to the start of each cycle, at Day 11 of cycles 1 to 8, and at the start of each cycle for cycles 9 to 16. For additional information please refer to the bortezomib and dexamethasone prescribing information. 3.3 Dose Adjustments and Modifications for Toxicity Dose and/or schedule modification of panobinostat may be required based on toxicity. Management of adverse drug reactions may require treatment interruption and/or dose reductions. If dose reduction is required, the dose of panobinostat should be reduced in increments of 5 mg (i.e., from 20 mg to 15 mg, or from 15 mg to 10 mg). If the dosing of panobinostat is reduced below 10 mg given 3 times per week, discontinue panobinostat. Keep the same treatment schedule (3-week treatment cycle) when reducing dose. The table also lists Bortezomib (BTZ) dose modification procedures from the clinical trials. Table 3: Dose Modifications for Most Common Toxicities BTZ = bortezomib ANC = absolute neutrophil count Hb = hemoglobin IV = intravenous Myelosuppression Interrupt or reduce the dose of panobinostat in patients who have thrombocytopenia, neutropenia or anemia according to instructions in Table 3. For patients with severe thrombocytopenia, consider platelet transfusions [see Warnings and Precautions (5.4), Adverse Reactions (6.1)]. Discontinue panobinostat treatment if thrombocytopenia does not improve despite the recommended treatment modifications or if repeated platelet transfusions are required. In the event of Grade 3 or 4 neutropenia, consider dose reduction and/or the use of growth factors (e.g., G-CSF). Discontinue panobinostat if neutropenia does not improve despite dose modifications, colony-stimulating factors, or in case of severe infection. Gastrointestinal Toxicity Gastrointestinal toxicity is common in patients treated with panobinostat. Patients who experience diarrhea, nausea, or vomiting may require treatment interruption or dose reduction (Table 3). At the first sign of abdominal cramping, loose stools, or onset of diarrhea, patients should be treated with anti-diarrheal medication (e.g., loperamide). Consider and administer prophylactic anti-emetics as clinically indicated. Other Adverse Drug Reactions For patients experiencing Grade 3/4 adverse drug reactions other than thrombocytopenia, neutropenia, or gastrointestinal toxicity, the recommendation is the following: • CTC Grade 2 toxicity recurrence and CTC Grade 3 and 4 -omit the dose until recovery to CTC Grade 1 or less and restart treatment at a reduced dose • CTC Grade 3 or 4 toxicity recurrence, a further dose reduction may be considered once the adverse events have resolved to CTC Grade 1 or less. 3.4 Dose Modifications for Use in Hepatic Impairment Reduce the starting dose of panobinostat to 15 mg in patients with mild hepatic impairment and 10 mg in patients with moderate hepatic impairment. Avoid use in patients with severe hepatic impairment. Monitor patients frequently for adverse events and adjust dose as needed for toxicity [see Dosing and Administration (2.2), Warnings and Precautions (5.6), Hepatic Impairment (8.6), Clinical Pharmacology]. 3.5 Dose Modifications for Use with Strong CYP3A Inhibitors Reduce the starting dose of panobinostat to 10 mg when coadministered with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir) [see Drug Interactions (7.1), Clinical Pharmacology]. 4. CONTRAINDICATIONS  None. 5. WARNINGS AND PRECAUTIONS  5.1 Diarrhea Severe diarrhea occurred in 25% of patients treated with panobinostat [see Adverse Reactions (6.1)]. Diarrhea of any grade occurred in 68% of patients treated with panobinostat compared to 42% of patients in the control arm. Diarrhea can occur at any time. Monitor patient hydration status and electrolyte blood levels, including potassium, magnesium and phosphate, at baseline and weekly (or more frequently as clinically indicated) during therapy and correct to prevent dehydration and electrolyte disturbances. Initiate anti-diarrheal medication at the onset of diarrhea. Interrupt panobinostat at the onset of moderate diarrhea (4 to 6 stools per day) [see Dosage and Administration (3.3)]. Ensure that patients initiating therapy with panobinostat have anti-diarrheal medications on hand. 5.2 Cardiac Toxicities Severe and fatal cardiac ischemic events, as well as severe arrhythmias, and electrocardiogram (ECG) changes occurred in patients receiving panobinostat. Arrhythmias occurred in 12% of patients receiving panobinostat, compared to 5% of patients in the control arm. Cardiac ischemic events occurred in 4% of patients treated with panobinostat compared with 1% of patients in the control arm. Do not initiate panobinostat treatment in patients with history of recent myocardial infarction or unstable angina. Electrocardiographic abnormalities such as ST-segment depression and T-wave abnormalities also occurred more frequently in patients receiving panobinostat compared to the control arm: 22% versus 4% and 40% versus 18%, respectively. Panobinostat may prolong cardiac ventricular repolarization (QT interval). Do not initiate treatment with panobinostat in patients with a QTcF >450 msec or clinically significant baseline ST-segment or T-wave abnormalities. Arrhythmias may be exacerbated by electrolyte abnormalities. If during treatment with panobinostat, the QTcF increases to ≥480 msec, interrupt treatment. Correct any electrolyte abnormalities. If QT prolongation does not resolve, permanently discontinue treatment with panobinostat. Obtain ECG at baseline and periodically during treatment as clinically indicated. Monitor electrolytes during treatment with panobinostat and correct abnormalities as clinically indicated. 5.3 Hemorrhage Fatal and serious hemorrhage occurred during treatment with panobinostat. In the clinical trial in patients with relapsed multiple myeloma, 5 patients receiving panobinostat compared to 1 patient in the control arm died due to a hemorrhagic event. All 5 patients had grade ≥3 thrombocytopenia at the time of the event. Grade 3/4 hemorrhage was reported in 4% of patients treated with the panobinostat arm and 2% of patients in the control arm. 5.4 Myelosuppression Panobinostat causes myelosuppression, including severe thrombocytopenia, neutropenia and anemia. In the clinical trial in patients with relapsed multiple myeloma, 67% of patients treated with panobinostat developed Grade 3 to 4 thrombocytopenia compared with 31% in the control arm. Thrombocytopenia led to treatment interruption and or dose modification in 31% of patients receiving panobinostat compared to 11% of patients in the control arm. For patients receiving panobinostat, 33% required platelet transfusion compared to 10% of patients in the control arm [see Dosage and Administration (3.2)]. Severe neutropenia occurred in 34% of patients treated with panobinostat, compared to 11% of patients in the control arm. Neutropenia led to treatment interruption and or dose modification in 10% of patients receiving panobinostat. The use of granulocyte-colony stimulating factor (G-CSF) was higher in patients treated with panobinostat compared to the control arm, 13% compared to 4%, respectively. Obtain a baseline CBC and monitor the CBC weekly during treatment (or more frequently if clinically indicated). Dose modifications are recommended for Myelosuppression [see Dosage and Administration (3.2)]. Monitor CBCs more frequently in patients over 65 years of age due to the increased frequency of myelosuppression in these patients [see Use in Specific Populations (8.5)]. 5.5 Infections Localized and systemic infections, including pneumonia, bacterial infections, invasive fungal infections, and viral infections have been reported in patients taking panobinostat. Severe infections occurred in 31% of patients (including 10 deaths) treated with panobinostat compared with 24% of patients (including 6 deaths) in the control arm. Infections of all grades occurred at a similar rate between arms. Panobinostat treatment should not be initiated in patients with active infections. Monitor patients for signs and symptoms of infections during treatment; if a diagnosis of infection is made, institute appropriate anti-infective treatment promptly and consider interruption or discontinuation of panobinostat. 5.6 Hepatotoxicity Hepatic dysfunction, primarily elevations in aminotransferases and total bilirubin, occurred in patients treated with panobinostat. Liver function should be monitored prior to treatment and regularly during treatment. If abnormal liver function tests are observed dose adjustments may be considered and the patient should be followed until values return to normal or pretreatment levels [see Dosage and Administration (3.4), Clinical Pharmacology]. 5.7 Embryo-Fetal Toxicity Panobinostat can cause fetal harm when administered to a pregnant woman. Panobinostat was teratogenic in rats and rabbits. If panobinostat is used during pregnancy, or if the patient becomes pregnant while taking panobinostat, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1, 8.3)]. Advise females of reproductive potential to avoid becoming pregnant while taking panobinostat. Advise sexually-active females of reproductive potential to use effective contraception while taking panobinostat and for at least 1 month after the last dose of panobinostat. Advise sexually active men to use condoms while on treatment and for 3 months after their last dose of panobinostat [see Use in Specific Populations (8.3)]. 6. ADVERSE REACTIONS  The following adverse reactions are described in detail in other sections of the label: • Diarrhea [see Warnings and Precaution (5.1)] • Cardiac Toxicities [see Warnings and Precaution (5.2)] • Hemorrhage [see Warnings and Precaution (5.3)] • Myelosuppression [see Warnings and Precaution (5.4)] • Infections [see Warnings and Precaution (5.5)] • Hepatotoxicity [see Warnings and Precaution (5.6)] • Embryo-Fetal Toxicity [see Warnings and Precaution (5.7)] 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. 6.1 Clinical Trials Experience The safety data reflect subject exposure to panobinostat from a clinical trial, in which 758 subjects with relapsed multiple myeloma received panobinostat in combination with bortezomib and dexamethasone or placebo in combination with bortezomib and dexamethasone (referred to as the control arm). The median duration of exposure to panobinostat was 5 months with 16% of patients exposed to study treatment for ≥48 weeks. Serious adverse events (SAEs) occurred in 60% of patients in the panobinostat, bortezomib, and dexamethasone compared to 42% of patients in the control arm. The most frequent (≥5%) treatment-emergent SAEs reported for patients treated with panobinostat were pneumonia (18%), diarrhea, (11%), thrombocytopenia (7%), fatigue (6%), and sepsis (6%). Adverse reactions that led to discontinuation of panobinostat occurred in 36% of patients. The most common adverse reactions leading to treatment discontinuations were diarrhea, fatigue, and pneumonia. Deaths occurred in 8% of patients in the panobinostat arm versus 5% on the control arm. The most frequent causes of death were infection and hemorrhage. Table 4 summarizes the adverse reactions occurring in at least 10% of patients with ≥ 5% greater incidence in the panobinostat arm, and Table 5 summarizes the treatment-emergent laboratory abnormalities. Table 4: Adverse Reactions (≥10% Incidence and ≥5% Greater Incidence in Panobinostat-Arm) in Patients with Multiple Myeloma [1] BTZ = bortezomib [2] Dex = dexamethasone [3] Arrhythmia includes the terms: arrhythmia, arrhythmia supraventricular, atrial fibrillation, atrial flutter, atrial tachycardia, bradycardia, cardiac arrest, cardio-respiratory arrest, sinus bradycardia, sinus tachycardia, supraventricular extra-systoles, tachycardia, ventricular arrhythmia, and ventricular tachycardia [4] Fatigue includes the terms: fatigue, malaise, asthenia, and lethargy Other Adverse Reactions Other notable adverse drug reactions of panobinostat not described above, which were either clinically significant, or occurred with a frequency less than 10% but had a frequency in the panobinostat arm greater than 2% over the control arm in the multiple myeloma clinical trial are listed below: Infections and infestations: hepatitis B. Endocrine disorders: hypothyroidism. Metabolism and nutrition disorders: hyperglycemia, dehydration, fluid retention, hyperuricemia, hypomagnesemia. Nervous system disorders: dizziness, headache, syncope, tremor, dysgeusia. Cardiac disorders: palpitations. Vascular disorders: hypotension, hypertension, orthostatic hypotension. Respiratory, thoracic and mediastinal disorders: cough, dyspnea, respiratory failure, rales, wheezing. Gastrointestinal disorders: abdominal pain, dyspepsia, gastritis, cheilitis, abdominal distension, dry mouth, flatulence, colitis, gastrointestinal pain. Skin and subcutaneous disorders: skin lesions, rash, erythema. Musculoskeletal and connective tissue disorders: joint swelling. Renal and urinary disorders: renal failure, urinary incontinence. General disorders and administration site conditions: chills. Investigations: blood urea increased, glomerular filtration rate decreased, blood alkaline phosphatase increased. Psychiatric disorders: insomnia. Table 5: Treatment-emergent Laboratory Abnormalities (≥10% Incidence and ≥5% Greater Incidence in Panobinostat-arm) in Patients with Multiple Myeloma [1] BTZ = bortezomib [2] Dex = dexamethasone Fatigue and Asthenia Grade 1 to Grade 4 asthenic conditions (fatigue, malaise, asthenia, and lethargy) were reported in 60% of the patients in the panobinostat arm compared to 42% of patients in the control arm. Grade ≥3 asthenic conditions were reported in 25% of the patients in the panobinostat arm compared to 12% of patients in the control arm. Asthenic conditions led to treatment discontinuation in 6% of patients in the panobinostat arm versus 3% of patients in the control arm. The prespecified sub-group upon which the efficacy and safety of panobinostat was based had a similar adverse reaction profile to the entire safety population of patients treated with panobinostat, bortezomib, and dexamethasone. 7. DRUG INTERACTIONS  Panobinostat is a CYP3A substrate and inhibits CYP2D6. Panobinostat is a P-glycoprotein (P-gp) transporter system substrate. 7.1 Agents that May Increase Panobinostat Blood Concentrations CYP3A Inhibitors: Coadministration of panobinostat with a strong CYP3A inhibitor increased the Cmax and AUC of panobinostat by 62% and 73% respectively, compared to when panobinostat was given alone [see Clinical Pharmacology]. Reduce dose to 10 mg when coadministered with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) [see Dosage and Administration (3.5)]. Instruct patients to avoid star fruit, pomegranate or pomegranate juice, and grapefruit or grapefruit juice because these foods are known to inhibit CYP3A enzymes. 7.2 Agents that May Decrease Panobinostat Plasma Concentrations CYP3A Inducers: Coadministration of panobinostat with strong CYP3A inducers was not evaluated in vitro or in a clinical trial however, a reduction in panobinostat exposure is likely. An approximately 70% decrease in the systemic exposure of panobinostat in the presence of strong inducers of CYP3A was observed in simulations using mechanistic models. Therefore, the concomitant use of strong CYP3A inducers should be avoided [see Clinical Pharmacology]. 7.3 Agents whose Plasma Concentrations May be Increased by Panobinostat CYP2D6 Substrates: Panobinostat increased the median Cmax and AUC of a sensitive substrate of CYP2D6 by approximately 80% and 60%, respectively; however this was highly variable [see Clinical Pharmacology]. Avoid coadministrating panobinostat with sensitive CYP2D6 substrates (i.e., atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, and venlafaxine) or CYP2D6 substrates that have a narrow therapeutic index (i.e., thioridazine, pimozide). If concomitant use of CYP2D6 substrates is unavoidable, monitor patients frequently for adverse reactions. 7.4 Drugs that Prolong QT interval Concomitant use of anti-arrhythmic medicines (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that are known to prolong the QT interval (including, but not limited to chloroquine, halofantrine, clarithromycin, methadone, moxifloxacin, bepridil and pimozide) is not recommended. Anti-emetic drugs with known QT prolonging risk, such as dolasetron, ondansetron, and tropisetron can be used with frequent ECG monitoring [see Warnings and Precautions (5.2)]. 8. USE IN SPECIFIC POPULATIONS  8.1 Usage in Pregnancy Risk Summary Panobinostat can cause fetal harm when administered to a pregnant woman. Panobinostat was teratogenic in rats and rabbits. If panobinostat is used during pregnancy or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus. Data Animal Data In embryofetal development studies, panobinostat was administered orally 3 times per week during the period of organogenesis to pregnant rats (30, 100, and 300 mg/kg) and rabbits (10, 40, and 80 mg/kg). In rats, maternal toxicity including death was observed at doses greater than or equal to 100 mg/kg/day. Embryofetal toxicities occurred at 30 mg/kg (the only dose with live fetuses) and consisted of fetal malformations and anomalies, such as cleft palate, short tail, extra presacral vertebrae, and extra ribs. The dose of 30 mg/kg resulted in exposures (AUCs) approximately 3-fold the human exposure at the human dose of 20 mg. In rabbits, maternal toxicity including death was observed at doses greater than or equal to 80 mg/kg. Increased pre-and/or post-implantation loss occurred at all doses tested. Embryofetal toxicities included decreased fetal weights at doses greater than or equal to 40 mg/kg and malformations (absent digits, cardiac interventricular septal defects, aortic arch interruption, missing gallbladder, and irregular ossification of skull) at 80 mg/kg. The dose of 40 mg/kg in rabbits results in systemic exposure approximately 4-fold the human exposure and the dose of 80 mg/kg results in exposure 7-fold the human exposure, at the human dose of 20 mg. 8.2 Lactation Risk Summary It is not known whether panobinostat is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse drug reactions in nursing infants, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.3 Females and Males of Reproductive Potential Embryofetal toxicity including malformations occurred in embryofetal development studies in rats [see Pregnancy (8.1)]. Pregnancy Testing Perform pregnancy testing in women of childbearing potential prior to starting treatment with panobinostat and intermittently during treatment with panobinostat. Contraception Females Panobinostat can cause fetal harm. Advise females of reproductive potential to avoid becoming pregnant while taking panobinostat. Advise sexually-active females of reproductive potential to use effective contraception while taking panobinostat and for at least 1 month after the last dose of panobinostat. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking panobinostat [see Use in Specific Populations (8.1)]. Males Advise sexually active men to use condoms while on treatment and for 3 months after their last dose of panobinostat. 8.4 Pediatric Use The safety and efficacy of panobinostat in children has not been established. 8.5 Geriatric Use In clinical trials of panobinostat in patients with multiple myeloma, 42% of patients were 65 years of age or older. Patients over 65 years of age had a higher frequency of selected adverse events and of discontinuation of treatment due to adverse events. In patients over 65 years of age, the incidence of deaths not related to disease progression was 9% in patients ≥65 years of age compared to 5 % in patients <65. In the randomized clinical trial in patients with relapsed multiple myeloma, no major differences in effectiveness were observed in older patients compared to younger patients. Adverse reactions leading to permanent discontinuation occurred in 45% of patients ≥65 years of age in the panobinostat treatment arm compared to 30% of patients <65 years age in the panobinostat treatment arm. Monitor for toxicity more frequently in patients over 65 years of age, especially for gastrointestinal toxicity, myelosuppression, and cardiac toxicity [see Warnings and Precautions (5.1, 5.4)]. 8.6 Hepatic Impairment The safety and efficacy of panobinostat in patients with hepatic impairment has not been evaluated. In a pharmacokinetic trial, patients with mild (bilirubin ≤1xULN and AST >1xULN, or bilirubin >1.0 to 1.5x ULN and any AST) or moderate (bilirubin >1.5x to 3.0x ULN, any AST) hepatic impairment (NCI-ODWG criteria) had increased AUC of panobinostat by 43% and 105%, respectively. Reduce the starting dose of panobinostat in patients with mild or moderate hepatic impairment. Avoid use in patients with severe hepatic impairment. Monitor patients with hepatic impairment frequently for adverse events [see Dosage and Administration (3.4), Warnings and Precautions (5.6), Clinical Pharmacology]. 8.7 Renal Impairment Mild [creatinine clearance (CrCl) ≥50 to <80 mL/min] to severe renal impairment (CrCl <30 mL/min) did not impact the plasma exposure of panobinostat. Panobinostat has not been studied in patients with end stage renal disease (ESRD) or patients on dialysis. The dialyzability of panobinostat is unknown [see Clinical Pharmacology]. 9. OVERDOSAGE  There is limited experience with overdosage. Expect exaggeration of adverse reactions observed during the clinical trial, including hematologic and gastrointestinal reactions such as thrombocytopenia, pancytopenia, diarrhea, nausea, vomiting and anorexia. Monitor cardiac status including ECGs, and assess and correct electrolytes. Consider platelet transfusions for thrombocytopenic bleeding. It is not known if panobinostat is dialyzable. 10. MECHANISM OF ACTION  Panobinostat is a histone deacetylase (HDAC) inhibitor that inhibits the enzymatic activity of HDACs at nanomolar concentrations. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some non-histone proteins. Inhibition of HDAC activity results in increased acetylation of histone proteins, an epigenetic alteration that results in a relaxing of chromatin, leading to transcriptional activation. In vitro, panobinostat caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells. Increased levels of acetylated histones were observed in xenografts from mice that were treated with panobinostat. Panobinostat shows more cytotoxicity towards tumor cells compared to normal cells. 11. PHARMACODYNAMICS   Cardiac Electrophysiology Panobinostat may prolong cardiac ventricular repolarization (QT interval) [see Warnings and Precautions (5.2)]. In the randomized multiple myeloma trial, QTc prolongation with values between 451 msec to 480 msec occurred in 10.8% of panobinostat treated patients. Events with values of 481 msec to 500 msec occurred in 1.3% of panobinostat treated patients. A maximum QTcF increase from baseline of between 31 msec and 60 msec was reported in 14.5% of panobinostat treated patients. A maximum QTcF increase from baseline of >60 msec was reported in 0.8% of panobinostat treated patients. No episodes of QTcF prolongation >500 msec have been reported with the dose of 20 mg panobinostat in the randomized multiple myeloma trial conducted in combination with bortezomib and dexamethasone. Pooled clinical data from over 500 patients treated with single agent panobinostat in multiple indications and at different dose levels has shown that the incidence of CTC Grade 3 QTc prolongation (QTcF >500 msec) was approximately 1% overall and 5% or more at a dose of 60 mg or higher. 12. PHARMACOKINETICS   Absorption The absolute oral bioavailability of panobinostat is approximately 21%. Peak concentrations of panobinostat are observed within 2 hours (Tmax) of oral administration in patients with advanced cancer. Panobinostat exhibits an approximate dose proportional increase in both Cmax and AUC over the dosing range. Plasma panobinostat Cmax and AUC0–48 were approximately 44% and 16% lower compared to fasting conditions, respectively, following ingestion of an oral panobinostat dose 30 minutes after a high-fat meal by 36 patients with advanced cancer. The median Tmax was also delayed by 2.5 hours in these patients. The aqueous solubility of panobinostat is pH dependent, with higher pH resulting in lower solubility [see Description (1)]. Coadministration of panobinostat with drugs that elevate the gastric pH was not evaluated in vitro or in a clinical trial; however, altered panobinostat absorption was not observed in simulations using physiologically-based pharmacokinetic (PBPK) models. Distribution Panobinostat is approximately 90% bound to human plasma proteins in vitro and is independent of concentration. Panobinostat is a P-gp substrate. Metabolism Panobinostat is extensively metabolized. Pertinent metabolic pathways involved in the biotransformation of panobinostat are reduction, hydrolysis, oxidation, and glucuronidation processes. The fraction metabolized through CYP3A accounts for approximately 40% of the total hepatic panobinostat elimination. In vitro, additional contributions from the CYP2D6 and CYP2C19 pathways are minor. In vitro, UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A9, and UGT2B4 contribute to the glucuronidation of panobinostat. Elimination Twenty-nine percent to 51% of administered radioactivity is excreted in urine and 44% to 77% in the feces after a single oral dose of [14C] panobinostat in 4 patients with advanced cancer. Unchanged panobinostat accounted for <2.5% of the dose in urine and <3.5% of the dose in feces with the remainder consisting of metabolites. An oral clearance (CL/F) and terminal elimination half-life (t1/2) of approximately 160 L/hr and 37 hours, respectively, was estimated using a population based pharmacokinetic (pop-PK) model in patients with advanced cancer. An inter-subject variability 65% on the clearance estimate was also reported. Up to 2-fold accumulation was observed with chronic oral dosing in patients with advanced cancer. Specific Populations Population pharmacokinetic (PK) analyses of panobinostat indicated that body surface area, gender, age, and race do not have a clinically meaningful influence on clearance. Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of panobinostat was evaluated in a phase 1 study in 24 patients with advanced cancer with varying degrees of hepatic impairment. In patients with NCI-CTEP class mild (i.e., Group B) and moderate (i.e., Group C) hepatic impairment, AUC0-inf increased 43% and 105% compared to the group with normal hepatic function, respectively. The relative change in Cmax followed a similar pattern. The effect of severe hepatic impairment was indeterminate in this study due to the small sample size (n=1). A dose modification is recommended for patients with mild and moderate hepatic impairment [see Use in Specific Populations (8.6)]. Renal Impairment: The effect of renal impairment on the pharmacokinetics of panobinostat was assessed in a phase 1 trial of 37 patients with advanced cancer and varying degrees of renal impairment. Panobinostat AUC0–inf in the mild, moderate and severe renal impairment groups were 64%, 99% and 59%, of the normal group, respectively. The relative change in Cmax followed a similar pattern [see Use in Specific Populations (8.7)]. Drug Interactions Strong CYP3A Inhibitors: Coadministration of a single 20 mg panobinostat dose with ketoconazole (200 mg twice daily for 14 days) increased the Cmax and AUC0–48 of panobinostat by 62% and 73% respectively, compared to when panobinostat was given alone in 14 patients with advanced cancer. Tmax was unchanged. A modified starting dose is recommended [see Dose and Administration (3.4), Drug Interactions (7.1)]. Strong CYP3A Inducers: The human oxidative metabolism of panobinostat via the cytochrome P450 system primarily involves CYP3A isozymes. Simulations using PBPK models, predicted an approximately 70% decrease in the systemic exposure of panobinostat in the presence of strong inducers of CYP3A. Avoid coadministration of panobinostat with strong CYP3A inducers [see Drug Interactions (7.2)]. CYP2D6 Substrates: Coadministration of a single 60 mg dextromethorphan (DM) dose with panobinostat (20 mg once per day, on Days 3, 5, and 8) increased the Cmax and AUC0-∞ of DM by 20% to 200% and 20% to 130% (interquartile ranges), respectively, compared to when DM was given alone in 14 patients with advanced cancer. These DM exposures were extremely variable (CV% >150%). Avoid coadministration of panobinostat with sensitive CYP2D6 substrates or CYP2D6 substrates that have a narrow therapeutic index [see Drug Interactions (7.3)]. CYP3A Substrates: Simulations using PBPK models predict that an exposure increase of less than 10% for the sensitive CYP3A substrate midazolam is likely following coadministration with panobinostat. The clinical implications of this finding are not known. In vitro studies with CYP or UDPglucuronosyltransferase (UGT) substrates: Panobinostat inhibits CYP2D6, CYP2C19 and CYP3A4 (time-dependent), but does not inhibit CYP1A2, CYP2C8, CYP2C9, and CYP2E. Panobinostat does not induce CYP1A1/2, CYP2B6, CYP2C8/9/19, CYP3A and UGT1A1. In vitro studies with drug transporter system substrates: Panobinostat inhibits OAT3, OCT1, OCT2, OATP1B1 and OATP1B3, but does not inhibit P-gp and breast cancer resistant protein (BCRP), or OAT1. Panobinostat does not induce P-gp and multidrug resistance protein 2 (MRP2) transporters. 13. HOW SUPPLIED/STORAGE AND HANDLING  1) How Available: a) Brand name: FARYDAK, by Novartis. b) Generic drugs: None. 2) How Supplied: FARYDAK 10 mg: Size # 3 light green opaque capsule, radial markings on cap with black ink “LBH 10 mg” and two radial bands with black ink on body, containing white to almost white powder. FARYDAK 15 mg: Size #1 orange opaque capsule, radial markings on cap with black ink “LBH 15 mg” and two radial bands with black ink on body, containing white to off-white powder. FARYDAK 20 mg: Size #1 red opaque capsule, radial markings on cap with black ink “LBH 20 mg” and two radial bands with black ink on body, containing white to off-white powder. FARYDAK capsules are packaged in PVC/PCTFE blister packs. 10 mg blister packs containing 6 capsules………………………….……..NDC 0078-0650-06 15 mg blister packs containing 6 capsules ………………………….…….NDC 0078-0651-06 20 mg blister packs containing 6 capsules ………………………….…….NDC 0078-0652-06 3) Storage and Handling: Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F). Store blister pack in original carton to protect from light.FARYDAK capsules should not be opened, crushed, or chewed. Direct contact of the powder in FARYDAK capsules with the skin or mucous membranes should be avoided. If such contact occurs wash thoroughly. Personnel should avoid exposure to crushed and/or broken capsules. FARYDAK is a cytotoxic drug. Follow special handling and disposal procedures [see References]. Rx only 02/15 2015年2月23日美国食品和药品监管局(FDA)批准Farydak(帕比司他[panobinostat])为多发性骨髓瘤患者的治疗。 多发性骨髓瘤是一种形式对血癌源自浆细胞，骨髓中发现的一种类型白血细胞。按照美国癌症研究所，每年约21,700美国人被诊断有多发性骨髓瘤和10,710 人死于该疾病。 主要地影响老年成年，多发性骨髓瘤致浆细胞迅速地倍增和从骨髓排挤其他健康血细胞。 当骨髓有太多浆细胞，细胞可能移动到身体其他部分，可能减弱机体的免疫系统，导致贫血和致其他骨和肾脏问题。 Farydak通过抑制酶活性起作用，被称为组蛋白去乙酰化酶(HDACs)。这个过程可能减慢在多发性骨髓瘤患者过度-发展的浆细胞或致这些危险细胞死亡。 Farydak是第一个HDAC抑制剂被批准治疗多发性骨髓瘤。它意向为患者曾接受至少两个以前标准治疗，包括硼替佐米[bortezomib]和一个免疫调节剂。Farydak是将与硼替佐米，一种类型化疗，和地塞米松，一种抗炎药物联用。 FDA的药品评价和研究中心血液学和肿瘤产品室主任Richard Pazdur，M.D.说：“Farydak 有一种新作用机制不同于以前被批准的治疗多发性骨髓瘤药物，使它是一种潜在诱人的为多发性骨髓瘤的治疗备选药，” “Farydak对被批准是特别重要因为它曾减慢多发性骨髓瘤的进展。” 2014年11月， FDA的肿瘤药物肿瘤药物咨询委员会建议监管局，根据审评的数据，药物对获益没有胜过它对有复发多发性骨髓瘤患者风险。在会议后，公司递交另一个资料支持 Farydak的对一个不同适应证对使用：有多发性骨髓瘤患者曾接受至少两种以前标准治疗，包括硼替佐米和一种免疫调节剂。 在193例临床试验多发性骨髓瘤参加者，接受至少两次以前治疗包括硼替佐米和一种免疫调节剂，证实Farydak与硼替佐米和地塞米松联用的安全性和疗效。参加者被随机地赋予接受一种Farydak，硼替佐米和地塞米松联用，或单独硼替佐米和地塞米松。 研究结果显示参加者接受Farydak组合见到其疾病进展延缓(无进展生存)共约10.6个月，与之比较用单独硼替佐米和地塞米松治疗参加者至5.8个月。此外，59 %的Farydak-治疗参加者见到治疗后其癌皱缩或消失(反应率)，相比接受硼替佐米和地塞米松参加者为41%。 Farydak带有一个黑框警告警戒患者和卫生保健专业人员，接受Farydak患者中曾发生严重腹泻和严重和致命性心脏事件，心律失常和心电图(ECG)变化。因为这些风险，Farydak正在批准与风险评估和缓解策略(REMS)由一个交流计划告知这些风险卫生保健专业人员和如何缩小风险组成。 Farydak的最常见副作用是腹泻，疲劳，恶心，臂或腿肿胀，食欲减低，发热，呕吐和虚弱。最常见实验室异常是低磷血症，低钾血症)，低钠血症，肌酐增加，血小板减少，白细胞减少和低红细胞计数(贫血)。卫生保健专业人员还应告知患者胃肠道和肺中出血风险，和肝损伤 (肝脏毒性)。 FDA授权Farydak优先审评和孤儿产品指定。优先审评提供对意向治疗某种严重疾病或情况和可能提供超过可得到治疗显著改善药物加快审评。孤儿产品指定是给予意向治疗罕见疾病药物。 FDA 是在监管局的加速批准程序下行动，允许批准治疗某种严重或危及生命疾病根据临床数据显示药物有对一种替代性终点合理地可能预测对患者获益影响。加速批准程序提供患者较早得到鼓舞人有前途新药而公司进行验证性临床试验。尚未对Farydak确定改善生存或疾病-相关症状。公司现在被要求进行验证性试验证明和描述Farydak的临床获益。 Farydak由总部新泽西East Hanover的诺华制药上市。