Sonidegib: Difference between revisions

Sonidegib
	Black Box Warning
	Adult Indications & Dosage
	Pediatric Indications & Dosage
	Contraindications
	Warnings & Precautions
	Adverse Reactions
	Drug Interactions
	Use in Specific Populations
	Administration & Monitoring
	Overdosage
	Pharmacology
	Clinical Studies
	How Supplied
	Images
	Patient Counseling Information
	Precautions with Alcohol
	Brand Names
	Look-Alike Names

VisualWikitext

Latest revision as of 19:34, 19 January 2017

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [2]

Disclaimer

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Black Box Warning

EMBRYO-FETAL TOXICITY

See full prescribing information for complete Boxed Warning.

-Sonidegib can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. Sonidegib is embryotoxic, fetotoxic, and teratogenic in animals.

-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 Sonidegib and for at least 20 months after the last dose.

-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 Sonidegib and for at least 8 months after the last dose.

Overview

Sonidegib is a hedgehog pathway inhibitor that is FDA approved 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. There is a Black Box Warning for this drug as shown here. Common adverse reactions include muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus (≥10%).

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

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.

Dosage

The recommended dose of Sonidegib 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.

Verify the pregnancy status of females of reproductive potential prior to initiating Sonidegib. Obtain serum creatine kinase (CK) levels and renal function tests prior to initiating Sonidegib in all patients.

If a dose of Sonidegib is missed, resume dosing with the next scheduled dose.

Dose Modifications

Interrupt Sonidegib 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 Sonidegib at 200 mg daily upon resolution of clinical signs and symptoms.

Permanently discontinue Sonidegib 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.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Pimavanserin in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Pimavanserin in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

The safety and effectiveness of Sonidegib have not been established in pediatric patients

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Pimavanserin in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Pimavanserin in pediatric patients.

Contraindications

None

Warnings

EMBRYO-FETAL TOXICITY

See full prescribing information for complete Boxed Warning.

-Sonidegib can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. Sonidegib is embryotoxic, fetotoxic, and teratogenic in animals.

-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 Sonidegib and for at least 20 months after the last dose.

-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 Sonidegib and for at least 8 months after the last dose.

Embryo-fetal Toxicity

Sonidegib 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.

Females of Reproductive Potential

Verify pregnancy status of females of reproductive potential prior to initiating Sonidegib treatment. Advise females to use effective contraception during treatment with Sonidegib and for at least 20 months after the last dose.

Males

Advise male patients with female partners to use condoms, even after a vasectomy, during treatment with Sonidegib and for at least 8 months after the last dose to avoid potential drug exposure in pregnant females or females of reproductive potential.

Blood Donation

Advise patients not to donate blood or blood products while taking Sonidegib and for at least 20 months after the last dose of Sonidegib because their blood or blood products might be given to a female of reproductive potential.

Musculoskeletal Adverse Reactions

Musculoskeletal adverse reactions, which may be accompanied by serum creatine kinase (CK) elevations, occur with Sonidegib 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 Sonidegib 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 Sonidegib 800 mg.

In Study 1, musculoskeletal adverse reactions occurred in 68% (54/79) of patients treated with Sonidegib 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). Sonidegib 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 Sonidegib, 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. Advise patients starting therapy with Sonidegib 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 Sonidegib.

Adverse Reactions

Clinical Trials 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 Sonidegib was evaluated in Study 1, a randomized, double-blind, multiple cohort trial in which 229 patients received Sonidegib 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 Sonidegib 800 mg as compared to 200 mg.

The data described below reflect exposure to Sonidegib 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 Sonidegib 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.

Sonidegib 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 Sonidegib 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

This image is provided by the National Library of Medicine.

ODOMZO: Sonidegib's Brand name

Table 2: Key Laboratory Abnormalities(a)

ODOMZO: Sonidegib's Brand name

Amenorrhea

Amenorrhea lasting for at least 18 months occurred in two of 14 pre-menopausal women treated with Sonidegib 200 mg or 800 mg once daily.

Postmarketing Experience

There is limited information regarding Sonidegib Postmarketing Experience in the drug label.

Drug Interactions

Effects of Other Drugs on Sonidegib

Strong and Moderate CYP3A Inhibitors

Avoid concomitant administration of Sonidegib with strong CYP3A inhibitors, including but not limited to saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole and nefazodone.

Avoid concomitant administration of Sonidegib with moderate CYP3A inhibitors, including but not limited to atazanavir, 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.

Strong and Moderate CYP3A Inducers

Avoid concomitant administration of Sonidegib 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).

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): N

Risk Summary

Based on its mechanism of action and data from animal reproduction studies, Sonidegib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Sonidegib 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. 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.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sonidegib in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Sonidegib during labor and delivery.

Nursing Mothers

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 Sonidegib and for 20 months after the last dose.

Pediatric Use

The safety and effectiveness of Sonidegib 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.

Geriatic Use

Of the 229 patients who received Sonidegib (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.

Gender

There is no FDA guidance on the use of Sonidegib with respect to specific gender populations.

Race

There is no FDA guidance on the use of Sonidegib with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Sonidegib in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Sonidegib in patients with hepatic impairment.

Females of Reproductive Potential and Males

Based on its mechanism of action and animal data, Sonidegib can cause fetal harm when administered to a pregnant woman.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating Sonidegib treatment.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with Sonidegib 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 Sonidegib and for at least 8 months after the last dose. Advise males not to donate semen during treatment with Sonidegib and for at least 8 months after the last dose.

Infertility

Based on findings from animal studies, female fertility may be compromised with Sonidegib.

Immunocompromised Patients

There is no FDA guidance one the use of Sonidegib in patients who are immunocompromised.

Administration and Monitoring

Administration

The recommended dose of Sonidegib 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.

Monitoring

There is limited information regarding Sonidegib Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Sonidegib and IV administrations.

Overdosage

There are no recommendations regarding management of overdosage.

Pharmacology


Sonidegib
Systematic (IUPAC) name
N-[6-[(2S,6R)-2,6-Dimethylmorpholin-4-yl]pyridin-3-yl]-2-methyl-3-[4-(trifluoromethoxy)phenyl]benzamide
Identifiers
CAS number	?
ATC code	L01XX48
PubChem	24775005
Chemical data
Formula	Template:OrganicBox atom Template:OrganicBox atom Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox atom Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox atom Template:OrganicBox Template:OrganicBox atom Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox
Mol. mass	485.498 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	<10%
Protein binding	>97%
Metabolism	Liver (CYP3A)
Half life	~28 days
Excretion	Feces (~70%), urine (30%)^[1]
Therapeutic considerations
Pregnancy cat.	?
Legal status	[[Prescription drug\|Template:Unicode-only]](US)
Routes	By mouth (capsules)

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.

Structure

There is limited information regarding Sonidegib Structure in the drug label.

Pharmacodynamics

There is limited information regarding Sonidegib Pharmacodynamics in the drug label.

Pharmacokinetics

Absorption

Less than 10% of an oral dose of Sonidegib is absorbed. Following the administration of a single Sonidegib 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 Sonidegib 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, AUC(0-24h) 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 AUC(inf) and Cmax) by 7.4- to 7.8-fold.

Distribution

The estimated apparent steady-state volume of distribution (Vss/F) was 9,166 L. Sonidegib was greater than 97% bound to human plasma proteins in vitro and the binding was concentration independent. In vitro studies suggested that sonidegib is not a substrate of P-glycoprotein, MRP2 or 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

Mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment had no clinically meaningful effect on Sonidegib exposure as compared to subjects with normal hepatic function.

Renal Impairment

Mild (CLcr 60 to 89 mL/min) and moderate (CLcr 30 to 59 mL/min) renal impairment had no effect on Sonidegib steady-state exposure as compared to patients with normal renal function (CLcr ≥90 mL/min).

Age, Sex, Weight and Race

Age, body weight, or sex had no clinically meaningful effect on Sonidegib steady-state 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 Sonidegib.

Drug Interaction Studies

Effects of CYP3A Inhibitors on Sonidegib

Strong CYP3A inhibitor: The geometric mean Sonidegib AUC(0-10d) increased by 2.2-fold and the Cmax increased by 1.5-fold when Sonidegib at a dose of 800 mg was taken with ketoconazole compared to Sonidegib alone. The geometric mean sonidegib steady-state AUC(0-24h) would similarly increase in cancer patients taking Sonidegib 200 mg once daily when coadministered with a strong CYP3A inhibitor for 14 days.

Moderate CYP3A inhibitor: The geometric mean sonidegib steady-state AUC(0-24h) would increase 1.8-fold when Sonidegib 200 mg once daily is coadministered with a moderate CYP3A inhibitor (erythromycin) for 14 days and would increase 2.8-fold when Sonidegib 200 mg once daily is coadministered with a moderate CYP3A inhibitor (erythromycin) for 4 months.

Effects of CYP3A Inducers on Sonidegib

Strong CYP3A inducer: The geometric mean Sonidegib AUC(0-10d) decreased by 72% and the Cmax decreased by 54% when Sonidegib at a dose of 800 mg was taken with rifampicin compared to Sonidegib alone.

Moderate CYP3A inducer: The geometric mean Sonidegib steady-state AUC(0-24h) would decrease 56% in cancer patients taking Sonidegib 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.

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 BCRP, but not P-glycoprotein, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2.

Effect of Acid Reducing Agents on Sonidegib

No clinically meaningful effect on Sonidegib exposure was observed when Sonidegib at dose of 200 mg was coadministered with esomeprazole, a proton pump inhibitor.

Nonclinical Toxicology

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.

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).

Clinical Studies

The safety and effectiveness of Sonidegib 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 Sonidegib 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 Sonidegib 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 Sonidegib 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 Sonidegib 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 Sonidegib 800 mg daily and followed for at least 12 months unless discontinued earlier.

How Supplied

Each Sonidegib capsule has an opaque pink color with ‘SONIDEGIB 200MG’ printed on the capsule body and ‘NVR’ printed on the cap in black ink. Sonidegib capsules are supplied as follows:

Bottle of 30 capsules (NDC 0078-0645-15)

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Images

Drug Images

{{#ask: Page Name::Sonidegib |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

{{#ask: Label Page::Sonidegib |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling.

Embryo-Fetal Toxicity

Advise female patients of the potential risk to a fetus.
Advise females of reproductive potential to use effective contraception during treatment with Sonidegib 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 Sonidegib 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 Sonidegib 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 Sonidegib 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.

Administration Instructions

Advise patients to take Sonidegib on an empty stomach, at least 1 hour before or 2 hours after a meal.

Lactation

Advise women not to breastfeed during treatment with Sonidegib and for up to 20 months after the last dose.

Precautions with Alcohol

Alcohol-Sonidegib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

ODOMZO®

Look-Alike Drug Names

There is limited information regarding Sonidegib Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

↑ "Odomzo (sonidegib) Capsules, for Oral Use. Full Prescribing Information" (PDF). Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936. Retrieved 2 October 2016.

[PI-1] "Odomzo (sonidegib) Capsules, for Oral Use. Full Prescribing Information" (PDF). Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936. Retrieved 2 October 2016.

[1]

@@ Line 3: / Line 3: @@
 |genericName=Sonidegib
 |aOrAn=a
-|drugClass=hedgehog pathway inhibitor
+|drugClass=[[Hedgehog signaling pathway|hedgehog pathway inhibitor]]
 |indicationType=treatment
-|indication=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
+|indication=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
 |hasBlackBoxWarning=Yes
-|adverseReactions=muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus (≥10%)
+|adverseReactions=[[muscle spasms]], [[alopecia]], [[dysgeusia]], [[fatigue]], [[nausea]], [[musculoskeletal pain]], [[diarrhea]], decreased weight, decreased appetite, [[myalgia]], [[abdominal pain]], [[headache]], [[pain]], [[vomiting]], and [[pruritus]] (≥10%)
 |blackBoxWarningTitle=EMBRYO-FETAL TOXICITY
-|blackBoxWarningBody=:*Sonidegib can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. Sonidegib is embryotoxic, fetotoxic, and teratogenic in animals.
+|blackBoxWarningBody=-Sonidegib can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. Sonidegib is embryotoxic, fetotoxic, and teratogenic in animals.
-:*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 Sonidegib and for at least 20 months after the last dose.
+-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 Sonidegib and for at least 20 months after the last dose.
-:*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 Sonidegib and for at least 8 months after the last dose.
+-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 Sonidegib and for at least 8 months after the last dose.
-|fdaLIADAdult=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.
+|fdaLIADAdult=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.
 ======Dosage======
-The recommended dose of Sonidegib 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.
+The recommended dose of Sonidegib 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]].
-Verify the pregnancy status of females of reproductive potential prior to initiating Sonidegib. Obtain serum creatine kinase (CK) levels and renal function tests prior to initiating Sonidegib in all patients.
+Verify the pregnancy status of females of reproductive potential prior to initiating Sonidegib. Obtain serum [[creatine kinase]] (CK) levels and [[renal function]] tests prior to initiating Sonidegib in all patients.
 If a dose of Sonidegib is missed, resume dosing with the next scheduled dose.
@@ Line 27: / Line 27: @@
 Interrupt Sonidegib for:
-::*Severe or intolerable musculoskeletal adverse reactions.
+::*Severe or intolerable [[musculoskeletal]] adverse reactions.
-::*First occurrence of serum CK elevation between 2.5 and 10 times upper limit of normal (ULN).
+::*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.
+::*Recurrent serum [[CK]] elevation between 2.5 and 5 times ULN.
 Resume Sonidegib at 200 mg daily upon resolution of clinical signs and symptoms.
@@ Line 35: / Line 35: @@
 Permanently discontinue Sonidegib for:
-::*Serum CK elevation greater than 2.5 times ULN with worsening renal function.
+::*Serum [[CK]] elevation greater than 2.5 times ULN with worsening [[renal function]].
-::*Serum CK elevation greater than 10 times ULN.
+::*Serum [[CK]] elevation greater than 10 times ULN.
-::*Recurrent serum CK elevation greater than 5 times ULN.
+::*Recurrent serum [[CK]] elevation greater than 5 times ULN.
-::*Recurrent severe or intolerable musculoskeletal adverse reactions.
+::*Recurrent severe or intolerable [[musculoskeletal]] adverse reactions.
+|offLabelAdultGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Pimavanserin in adult patients.
+|offLabelAdultNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Pimavanserin in adult patients.
 |fdaLIADPed=The safety and effectiveness of Sonidegib have not been established in pediatric patients
+|offLabelPedGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Pimavanserin in pediatric patients.
+|offLabelPedNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Pimavanserin in pediatric patients.
 |contraindications=None
 |warnings=======Embryo-fetal Toxicity======
-Sonidegib 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.
+Sonidegib 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.
 :*Females of Reproductive Potential
-Verify pregnancy status of females of reproductive potential prior to initiating Sonidegib treatment. Advise females to use effective contraception during treatment with Sonidegib and for at least 20 months after the last dose.
+Verify pregnancy status of females of reproductive potential prior to initiating Sonidegib treatment. Advise females to use effective [[contraception]] during treatment with Sonidegib and for at least 20 months after the last dose.
 :*Males
-Advise male patients with female partners to use condoms, even after a vasectomy, during treatment with Sonidegib and for at least 8 months after the last dose to avoid potential drug exposure in pregnant females or females of reproductive potential.
+Advise male patients with female partners to use condoms, even after a [[vasectomy]], during treatment with Sonidegib and for at least 8 months after the last dose to avoid potential drug exposure in pregnant females or females of reproductive potential.
-:*Blood Donation
+:*[[Blood Donation]]
-Advise patients not to donate blood or blood products while taking Sonidegib and for at least 20 months after the last dose of Sonidegib because their blood or blood products might be given to a female of reproductive potential.
+Advise patients not to donate blood or [[blood products]] while taking Sonidegib and for at least 20 months after the last dose of Sonidegib because their blood or blood products might be given to a female of reproductive potential.
-======Musculoskeletal Adverse Reactions======
+======[[Musculoskeletal]] Adverse Reactions======
-Musculoskeletal adverse reactions, which may be accompanied by serum creatine kinase (CK) elevations, occur with Sonidegib and other drugs which inhibit the hedgehog pathway.
+Musculoskeletal adverse reactions, which may be accompanied by serum [[creatine kinase]] (CK) elevations, occur with Sonidegib and other drugs which inhibit the [[Hedgehog signaling pathway|hedgehog pathway]].
-In a pooled safety analysis of 12 clinical studies involving 571 patients with various advanced cancers treated with Sonidegib 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 Sonidegib 800 mg.
+In a pooled safety analysis of 12 [[clinical studies]] involving 571 patients with various advanced cancers treated with Sonidegib 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 Sonidegib 800 mg.
-In Study 1, musculoskeletal adverse reactions occurred in 68% (54/79) of patients treated with Sonidegib 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). Sonidegib 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.
+In Study 1, [[musculoskeletal]] adverse reactions occurred in 68% (54/79) of patients treated with Sonidegib 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). Sonidegib 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 relaxant]]s, 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 Sonidegib, 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. Advise patients starting therapy with Sonidegib 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 Sonidegib.
+Obtain baseline [[serum]] [[CK]] and [[creatinine]] levels prior to initiating Sonidegib, 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. Advise patients starting therapy with Sonidegib 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 Sonidegib.
-|clinicalTrials=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.
+|clinicalTrials=Because [[clinical trial]]s 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 Sonidegib was evaluated in Study 1, a randomized, double-blind, multiple cohort trial in which 229 patients received Sonidegib 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 Sonidegib 800 mg as compared to 200 mg.
+The safety of Sonidegib was evaluated in Study 1, a randomized, double-blind, multiple cohort trial in which 229 patients received Sonidegib 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 Sonidegib 800 mg as compared to 200 mg.
-The data described below reflect exposure to Sonidegib 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 Sonidegib 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.
+The data described below reflect exposure to Sonidegib 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 Sonidegib 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 signaling pathway|hedgehog pathway inhibitor]].
-Sonidegib 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.
+Sonidegib 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 Sonidegib 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 most common adverse reactions occurring in ≥10% of patients treated with Sonidegib 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
+:*'''Table 1: Adverse Reactions Occurring in ≥10% of Patients in Study 1'''
+[[File:table1_soni.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
+ODOMZO: Sonidegib's Brand name
-TABLE 2
+:*'''Table 2: Key Laboratory Abnormalities(a)'''
+[[File:table2_soni.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
+ODOMZO: Sonidegib's Brand name
-:*Amenorrhea
+:*[[Amenorrhea]]
-Amenorrhea lasting for at least 18 months occurred in two of 14 pre-menopausal women treated with Sonidegib 200 mg or 800 mg once daily.
+Amenorrhea lasting for at least 18 months occurred in two of 14 [[pre-menopausal]] women treated with Sonidegib 200 mg or 800 mg once daily.
 |drugInteractions=======Effects of Other Drugs on Sonidegib======
-:*Strong and Moderate CYP3A Inhibitors
+:*Strong and Moderate [[CYP3A]] Inhibitors
-Avoid concomitant administration of Sonidegib with strong CYP3A inhibitors, including but not limited to saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole and nefazodone.
+Avoid concomitant administration of Sonidegib with strong CYP3A inhibitors, including but not limited to [[saquinavir]], [[telithromycin]], [[ketoconazole]], [[itraconazole]], [[voriconazole]], [[posaconazole]] and [[nefazodone]].
-Avoid concomitant administration of Sonidegib with moderate CYP3A inhibitors, including but not limited to atazanavir, 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.
+Avoid concomitant administration of Sonidegib with moderate [[CYP3A]] inhibitors, including but not limited to [[atazanavir]], [[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.
-:*Strong and Moderate CYP3A Inducers
+:*Strong and Moderate [[CYP3A]] Inducers
-Avoid concomitant administration of Sonidegib 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).
+Avoid concomitant administration of Sonidegib 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]]).
 |FDAPregCat=N
 |useInPregnancyFDA=:*Risk Summary
-Based on its mechanism of action and data from animal reproduction studies, Sonidegib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Sonidegib 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. 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.
+Based on its mechanism of action and data from animal reproduction studies, Sonidegib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Sonidegib 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. [[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.
+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
@@ Line 104: / Line 112: @@
 ::*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.
+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.
 |useInNursing=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 Sonidegib and for 20 months after the last dose.
 |useInPed=The safety and effectiveness of Sonidegib have not been established in pediatric patients.
@@ Line 110: / Line 118: @@
 :*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.
+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.
 |useInGeri=Of the 229 patients who received Sonidegib (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.
 |useInReproPotential=Based on its mechanism of action and animal data, Sonidegib can cause fetal harm when administered to a pregnant woman.
-'''Pregnancy Testing'''
+:*'''Pregnancy Testing'''
 Verify the pregnancy status of females of reproductive potential prior to initiating Sonidegib treatment.
-'''Contraception'''
+:*'''Contraception'''
-:*Females
+::*Females
-Advise females of reproductive potential to use effective contraception during treatment with Sonidegib and for at least 20 months after the last dose.
+Advise females of reproductive potential to use effective [[contraception]] during treatment with Sonidegib and for at least 20 months after the last dose.
-:*Males
+::*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 Sonidegib and for at least 8 months after the last dose. Advise males not to donate semen during treatment with Sonidegib and for at least 8 months after the last dose.
+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 Sonidegib and for at least 8 months after the last dose. Advise males not to donate semen during treatment with Sonidegib and for at least 8 months after the last dose.
-'''Infertility'''
+:*'''[[Infertility]]'''
 Based on findings from animal studies, female fertility may be compromised with Sonidegib.
-|administration=The recommended dose of Sonidegib 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.
+|administration=The recommended dose of Sonidegib 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]].
 |overdose=There are no recommendations regarding management of overdosage.
-|mechAction=Sonidegib is an inhibitor of the Hedgehog pathway. Sonidegib binds to and inhibits Smoothened, a transmembrane protein involved in Hedgehog signal transduction.
-|PK='''Absorption'''
-Less than 10% of an oral dose of Sonidegib is absorbed. Following the administration of a single Sonidegib 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 Sonidegib 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.
+|drugBox={{Drugbox2
+| drug_name =
+| IUPAC_name = ''N''-[6-[(2''S'',6''R'')-2,6-Dimethylmorpholin-4-yl]pyridin-3-yl]-2-methyl-3-[4-(trifluoromethoxy)phenyl]benzamide
+| image = soni1.png
+| width = 275
+<!-- Clinical data-->
+| tradename = Odomzo<ref>[http://www.drugs.com/newdrugs/fda-approves-odomzo-sonidegib-locally-advanced-basal-cell-carcinoma-4235.html FDA Approves Odomzo (sonidegib) for Locally Advanced Basal Cell Carcinoma]</ref>
+| Drugs.com = {{Drugs.com|parent|Odomzo}}
+| legal_US = Rx-only
+| routes_of_administration = [[Oral administration|By mouth]] ([[Capsule (pharmacy)|capsules]])
+<!--Pharmacokinetic data-->
+| bioavailability = <10%
+| protein_bound = >97%
+| metabolism = [[Liver]] ([[CYP3A]])
+| elimination_half-life = ~28 days
+| excretion = Feces (~70%), [[urine]] (30%)<ref name="PI">{{cite web|title=Odomzo (sonidegib) Capsules, for Oral Use. Full Prescribing Information|url=https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/odomzo.pdf|publisher=Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936|accessdate=2 October 2016}}</ref>
+<!-- Identifiers-->
+| PubChem = 24775005
+| ChEBI_Ref = {{ebicite|correct|EBI}}
+| ChEBI = 90863
+| ChemSpiderID = 25027390
+| ATC_prefix = L01
+| ATC_suffix = XX48
+| KEGG = D10119
+| UNII_Ref = {{fdacite|correct|FDA}}
+| UNII = 0RLU3VTK5M
+<!-- Chemical data-->
+| C=26|H=26|F=3|N=3|O=3
+| molecular_weight = 485.498 g/mol
+| smiles = C[C@@H]1CN(C[C@@H](O1)C)C2=NC=C(C=C2)NC(=O)C3=CC=CC(=C3C)C4=CC=C(C=C4)OC(F)(F)F
+| StdInChI = 1S/C26H26F3N3O3/c1-16-14-32(15-17(2)34-16)24-12-9-20(13-30-24)31-25(33)23-6-4-5-22(18(23)3)19-7-10-21(11-8-19)35-26(27,28)29/h4-13,16-17H,14-15H2,1-3H3,(H,31,33)/t16-,17+
+| StdInChIKey = VZZJRYRQSPEMTK-CALCHBBNSA-N
+}}
+|mechAction=Sonidegib is an inhibitor of the [[Hedgehog signaling pathway|Hedgehog pathway]]. Sonidegib binds to and inhibits [[Smoothened]], a [[transmembrane protein]] involved in Hedgehog signal [[transduction]].
+|PK='''[[Absorption]]'''
+Less than 10% of an oral dose of Sonidegib is absorbed. Following the administration of a single Sonidegib 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 Sonidegib 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, AUC(0-24h) 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.
+A high-fat meal (approximately 1000 calories with 50% of calories from fat) increased exposure to Sonidegib (geometric mean [[AUC]](inf) and [[Cmax]]) by 7.4- to 7.8-fold.
-'''Distribution'''
+'''[[Distribution]]'''
-The estimated apparent steady-state volume of distribution (Vss/F) was 9,166 L. Sonidegib was greater than 97% bound to human plasma proteins in vitro and the binding was concentration independent. In vitro studies suggested that sonidegib is not a substrate of P-glycoprotein, MRP2 or BCRP.
+The estimated apparent steady-state [[volume of distribution]] ([[Vss/F]]) was 9,166 L. Sonidegib was greater than 97% bound to [[human plasma proteins]] [[in vitro]] and the binding was concentration independent. In vitro studies suggested that sonidegib is not a substrate of [[P-glycoprotein]], [[MRP2]] or [[BCRP]].
-'''Elimination'''
+'''[[Elimination]]'''
-The elimination half-life (t1/2) of Sonidegib estimated from population pharmacokinetic (PK) modeling was approximately 28 days.
+The elimination [[half-life]] (t1/2) of Sonidegib estimated from population [[pharmacokinetic]] (PK) modeling was approximately 28 days.
-:*Metabolism
+:*[[Metabolism]]
-Sonidegib is primarily metabolized by CYP3A. The main circulating compound was unchanged sonidegib (36% of circulating radioactivity).
+Sonidegib is primarily metabolized by [[CYP3A]]. The main circulating compound was unchanged sonidegib (36% of circulating [[radioactivity]]).
-:*Excretion
+:*[[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.
+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
+:*[[Hepatic Impairment]]
-Mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment had no clinically meaningful effect on Sonidegib exposure as compared to subjects with normal hepatic function.
+Mild ([[Child-Pugh]] class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment had no clinically meaningful effect on Sonidegib exposure as compared to subjects with normal hepatic function.
-:*Renal Impairment
+:*[[Renal Impairment]]
-Mild (CLcr 60 to 89 mL/min) and moderate (CLcr 30 to 59 mL/min) renal impairment had no effect on Sonidegib steady-state exposure as compared to patients with normal renal function (CLcr ≥90 mL/min).
+Mild ([[CLcr]] 60 to 89 mL/min) and moderate (CLcr 30 to 59 mL/min) renal impairment had no effect on Sonidegib steady-state exposure as compared to patients with normal [[renal function]] (CLcr ≥90 mL/min).
 :*Age, Sex, Weight and Race
@@ Line 174: / Line 221: @@
 '''Drug Interaction Studies'''
-:*Effects of CYP3A Inhibitors on Sonidegib
+:*Effects of [[CYP3A]] Inhibitors on Sonidegib
-Strong CYP3A inhibitor: The geometric mean Sonidegib AUC(0-10d) increased by 2.2-fold and the Cmax increased by 1.5-fold when Sonidegib at a dose of 800 mg was taken with ketoconazole compared to Sonidegib alone. The geometric mean sonidegib steady-state AUC(0-24h) would similarly increase in cancer patients taking Sonidegib 200 mg once daily when coadministered with a strong CYP3A inhibitor for 14 days.
+Strong CYP3A inhibitor: The geometric mean Sonidegib [[AUC]](0-10d) increased by 2.2-fold and the [[Cmax]] increased by 1.5-fold when Sonidegib at a dose of 800 mg was taken with [[ketoconazole]] compared to Sonidegib alone. The geometric mean sonidegib steady-state AUC(0-24h) would similarly increase in cancer patients taking Sonidegib 200 mg once daily when coadministered with a strong CYP3A inhibitor for 14 days.
-Moderate CYP3A inhibitor: The geometric mean sonidegib steady-state AUC(0-24h) would increase 1.8-fold when Sonidegib 200 mg once daily is coadministered with a moderate CYP3A inhibitor (erythromycin) for 14 days and would increase 2.8-fold when Sonidegib 200 mg once daily is coadministered with a moderate CYP3A inhibitor (erythromycin) for 4 months.
+Moderate CYP3A inhibitor: The geometric mean sonidegib steady-state [[AUC]](0-24h) would increase 1.8-fold when Sonidegib 200 mg once daily is coadministered with a moderate CYP3A inhibitor ([[erythromycin]]) for 14 days and would increase 2.8-fold when Sonidegib 200 mg once daily is coadministered with a moderate CYP3A inhibitor ([[erythromycin]]) for 4 months.
 :*Effects of CYP3A Inducers on Sonidegib
-Strong CYP3A inducer: The geometric mean Sonidegib AUC(0-10d) decreased by 72% and the Cmax decreased by 54% when Sonidegib at a dose of 800 mg was taken with rifampicin compared to Sonidegib alone.
+Strong CYP3A inducer: The geometric mean Sonidegib [[AUC]](0-10d) decreased by 72% and the [[Cmax]] decreased by 54% when Sonidegib at a dose of 800 mg was taken with [[rifampicin]] compared to Sonidegib alone.
-Moderate CYP3A inducer: The geometric mean Sonidegib steady-state AUC(0-24h) would decrease 56% in cancer patients taking Sonidegib 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.
+Moderate CYP3A inducer: The geometric mean Sonidegib steady-state [[AUC]](0-24h) would decrease 56% in cancer patients taking Sonidegib 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.
-:*Effect of Sonidegib on Cytochrome P450 Enzymes and Transporters
+:*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 [[CYP2B6]] and [[CYP2C9]] and it does not induce [[CYP1A2]], [[CYP2B6]] or [[CYP3A]] expression or activity.
-In vitro studies suggested that Sonidegib inhibits BCRP, but not P-glycoprotein, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2.
+In vitro studies suggested that Sonidegib inhibits [[BCRP]], but not [[P-glycoprotein]], [[MRP2]], [[OATP1B1]], [[OATP1B3]], [[OAT1]], [[OAT3]], [[OCT1]] or [[OCT2]].
 :*Effect of Acid Reducing Agents on Sonidegib
-No clinically meaningful effect on Sonidegib exposure was observed when Sonidegib at dose of 200 mg was coadministered with esomeprazole, a proton pump inhibitor.
+No clinically meaningful effect on Sonidegib exposure was observed when Sonidegib at dose of 200 mg was coadministered with [[esomeprazole]], a [[proton pump inhibitor]].
-|nonClinToxic=======Carcinogenesis, Mutagenesis, Impairment of Fertility======
+|nonClinToxic=======[[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 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.
+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 organ]]s 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.
-======Animal Toxicology and/or Pharmacology======
+======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).
+Body [[tremor]]s 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]]).
-|clinicalStudies=The safety and effectiveness of Sonidegib 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 Sonidegib 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.
+|clinicalStudies=The safety and effectiveness of Sonidegib 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 Sonidegib 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.
+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 Sonidegib 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.
+A total of 66 patients randomized to Sonidegib 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 Sonidegib 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.
+Patients with laBCC randomized to receive Sonidegib 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 Sonidegib 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 Sonidegib 800 mg daily and followed for at least 12 months unless discontinued earlier.
+A total of 128 patients randomized to Sonidegib 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 Sonidegib 800 mg daily and followed for at least 12 months unless discontinued earlier.
 |howSupplied=Each Sonidegib capsule has an opaque pink color with ‘SONIDEGIB 200MG’ printed on the capsule body and ‘NVR’ printed on the cap in black ink. Sonidegib capsules are supplied as follows:
-Bottle of 30 capsules               NDC 0078-0645-15
+Bottle of 30 capsules               (NDC 0078-0645-15)
 |storage=Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
+|packLabel=[[File:soni.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
 |fdaPatientInfo=Advise the patient to read the FDA-approved patient labeling.
@@ Line 224: / Line 272: @@
 :*Advise female patients of the potential risk to a fetus.
-:*Advise females of reproductive potential to use effective contraception during treatment with Sonidegib and for at least 20 months after the last dose.
+:*Advise females of reproductive potential to use effective [[contraception]] during treatment with Sonidegib 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 Sonidegib and for at least 8 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 Sonidegib 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 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 Sonidegib during pregnancy, either directly or through seminal fluid, to contact the Novartis Pharmaceuticals Corporation at 1-888-669-6682.
+:*Advise females who may have been exposed to Sonidegib during pregnancy, either directly or through [[seminal fluid]], to contact the Novartis Pharmaceuticals Corporation at 1-888-669-6682.
-'''Blood Donation'''
+'''[[Blood Donation]]'''
-Advise patients not to donate blood or blood products while taking Sonidegib and for 20 months after stopping treatment.
+Advise patients not to donate blood or [[blood products]] while taking Sonidegib and for 20 months after stopping treatment.
-'''Musculoskeletal Adverse Reactions'''
+'''[[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.
+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.
 '''Administration Instructions'''

Sonidegib: Difference between revisions

Latest revision as of 19:34, 19 January 2017

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