英文药名：ODOMZO(sonidegib capsules) 中文药名：索尼得吉硬明胶胶囊 生产厂家：诺华（Novartis） 药品介绍 2015年7月27日，新类抗癌药获FDA加速批准Odomzo（sonidegib，原名：LDE225 200mg）用于经手术或放射治疗后病情复发、以及不适合这2种治疗方案的局部晚期基底细胞癌（laBCC）成人患者。 基底细胞癌（BCC）是一种最常见的皮肤癌，约占非黑色素瘤皮肤癌的80%以上，该病常发于头颈部，晚期BCC可导致高度毁容。Odomzo将为局部晚期laBCC群体提供一种新的非侵入性治疗方案。 Odomzo的获批，是基于一项国际II期BOLT研究中所取得的可持续的客观缓解率（ORR）数据。该研究在局部晚期基底细胞癌（laBCC）成人患者中开展，评估了Odomzo 200mg和800mg剂量的疗效和安全性。数据显示，200mg剂量组客观缓解率（ORR）为58%，其中完全缓解率（CR）为5%，部分缓解率（PR）为53%；实现客观缓解的患者中，有81%在随访至少1.9个月至18.6个月期间，仍然持续缓解。目前，中位缓解持续时间尚未达到。此外，无证据表明800mg剂量组ORR数据好于200mg剂量组。 Odomzo（sonidegib，原名LDE225）是一种口服选择性Smoothened（SMO）抑制剂。SMO是一种7次跨膜蛋白，调控Hedgehog（Hh）信号通路，该通路在干细胞维持、组织修复、晚期基底细胞癌中发挥关键作用。目前，诺华正在调查sonidegib用于多种疾病的治疗，包括骨髓纤维化、白血病及实体瘤（如胰腺癌、乳腺癌和非小细胞肺癌）。 基底细胞癌（BCC）是发生于皮肤基底细胞的异常、不受控增生或病变，占所有非黑色素瘤皮肤癌病例的80%以上。该病最常见于头部和颈部。鼻子是最常见部位。局部晚期是指BCC从最初部位扩散至附近组织，可导致高度毁容。晚期BCC约占BCC病例的1-10%。尽管BCC通常可在早期确诊并治疗，但约3%的患者在治疗5年后病情复发，治疗选择。 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ODOMZO safely and effectively. See full prescribing information for ODOMZO. ODOMZO® (sonidegib) capsules, for oral use Initial U.S. Approval: 2015 WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. ODOMZO can cause embryo-fetal death or severe birth defects when administered to a pregnant woman and is embryotoxic, fetotoxic, and teratogenic in animals. (5.1, 8.1) Verify the pregnancy status of females of reproductive potential prior to initiating therapy. Advise females of reproductive potential to use effective contraception during treatment with ODOMZO and for at least 20 months after the last dose. (5.1, 8.3) Advise males of the potential risk of exposure through semen and to use condoms with a pregnant partner or a female partner of reproductive potential during treatment with ODOMZO and for at least 8 months after the last dose. (5.1, 8.3) INDICATIONS AND USAGE ODOMZO is a hedgehog pathway inhibitor indicated for the treatment of adult patients with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy. (1) DOSAGE AND ADMINISTRATION Recommended dose: 200 mg orally once daily taken on an empty stomach, at least 1 hour before or 2 hours after a meal. (2.1) DOSAGE FORMS AND STRENGTHS 200 mg capsules (3) CONTRAINDICATIONS None. (4) WARNINGS AND PRECAUTIONS Blood donation: Advise patients not to donate blood or blood products during treatment with ODOMZO and for at least 20 months after the last dose. (5.1) Musculoskeletal adverse reactions: Obtain serum creatine kinase (CK) and creatinine levels prior to initiating therapy, periodically during treatment, and as clinically indicated. Temporary dose interruption or discontinuation of ODOMZO may be required based on the severity of musculoskeletal adverse reactions. (2.2, 5.2) ADVERSE REACTIONS The most common adverse reactions occurring in ≥10% of patients are muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS CYP3A inhibitors: Avoid strong CYP3A inhibitors. Avoid long-term (greater than 14 days) use of moderate CYP3A inhibitors. (7.1) CYP3A inducers: Avoid strong and moderate CYP3A inducers. (7.1) USE IN SPECIFIC POPULATIONS Lactation: Do not breastfeed during treatment with ODOMZO and for at least 20 months after the last dose. (8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 7/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE ODOMZO (sonidegib) is indicated for the treatment of adult patients with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy. 2 DOSAGE AND ADMINISTRATION 2.1  Recommended Dosing The recommended dose of ODOMZO is 200 mg taken orally once daily on an empty stomach, at least 1 hour before or 2 hours after a meal, administered until disease progression or unacceptable toxicity [see Clinical Pharmacology (12.3)]. Verify the pregnancy status of females of reproductive potential prior to initiating ODOMZO. Obtain serum creatine kinase (CK) levels and renal function tests prior to initiating ODOMZO in all patients [see Dosage and Administration (2.2) and Warnings and Precautions (5.2)]. If a dose of ODOMZO is missed, resume dosing with the next scheduled dose. 2.2 Dose Modifications Interrupt ODOMZO for Severe or intolerable musculoskeletal adverse reactions. First occurrence of serum CK elevation between 2.5 and 10 times upper limit of normal (ULN). Recurrent serum CK elevation between 2.5 and 5 times ULN. Resume ODOMZO at 200 mg daily upon resolution of clinical signs and symptoms. Permanently discontinue ODOMZO for Serum CK elevation greater than 2.5 times ULN with worsening renal function. Serum CK elevation greater than 10 times ULN. Recurrent serum CK elevation greater than 5 times ULN. Recurrent severe or intolerable musculoskeletal adverse reactions. 3  DOSAGE FORMS AND STRENGTHS 200 mg opaque pink colored capsules with ‘SONIDEGIB 200MG’ printed on the body and ‘NVR’ printed on the cap in black ink. 4  CONTRAINDICATIONS None. 5  WARNINGS AND PRECAUTIONS 5.1  Embryo-fetal Toxicity ODOMZO can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. In animal reproduction studies, sonidegib was embryotoxic, fetotoxic, and teratogenic at maternal exposures below the recommended human dose of 200 mg. Advise pregnant women of the potential risk to a fetus [see Use in Specific Populations (8.1)]. Females of Reproductive Potential Verify pregnancy status of females of reproductive potential prior to initiating ODOMZO treatment. Advise females to use effective contraception during treatment with ODOMZO and for at least 20 months after the last dose [see Use in Specific Populations (8.3)]. Males Advise male patients with female partners to use condoms, even after a vasectomy, during treatment with ODOMZO and for at least 8 months after the last dose to avoid potential drug exposure in pregnant females or females of reproductive potential [see Use in Specific Populations (8.3)]. Blood Donation Advise patients not to donate blood or blood products while taking ODOMZO and for at least 20 months after the last dose of ODOMZO because their blood or blood products might be given to a female of reproductive potential. 5.2 Musculoskeletal Adverse Reactions Musculoskeletal adverse reactions, which may be accompanied by serum creatine kinase (CK) elevations, occur with ODOMZO and other drugs which inhibit the hedgehog pathway. In a pooled safety analysis of 12 clinical studies involving 571 patients with various advanced cancers treated with ODOMZO at doses ranging from 100 mg to 3000 mg, rhabdomyolysis (defined as serum CK increase of more than ten times the baseline value with a concurrent 1.5-fold or greater increase in serum creatinine above baseline value) occurred in one patient (0.2%) treated with ODOMZO 800 mg. In Study 1, musculoskeletal adverse reactions occurred in 68% (54/79) of patients treated with ODOMZO 200 mg daily with 9% (7/79) reported as Grade 3 or 4. The most frequent manifestations of musculoskeletal adverse reactions reported as an adverse event were muscle spasms (54%), musculoskeletal pain (32%), and myalgia (19%). Increased serum CK laboratory values occurred in 61% (48/79) of patients with 8% (6/79) of patients having Grade 3 or 4 serum CK elevations. Musculoskeletal pain and myalgia usually preceded serum CK elevation. Among patients with Grade 2 or higher CK elevations, the median time to onset was 12.9 weeks (range: 2 to 39 weeks) and the median time to resolution (to ≤ Grade 1) was 12 days (95% CI: 8 to 14 days). ODOMZO was temporarily interrupted in 8% of patients or permanently discontinued in 8% of patients for musculoskeletal adverse reactions. The incidence of musculoskeletal adverse reactions requiring medical intervention (magnesium supplementation, muscle relaxants, and analgesics or narcotics) was 29%, including four patients (5%) who received intravenous hydration or were hospitalized. Obtain baseline serum CK and creatinine levels prior to initiating ODOMZO, periodically during treatment, and as clinically indicated (e.g., if muscle symptoms are reported). Obtain serum creatinine and CK levels at least weekly in patients with musculoskeletal adverse reactions with concurrent serum CK elevation greater than 2.5 times ULN until resolution of clinical signs and symptoms. Depending on the severity of symptoms, temporary dose interruption or discontinuation may be required for musculoskeletal adverse reactions or serum CK elevation [see Dosage and Administration (2.2)]. Advise patients starting therapy with ODOMZO of the risk of muscle-related adverse reactions. Advise patients to report promptly any new unexplained muscle pain, tenderness or weakness occurring during treatment or that persists after discontinuing ODOMZO.  6  ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: Musculoskeletal Adverse Reactions [see Warnings and Precautions (5.2)]. 6.1  Clinical Trial Experience 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 clinical practice. The safety of ODOMZO was evaluated in Study 1, a randomized, double-blind, multiple cohort trial in which 229 patients received ODOMZO at either 200 mg (n=79) or 800 mg (n=150) daily. The frequency of common adverse reactions including muscle spasms, alopecia, dysgeusia, fatigue, nausea, decreased weight, decreased appetite, myalgia, pain, and vomiting was greater in patients treated with ODOMZO 800 mg as compared to 200 mg. The data described below reflect exposure to ODOMZO 200 mg daily in 79 patients with locally advanced BCC (laBCC; n=66) or metastatic BCC (mBCC; n=13) enrolled in Study 1. Patients were followed for at least 18 months unless discontinued earlier. The median duration of treatment with ODOMZO was 11.0 months (range 1.3 to 33.5 months). The study population characteristics were: median age of 67 years (range 25 to 92; 59% were ≥65 years), 61% male, and 90% white. The majority of patients had prior surgery (75%), radiotherapy (24%), systemic chemotherapy (4%), or topical or photodynamic therapies (18%) for treatment of BCC. No patient had prior exposure to a hedgehog pathway inhibitor. ODOMZO was permanently discontinued in 34% of patients or temporarily interrupted in 20% of patients for adverse reactions. Adverse reactions reported in at least two patients that led to discontinuation of the drug were: muscle spasms and dysgeusia (each 5%), asthenia, increased lipase, and nausea (each 4%), fatigue, decreased appetite, alopecia, and decreased weight (each 3%). Serious adverse reactions occurred in 18% of patients. The most common adverse reactions occurring in ≥10% of patients treated with ODOMZO 200 mg were muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus (Table 1). The key laboratory abnormalities are described in Table 2. Table 1: Adverse Reactions Occurring in ≥10% of Patients in Study 1  Adverse Reaction ODOMZO 200 mg (N=79) All Gradesa % Grade 3% Musculoskeletal and connective tissue disorders     Muscle spasms 54 3     Musculoskeletal pain 32 1     Myalgia 19 0 Skin and subcutaneous tissue disorder     Alopecia 53 0     Pruritus 10 0 Nervous system disorders     Dysgeusia 46 0     Headache 15 1 General disorders and administration site conditions     Fatigue 41 4     Pain 14 1 Gastrointestinal disorders     Nausea 39 1     Diarrhea 32 1     Abdominal pain 18 0     Vomiting 11 1 Investigations     Decreased weight 30 3 Metabolism and nutrition disorders     Decreased appetite 23 1 a No Grade 4 adverse reactions were reported. Table 2: Key Laboratory Abnormalitiesa Laboratory Test ODOMZO 200 mg (N=79) All Grades % Grades 3-4% Chemistry     Increased serum creatinine 92b 0     Increased serum creatine kinase (CK) 61 8     Hyperglycemia 51 4     Increased lipase 43 13     Increased alanine aminotransferase 19 4     Increased aspartate aminotransferase 19 4     Increased amylase 16 1 Hematology     Anemia 32 0     Lymphopenia 28 3 a Based on worst post-treatment laboratory value regardless of baseline; grading by CTCAE v4.03. b The serum creatinine level remained within normal range in 76% (60/79) of patients. Amenorrhea Amenorrhea lasting for at least 18 months occurred in two of 14 pre-menopausal women treated with ODOMZO 200 mg or 800 mg once daily. 7  DRUG INTERACTIONS 7.1  Effects of Other Drugs on Sonidegib Strong and Moderate CYP3A Inhibitors Avoid concomitant administration of ODOMZO with strong CYP3A inhibitors, including but not limited to saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole and nefazodone [see Clinical Pharmacology (12.3)]. Avoid concomitant administration of ODOMZO with moderate CYP3A inhibitors, including but not limited to atanzavir, diltiazem, and fluconazole. If a moderate CYP3A inhibitor must be used, administer the moderate CYP3A inhibitor for less than 14 days and monitor closely for adverse reactions particularly musculoskeletal adverse reactions [see Clinical Pharmacology (12.3)]. Strong and Moderate CYP3A Inducers Avoid concomitant administration of ODOMZO with strong and moderate CYP3A inducers, including but not limited to carbamazepine, efavirenz, modafinil, phenobarbital, phenytoin, rifabutin, rifampin and St. John’s Wort (Hypericum perforatum) [see Clinical Pharmacology (12.3)]. 8  USE IN SPECIFIC POPULATIONS 8.1  Pregnancy Risk Summary Based on its mechanism of action and data from animal reproduction studies, ODOMZO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of ODOMZO in pregnant women. In animal reproduction studies, oral administration of sonidegib during organogenesis at doses below the recommended human dose of 200 mg resulted in embryotoxicity, fetotoxicity, and teratogenicity in rabbits [see Data]. Teratogenic effects observed included severe midline defects, missing digits, and other irreversible malformations. Advise pregnant women of the potential risk to a fetus. Report pregnancies to Novartis Pharmaceuticals Corporation at 1-888-669-6682. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Data Animal Data Daily oral administration of sonidegib to pregnant rabbits resulted in abortion, complete resorption of fetuses, or severe malformations at ≥ 5 mg/kg/day (approximately 0.05 times the recommended human dose based on AUC). Teratogenic effects included vertebral, distal limb and digit malformations, severe craniofacial malformations, and other severe midline defects. Skeletal variations were observed when maternal exposure to sonidegib was below the limit of detection. 8.2  Lactation No data are available regarding the presence of sonidegib in human milk, the effects of the drug on the breast fed infant, or the effects of the drug on milk production. Because of the potential for serious adverse reactions in breastfed infants from sonidegib, advise a nursing woman not to breastfeed during treatment with ODOMZO and for 20 months after the last dose. 8.3  Females and Males of Reproductive Potential Based on its mechanism of action and animal data, ODOMZO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating ODOMZO treatment. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with ODOMZO and for at least 20 months after the last dose. Males It is not known if sonidegib is present in semen. Advise male patients to use condoms, even after a vasectomy, to avoid potential drug exposure to pregnant partners and female partners of reproductive potential during treatment with ODOMZO and for at least 8 months after the last dose. Advise males not to donate semen during treatment with ODOMZO and for at least 8 months after the last dose. Infertility Based on findings from animal studies, female fertility may be compromised with ODOMZO [see Nonclinical Toxicology (13.1)]. 8.4  Pediatric Use The safety and effectiveness of ODOMZO have not been established in pediatric patients. Juvenile Animal Data In a 5-week juvenile rat toxicology study, effects of sonidegib were observed in bone, teeth, reproductive tissues, and nerves at doses ≥10 mg/kg/day (approximately 1.2 times the recommended human dose based on AUC). Bone findings included thinning/closure of bone growth plate, decreased bone length and width, and hyperostosis. Findings in teeth included missing or fractured teeth, and atrophy. Reproductive tissue toxicity was evidenced by atrophy of testes, ovaries, and uterus, partial development of the prostate gland and seminal vesicles, and inflammation and aspermia of the epididymis. Nerve degeneration was also noted. 8.5  Geriatric Use Of the 229 patients who received ODOMZO (79 patients receiving 200 mg daily and 150 patients receiving 800 mg daily) in Study 1, 54% were 65 years and older, while 28% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. There was a higher incidence of serious adverse events, Grade 3 and 4 adverse events, and adverse events requiring dose interruption or discontinuation in patients ≥65 years compared with younger patients; this was not attributable to an increase in any specific adverse event. 8.6  Hepatic Impairment No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) >ULN or total bilirubin >1.0 to 1.5 times ULN). ODOMZO has not been studied in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3)]. 8.7  Renal Impairment No dose adjustment is recommended for patients with renal impairment [see Clinical Pharmacology (12.3)]. 10  OVERDOSAGE There are no recommendations regarding management of overdosage. 11  DESCRIPTION ODOMZO (sonidegib) is a Smoothened (Smo) antagonist which inhibits the Hedgehog (Hh) signaling pathway. The molecular formula for sonidegib phosphate is C26H26 F3N3O3• 2H3PO4. The molecular weight is 681.49 daltons. The chemical name is N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4’-(trifluoromethoxy) [1,1’-biphenyl]-3-carboxamide diphosphate. The molecular structure is shown below:  Sonidegib phosphate is a white to off-white powder. Sonidegib freebase is practically insoluble. Each ODOMZO capsule for oral use contains 200 mg of sonidegib as the freebase and the following inactive ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, poloxamer and sodium lauryl sulfate. The opaque pink hard gelatin capsule shell contains gelatin, red iron oxide, and titanium dioxide. The black printing ink contains ammonium hydroxide, black iron oxide, propylene glycol, and shellac. 12  CLINICAL PHARMACOLOGY 12.1  Mechanism of Action Sonidegib is an inhibitor of the Hedgehog pathway. Sonidegib binds to and inhibits Smoothened, a transmembrane protein involved in Hedgehog signal transduction. 12.2  Pharmacodynamics Cardiac Electrophysiology At a dose of 800 mg once daily, sonidegib does not prolong the QTc interval. 12.3  Pharmacokinetics Absorption Less than 10% of an oral dose of ODOMZO is absorbed. Following the administration of a single ODOMZO dose (100 mg to 3000 mg) under fasted conditions in patients with cancer, the median time-to-peak concentration (Tmax) was 2 to 4 hours. Sonidegib exhibited dose-proportional increases in the area under the curve (AUC) and the maximal concentration (Cmax) over the dose range of 100 mg to 400 mg, but less than dose-proportional increases at doses greater than 400 mg. Steady-state was reached approximately 4 months after starting ODOMZO and the estimated accumulation at steady-state was 19-fold. Following a dose of 200 mg once daily, the estimated mean steady-state Cmax is 1030 ng/mL, AUC0-24h is 22 μg*h/mL and minimal concentration (Cmin) is 890 ng/mL. A high-fat meal (approximately 1000 calories with 50% of calories from fat) increased exposure to sonidegib (geometric mean AUCinf and Cmax) by 7.4- to 7.8-fold [see Dosage and Administration (2.1)]. Distribution The estimated apparent steady-state volume of distribution (Vss/F) was 9,166 L. Sonidegib was highly bound to human plasma proteins in vitro (>97%) and the binding was concentration independent. In vitro studies suggested that sonidegib is not a substrate of ABCB1 (P-glycoprotein), ABCC2 (MRP2, cMOAT) or ABCG2 (BCRP). Elimination The elimination half-life (t1/2) of sonidegib estimated from population pharmacokinetic (PK) modeling was approximately 28 days. Metabolism Sonidegib is primarily metabolized by CYP3A. The main circulating compound was unchanged sonidegib (36% of circulating radioactivity). Excretion Sonidegib and its metabolites are eliminated primarily by the hepatic route. Of the absorbed dose, approximately 70% was eliminated in the feces and 30% was eliminated in the urine. Unchanged sonidegib was not detectable in the urine. Specific Populations Hepatic Impairment Based on the population PK analyses, mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) >ULN or total bilirubin >1.0 to 1.5 times ULN, n=35) had no effect on sonidegib steady-state exposure as compared to patients with normal hepatic function (total bilirubin ≤ULN and AST ≤ULN, n=315) [see Use in Specific Populations (8.6)]. Renal Impairment Based on the population PK analyses, mild (CLcr 60 to 89 mL/min, n=129) and moderate (CLcr 30 to 59 mL/min, n=60) renal impairment had no effect on sonidegib steady-state exposure as compared to patients with normal renal function (CLcr ≥90 mL/min, n=161) [see Use in Specific Populations (8.7)]. Age, Sex, Weight and Race Based on population PK analyses, age, body weight, or sex has no clinically meaningful effect on sonidegib exposure. A cross study comparison suggests that geometric mean AUCinf of sonidegib is 1.7-fold higher in Japanese healthy subjects compared to Western healthy subjects (Whites and Blacks) following a single 200 mg dose of ODOMZO. Drug Interaction Studies Effects of CYP3A Inhibitors on Sonidegib Strong CYP3A inhibitor: Healthy subjects received a single 800 mg dose of ODOMZO alone (n=16) or 5 days after starting oral ketoconazole (200 mg twice daily for 14 days) (n=15). The geometric mean sonidegib AUC0-10d increased by 2.2-fold and the Cmax increased by 1.5-fold when ODOMZO was taken with ketoconazole compared to ODOMZO alone [see Drug Interactions (7.1)]. Based on physiologic based pharmacokinetics (PBPK) simulations, the geometric mean sonidegib steady-state AUC0-24h would similarly increase in cancer patients taking ODOMZO 200 mg once daily when coadministered with a strong CYP3A inhibitor for 14 days. Moderate CYP3A inhibitor: Based on PBPK simulations, the geometric mean sonidegib steady-state AUC0-24h would increase 1.8-fold when ODOMZO 200 mg once daily is coadministered with a moderate CYP3A inhibitor (erythromycin) for 14 days and would increase 2.8-fold when ODOMZO 200 mg once daily is coadministered with a moderate CYP3A inhibitor (erythromycin) for 4 months. Effects of CYP3A Inducers on Sonidegib Strong CYP3A inducer: Healthy subjects received a single 800 mg dose of ODOMZO alone (n=16) or 5 days after starting oral rifampicin (600 mg daily for 14 days) (n=16). The geometric mean sonidegib AUC0-10d decreased by 72% and the Cmax decreased by 54% when ODOMZO was taken with rifampicin compared to ODOMZO alone [see Drug Interactions (7.1)]. Moderate CYP3A inducer: Based on PBPK simulations, the geometric mean sonidegib steady-state AUC0-24h would decrease 56% in cancer patients taking ODOMZO 200 mg once daily when coadministered with a moderate CYP3A inducer (efavirenz) for 14 days and would decrease 69% when coadministered with a moderate CYP3A inducer (efavirenz) for 4 months [see Drug Interactions (7.1)]. Effect of Sonidegib on Cytochrome P450 Enzymes and Transporters In vitro studies suggested that sonidegib inhibits CYP2B6 and CYP2C9 and it does not induce CYP1A2, CYP2B6 or CYP3A expression or activity. In vitro studies suggested that sonidegib inhibits ABCG2, but it does not inhibit ABCB1, ABCC2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2. Effect of Acid Reducing Agents on Sonidegib Based on population PK analysis, concomitant administration of a proton pump inhibitor or a histamine-2-receptor antagonist decreases the geometric mean sonidegib steady-state AUC0-24h by 34%. 13  NONCLINICAL TOXICOLOGY 13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with sonidegib have not been performed. Sonidegib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay and was not clastogenic or aneugenic in the in vitro human chromosome aberration assay or in vivo rat bone marrow micronucleus assay. Sonidegib resulted in a lack of fertility when administered to female rats at ≥20 mg/kg/day (approximately 1.3 times the recommended human dose based on body surface area (BSA). A reduction of the number of pregnant females, an increase in the number of early resorptions, and a decrease in the number of viable fetuses was also noted at 2 mg/kg/day (approximately 0.12 times the recommended human dose based on BSA). In addition, in a 6 month repeat-dose toxicology study in rats, effects on female reproductive organs included atrophy of the uterus and ovaries at doses of 10 mg/kg (approximately ≥2 times the exposure in humans at the recommended dose of 200 mg based on AUC). No adverse effects on fertility were noted when male rats were administered sonidegib at doses up to 20 mg/kg/day, the highest dose tested. 13.2  Animal Toxicology and/or Pharmacology Body tremors along with significant increases in creatine kinase were observed in rats administered oral sonidegib for 13 weeks or longer at ≥10 mg/kg/day (approximately ≥2 times the recommended human dose based on AUC). 14  CLINICAL STUDIES The safety and effectiveness of ODOMZO were evaluated in a single, multicenter, double-blind, multiple cohort clinical trial conducted in patients with locally advanced basal cell carcinoma (laBCC) (n=194) or metastatic basal cell carcinoma (mBCC) (n=36) (Study 1). Patients were randomized (2:1) to receive either ODOMZO 800 mg or 200 mg orally, once daily, until disease progression or intolerable toxicity. Randomization was stratified by stage of disease (locally advanced or metastatic), laBCC disease histology (aggressive vs. non-aggressive), and geographic region. Patients with laBCC were required to have lesions for which radiotherapy was contraindicated or inappropriate (e.g., Gorlin syndrome or limitations because of location of tumor), that had recurred after radiotherapy, that were unresectable or for which surgical resection would result in substantial deformity, or that had recurred after prior surgical resection. The major efficacy outcome measure of the trial was objective response rate (ORR) as determined by blinded central review according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) for patients with laBCC or RECIST version 1.1 for patients with mBCC. Duration of response (DoR), determined by blinded central review, was a key secondary outcome measure. For patients with laBCC, the evaluation of tumor response was based on a composite assessment that integrated tumor measurements obtained by radiographic assessments of target lesions (per RECIST 1.1), digital clinical photography, and histopathology assessments (via punch biopsies). All modalities used must have demonstrated absence of tumor to achieve a composite assessment of complete response (CR). Response by digital clinical photography was evaluated by World Health Organization (WHO) adapted criteria [partial response (PR): ≥50% decrease in the sum of the product of perpendicular diameters (SPD) of the lesions, CR: disappearance of all lesions, progressive disease (PD): ≥25% increase in the SPD of the lesions]. Multiple punch biopsies of target lesions were performed to confirm a CR or when a response assessment was confounded by presence of lesion ulceration, cyst, and or scarring/fibrosis. A total of 66 patients randomized to ODOMZO 200 mg daily had laBCC. Three of these patients had a diagnosis of Gorlin Syndrome. The demographic characteristics of the 66 patients with laBCC were: median age of 67 years (range: 25 to 92 years; 58% were ≥65 years); 58% male, 89% white, and ECOG performance status of 0 (67%). Seventy-six percent of patients had prior therapy for treatment of BCC; this included surgery (73%), radiotherapy (18%), and topical/photodynamic therapies (21%). Approximately half of these patients (56%) had aggressive histology. Patients with laBCC randomized to receive ODOMZO 200 mg daily were followed for at least 12 months unless discontinued earlier. The ORR was 58% (95% confidence interval: 45, 70), consisting of 3 (5%) complete responses and 35 (53%) partial responses. A pre-specified sensitivity analysis using an alternative definition for complete response, defined as at least a PR according to MRI and/or photography and no evidence of tumor on biopsy of the residual lesion, yielded a CR rate of 20%. Among the 38 patients with an objective response, 7 (18%) patients experienced subsequent disease progression with 4 of these 7 patients having maintained a response of 6 months or longer. The remaining 31 patients (82%) have ongoing responses ranging from to 1.9+ to 18.6+ months and the median duration of response has not been reached. A total of 128 patients randomized to ODOMZO 800 mg daily had laBCC. Twelve of these patients had a diagnosis of Gorlin Syndrome. There was no evidence of better antitumor activity (ORR) among patients with laBCC randomized to receive ODOMZO 800 mg daily and followed for at least 12 months unless discontinued earlier. 16 HOW SUPPLIED/STORAGE AND HANDLING Each ODOMZO capsule has an opaque pink color with ‘SONIDEGIB 200MG’ printed on the capsule body and ‘NVR’ printed on the cap in black ink. ODOMZO capsules are supplied as follows: Bottle of 30 capsules          NDC 0078-0645-15 Unit dose blister package of 30 capsules        NDC 0078-0645-30 Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. 17  PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Embryo-Fetal Toxicity [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)]. Advise female patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ODOMZO and for at least 20 months after the last dose. Advise males, even those with prior vasectomy, to use condoms, to avoid potential drug exposure in both pregnant partners and female partners of reproductive potential during treatment with ODOMZO and for at least 8 months after the last dose. Advise female patients and female partners of male patients to contact their healthcare provider with a known or suspected pregnancy. Advise females who may have been exposed to ODOMZO during pregnancy, either directly or through seminal fluid, to contact the Novartis Pharmaceuticals Corporation at 1-888-669-6682. Blood Donation Advise patients not to donate blood or blood products while taking ODOMZO and for 20 months after stopping treatment. Musculoskeletal Adverse Reactions Advise patients to contact their healthcare provider immediately for new or worsening signs or symptoms of muscle toxicity, dark urine, decreased urine output, or the inability to urinate [see Warnings and Precautions (5.2)]. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=77bd079b-7168-454a-ac38-963f8ba34324 美国FDA批准诺华药物Odomzo®（sonidegib），用于局部晚期基底细胞癌（laBCC），皮肤癌的一种形式 2015年7月24日，诺华公司今天宣布，美国食品和药物管理局FDA批准Odomzo®（sonidegib，原LDE225）200毫克胶囊成年患者的局部晚期基底细胞癌（laBCC）治疗已复发下列手术或放射治疗，或谁是不适合外科手术或放射治疗。 “Odomzo的FDA批准提供了一个新的，非侵入性的治疗选择的潜在破坏性的疾病，是很难治疗，可以是毁容，”布鲁诺Strigini，总裁，诺华肿瘤说。“Odomzo是一个重要的除了我们的成长有针对性的治疗组合先进的皮肤癌，并强调了我们致力于开发和向市场为患者的新选择的承诺。” 该Odomzo批准是基于一个持久的目标响应率（ORR）在国际多中心，双盲，随机，双臂，患者laBCC不适于局部治疗或转移性非比较试验的示范基底细胞癌（MBCC）。 患者laBCC与Odomzo 200毫克（N = 66），治疗随访至少12个月，除非更早停产。ORR为58％（95％置信区间：45，70），由5％（N = 3）完全缓解（CR）和53％（N = 35），部分缓解（PR）。根据MRI和/或摄影，没有证据表明对肿瘤病灶残留活检的至少PR预先指定的敏感性分析使用的CR替代的定义，定义为，产生了CR率为20％。其中38例患者有客观反应，31例（82％）有持续反应，从至少1.9至18.6个月，响应时间中位数尚未达到。 Odomzo的最严重的风险是胚胎-胎仔毒性和肌肉骨骼不良反应，包括横纹肌溶解症。肌肉骨骼不良反应，这可能伴有血清肌酸激酶（CK）升高，可能与Odomzo和其他药物抑制刺猬蛋白通路发生。肌肉骨骼不良反应的患者laBCC与Odomzo 200毫克处理的发生率为68％，9％，报告为3级或以与Odomzo 200毫克处理是肌肉痉挛的病人的10％以上发生4.不良反应，脱发，味觉障碍，乏力，恶心，肌肉骨骼痛，腹泻，体重下降，食欲下降，肌肉痛，腹痛，头痛，疼痛，呕吐，瘙痒。的患者为至少5％发生的最常见的3级和4级实验室异常是血清肌酸激酶（CK）升高和脂肪酶海拔。 关于螺栓临床试验 数据的二期，随机，双盲多中心螺栓（基底细胞癌成果LDE225试行）形成了FDA的批准依据。主要终点是与Odomzo 200毫克和800毫克的治疗的患者的ORR，定义为患者证实完全或部分肿瘤应答，或收缩的比例，如通过一个中央审查委员会测量。有患者中laBCC没有证据更好ORR的随机分配接受每天Odomzo 800毫克。 肿瘤反应的评估是基于实体瘤（mRECIST），其通过整合目标病灶（RECIST每1.1），数码摄影的临床影像学评估获得的肿瘤测量修改疗效评价标准的综合评估（世界卫生组织（WHO）改编条件），和组织病理学评估（通过钻取活组织检查）。必须使用已经证明不存在肿瘤所有方式来实现CR的复合评估。 关于基底细胞癌 的BCC由出现在皮肤的基底细胞，其中一线表皮的最深层（皮肤的最外层）异常，不受控制的生长或病变和占80％以上的非黑素瘤皮肤癌。它最常发生在头部和颈部，用鼻子是最常见的部位。BCC进行传播，从那里开始到附近的组织被称为局部晚期[8]和可高度毁容。先进的BCC被认为代表的BCC所有病例的大约1-10％的。而BCC通常诊断和早期治疗，则可能在五年后的患者，估计的3％复发。虽然BCC很少成为先进，有在此阶段的疾病的已治疗选择很少。BCC的发病率在全球是每年10％，原因是上升的因素，如人口老龄化和增加紫外线照射。发病率估计为全世界0.003％和0.55％之间。 关于Odomzo Odomzo（sonidegib，原LDE225）是一种口服的，有选择性的平滑（SMO）抑制剂被FDA批准用于成人患者的局部晚期基底细胞癌（laBCC）治疗已复发手术或放射治疗，或谁是不适合手术或放射治疗。SMO是调节刺猬（Hh）信号通路，它在干细胞维持和组织修复的关键角色，以及在先进基底细胞癌的分子。Odomzo目前在其他疾病的临床开发。 Odomzo被批准在瑞士的先进BCC的治疗是不适合根治性手术或放疗6月30日，2015年CHMP给予了积极的意见6月25日，2015年更多的监管意见书是由卫生当局正在审查全球范围内。  重要安全信息 含200毫克sonidegib硬明胶胶囊。 适应症： Odomzo被指示为成人患者的治疗局部晚期基底细胞癌（BCC）谁不适合于治疗性手术或放射治疗。 用法与用量： 成人：口服，每日一次空腹，每天服用，同时一200毫克的剂量。儿童： 安全性和有效性尚未确定在儿童患者中有BCC。 肾功能不全患者：Sonidegib尚未研究患者的肾功能损害。根据现有数据，通过肾脏sonidegib淘汰是可以忽略不计。群体药代动力学分析，未发现肾功能上sonidegib表明调整剂量的表观清除率（CL / F）显著的影响是没有必要患者的肾功能损害。 肝损伤患者：没有必要调整剂量的患者有轻度（Child-Pugh分级A级）或中度（Child-Pugh分级B级）肝功能损害。Sonidegib尚未研究的患者有严重肝损伤（Child-Pugh分级C级）。应谨慎，因此患者严重肝损伤被使用。 禁忌： 妇女谁是怀孕或哺乳。 警告和注意事项： 肌肉相关的不良事件：肌酸磷酸激酶（CK）水平应在开始治疗前和其后作为临床指征，例如，如果肌肉相关的症状报告检查。如果检测到的CK的临床显着升高，肾功能进行评估。调整剂量或中断的准则应遵循。患者应为肌肉相关的症状进行密切监测如果Odomzo用于与某些药物组合，可能会增加显影肌肉毒性（例如CYP3A4抑制剂，氯喹，羟氯喹，纤维酸衍生物，青霉胺，齐多夫定，烟酸，HMG辅酶A的潜在风险还原酶抑制剂）。 密切监测患者的神经肌肉障碍（例如炎性肌病，肌营养不良，肌萎缩性侧索硬化症和脊髓性肌萎缩）由于肌肉毒性的风险增加。 献血： 应指导患者不能献血而采取Odomzo和治疗结束后至少20个月。 女性生育潜力： 育龄妇女必须采用避孕的一种非常有效的方法，同时接收Odomzo。避孕必须持续治疗结束后20个月。 妊娠： 阴性妊娠状态必须通过由健康护理提供者之前Odomzo治疗开始进行一个试验来确认。Odomzo不能在怀孕期间使用。 哺乳： 女性不能母乳喂养同时服用Odomzo和治疗结束后至少20个月。 性活跃的男性： 男性不应该的父亲一个孩子或捐赠同时服用Odomzo精液和进行至少6个月结束后的治疗。性活跃的男性必须使用安全套，无论输精管结扎地位，性交过程中和至少6个月结束治疗，以防止通过精液的女性伴侣对药物曝光后。 生育： 男性和女性的生育能力可能会受到影响与Odomzo。保留生育功能的策略之前，应先用Odomzo开始治疗的讨论。 药物不良反应： 很常见（> = 10％）：闭经，食欲下降，味觉障碍，头痛，恶心，腹泻，呕吐，腹痛，脱发，皮肤瘙痒，肌肉痉挛，肌肉痛，肌肉骨骼疼痛，乏力，疼痛，体重下降。 常见（介于1至10％）：便秘，消化不良，胃食道反流症，皮疹，异常毛发生长，肌病（肌肉疲劳和肌肉无力），脱水。 实验室异常： 非常常见（> = 10％）：血红蛋白减少，淋巴细胞计数下降，淀粉酶增加，血糖升高，脂肪酶升高，血清肌酸磷酸增加，血清肌酐升高，丙氨酸氨基转氨酶（ALT）升高，天冬氨酸氨基转氨酶（ AST）升高。 相互作用： 避免同时使用强CYP3A抑制剂，包括但不限于利托那韦，沙奎那韦，泰利霉素，酮康唑，伊曲康唑，伏立康唑，泊沙康唑和奈法唑酮。 避免同时使用强CYP3A诱导剂，包括但不限于卡马西平，苯巴比妥，苯妥英钠，利福布丁，利福平和圣约翰草（贯叶连翘）。如果一个强CYP3A诱导剂必须同时使用与sonidegib，应考虑到增加sonidegib的剂量由200毫克的增量为最大日剂量为800毫克。 仔细监测患者的药物不良反应与同时使用CYP2B6 CYP2C9和酶或BCRP转运，尤其是那些有狭窄的治疗范围的底物。 由于重叠的毒性，考虑Odomzo谁也采取已知增加肌肉相关的毒性的风险的药物的患者可以是有发展肌肉相关的不良事件的风险增加。患者应密切监测，如果肌肉症状发展的剂量调整应予以考虑。