近日，美国食品和药物管理局(FDA)批准的新药Tolsura(itraconazole，伊曲康唑)65毫克胶囊。TOLSURA是伊曲康唑的一种新剂型，用于治疗成人某些全身真菌感染。
批准日期：2018年12月11日 公司：Mayne Pharma
TOLSURA(伊曲康唑[itraconazole])胶囊，供口服使用
美国最初批准:1992年
警告:充血性心力衰竭和药物的相互作用
请参阅完整的处方信息的完整框警告。
•充血性心力衰竭
TOLSURA引起或加重充血性心力衰竭(CHF)。当静脉注射伊曲康唑给健康的志愿者和狗时，观察到不良的肌力反应。如果在给药期间出现或恶化充血性心力衰竭的体征或症状，重新评估继续治疗的益处-风险。
•药物的相互作用
o由于人CYP3A4酶代谢的某些药物的血浆浓度增加，因此与tolsura联合用药是禁忌的。
与秋水仙碱、非索非那星、非索非那星联合用药是肾、肝损害程度不同者的禁忌症。
o与eliglustat联合给药禁忌用于CYP2D6的低质量或中间代谢物和强或中度CYP2D6抑制剂。
一些药物的血浆浓度升高会导致QT延长和室性心动过速，包括出现点曲(一种可能致命的心律失常)。
作用机制
伊曲康唑是一种唑类抗真菌药物[见微生物学]。
适应症和用法
TOLSURA是一种唑类抗真菌药物，用于治疗免疫缺陷和非免疫缺陷的成人患者的后续真菌感染:
•囊胚菌病，肺和肺外的
•组织胞浆菌病，包括慢性空洞性肺疾病及播散性，非脑膜组织胞浆菌病，以及
•曲霉病，肺和肺外曲霉病，患者对两性霉素B治疗不能耐受或对两性霉素B治疗不能耐受。
使用限制:
TOLSURA不能用于甲真菌病的治疗。
TOLSURA不能与其他伊曲康唑产品互换或替代。
剂量和管理
•囊胚菌病和组织胞浆菌病- 130毫克至260毫克每日。
•曲霉病- 130毫克至260毫克每日。
•有关生命威胁情况的额外剂量，请参阅完整的处方信息。
•TOLSURA必须与食物一起服用。
•整个吞下。切勿嚼碎或折断。
剂型和强度
胶囊:65毫克
禁忌症
•与某些影响伊曲康唑代谢或其代谢受伊曲康唑影响的药物共服。
•对伊曲康唑过敏。
警告和预防措施
•肝毒性:伊曲康唑有严重的肝毒性，包括肝衰竭和死亡。如果出现肝功能障碍的迹象，停止治疗。
•心律失常:某些药物经人CYP450酶与oralitraconazole和/或其他CYP3A4抑制剂同时代谢后，患者出现危及生命的心律失常和/或猝死。
•周围神经病变:在长期使用伊曲康唑治疗的患者中有报道。监测并及时评估神经症状。
•听力损失:据报道，患者的听力损失是可逆的或永久性的。
如发生听力损失，应停止治疗.
不良反应
最常见的不良反应(发生率≥1%)恶心、皮疹,呕吐、水肿、头痛、腹泻、疲劳、发热、瘙痒、高血压、异常、肝功能、腹痛、头晕、低钾、厌食、不适、性欲减退、嗜睡、蛋白尿、阳痿。
如有不良反应，请致电1-844-825-8500与美耐药联系，或致电1-800-FDA-1088或www.fda.gov/medwatch与FDA联系。
药物的相互作用
伊曲康唑主要通过CYP3A4代谢。其他药物，无论是共享这一代谢途径或修改CYP3A4活性，都可能影响伊曲康唑的药代动力学。
包装提供/储存和处理
TOLSURA(伊曲康唑胶囊)是一种1号尺寸的硬明胶胶囊，带有浅蓝色底纹和白色的身体，瓶盖上印有黑色的i-65，含有65毫克的伊曲康唑。
TOLSURA胶囊有60瓶，NDC 51862-462-60
商店在25°C(77°F);远足允许15°C到30°C(59°F到86°F)(见USP ControlledRoom温度)。在密封、耐光的容器中分发
完整说明资料附件：https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208901s000lbl.pdf
FDA Approves Tolsura (SUBA®-itraconazole capsules) for the Treatment of Certain Fungal Infections
US Food and Drug Administration (FDA) has approved the New Drug Application (NDA) for Tolsura™ (SUBA®-itraconazole) 65mg capsules. Tolsura is a new formulation of itraconazole indicated for the treatment of certain systemic fungal infections in adult patients.
Tolsura is indicated for the treatment of blastomycosis (pulmonary and extrapulmonary), histoplasmosis (including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis) and aspergillosis (pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy). These serious infections most commonly occur in vulnerable or immunocompromised patients, for example, those with a history of cancer, transplants (solid organ or bone marrow), HIV/AIDS, or chronic rheumatic disorders, and are often associated with high mortality rates or long-term health issues.
Mayne Pharma's CEO, Mr Scott Richards said, "We are very pleased to have received FDA approval of this patented formulation of itraconazole which incorporates Mayne Pharma's proprietary SUBA technology to improve the bioavailability of poorly soluble drugs. Reformulation of existing drugs plays an important role in improving patient compliance and clinical outcomes. We are proud to offer a new treatment option for patients with these life-threatening infections. We believe physicians will appreciate having access to Tolsura, which has been shown in clinical studies to have increased bioavailability and significantly reduced variability when compared to conventional oral itraconazole capsules."
"After many years of research and development and working closely with key global opinion leaders in infectious disease management, Tolsura represents a major milestone in the SUBA (SUper-BioAvailable) drug delivery platform at Mayne Pharma."
The Company will directly commercialise Tolsura and plans to launch in January 2019 with a new institutional sales team focused primarily on hospital-based infectious disease specialists. Tolsura has four granted patents from the United States Patent and Trademark Office with expiry dates ranging from 2023 to 2033.
The US anti-fungal triazole market has a current value of US$600m according to IQVIA and based on the clear unmet clinical need in serious systemic infections, the addressable market is estimated at US$200m[1].
Mayne Pharma directly markets more than 60 products in the US including three patent protected dermatology products Fabior® (tazarotene) foam, Sorilux® (calcipotriene) foam and Doryx® MPC (doxycycline) delayed-release tablets. The Company recently acquired Lexette® (halobetasol) foam used to treat plaque psoriasis which it expects to also launch in January 2019.
[1] Management estimate
About Mayne Pharma
At Mayne Pharma we believe that everyone deserves medicines that are better, safe and more affordable. That's why our people are determined to create innovative products and services for our changing world.
Mayne Pharma is an ASX-listed specialty pharmaceutical company focused on applying its drug delivery expertise to commercialise branded and generic pharmaceuticals. Mayne Pharma also provides contract development and manufacturing services to more than 100 clients worldwide.
Mayne Pharma has a 30-year track record of innovation and success in developing new oral drug delivery systems and these technologies have been successfully commercialised in numerous products that have been marketed around the world.
Mayne Pharma has two product development and manufacturing facilities based in Salisbury, Australia and Greenville, USA with expertise in formulation of complex oral and topical dose forms including potent compounds, modified-release products and inherently unstable compounds.
About Tolsura (SUBA-itraconazole) capsules
Indications and Usage
Tolsura is an azole antifungal indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised adult patients:
Blastomycosis, pulmonary and extrapulmonary
Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis, and
Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy.
Limitations of Use:
Tolsura is not indicated for the treatment of onychomycosis
Tolsura is NOT interchangeable or substitutable with other itraconazole products
IMPORTANT SAFETY INFORMATION
WARNING: CONGESTIVE HEART FAILURE and DRUG INTERACTIONS
See full prescribing information for complete boxed warning.
Congestive Heart Failure Tolsura can cause or exacerbate congestive heart failure (CHF). When itraconazole was administered intravenously to healthy human volunteers and dogs, negative inotropic effects were seen.  If signs or symptoms of congestive heart failure occur or worsen during administration of Tolsura, reassess the benefit-risk of continuing treatment.
Drug Interactions
Co-administration of certain drugs that are metabolized by human CYP3A4 enzymes are contraindicated with Tolsura because plasma concentrations of such drugs are increased
Co-administration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment.
Co-administration with eliglustat is contraindicated in poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors.
Increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsades de pointes, a potentially fatal arrhythmia.
Contraindications
Co-administration with certain drugs that either affect metabolism of itraconazole or whose metabolism is affected by itraconazole.
Hypersensitivity to itraconazole
Warnings and Precautions
Hepatotoxicity: Serious hepatotoxicity, including liver failure and death were reported with the use of itraconazole. Discontinue treatment if signs of liver dysfunction occur.
Cardia Dysrhythmias: Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using certain drugs that are metabolized by human CYP450 enzymes concomitantly with oral itraconazole and/or other CYP3A4 inhibitors.
Peripheral Neuropathy: This has been reported in patients on long-term therapy with itraconazole. Monitor and promptly eva luate neurologic symptoms.
Hearing loss: Reversible or permanent has been reported in patients. Discontinue treatment if hearing loss occurs.
Adverse Reactions
Most common adverse reactions (incidence ≥ 1%) are nausea, rash, vomiting, edema, headache, diarrhea, fatigue, fever, pruritus, hypertension, abnormal hepatic function, abdominal pain, dizziness, hypokalemia, anorexia, malaise, decreased libido, somnolence, albuminuria, impotence.