NDC 47335-303 Odomzo

Sonidegib

NDC Product Information

Odomzo with NDC 47335-303 is a a human prescription drug product labeled by Sun Pharmaceutical Industries, Inc.. The generic name of Odomzo is sonidegib. The product's dosage form is capsule and is administered via oral form.

Labeler Name: Sun Pharmaceutical Industries, Inc.

Dosage Form: Capsule - A solid oral dosage form consisting of a shell and a filling. The shell is composed of a single sealed enclosure, or two halves that fit together and which are sometimes sealed with a band. Capsule shells may be made from gelatin, starch, or cellulose, or other suitable materials, may be soft or hard, and are filled with solid or liquid ingredients that can be poured or squeezed.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Odomzo Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • SONIDEGIB PHOSPHATE 200 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • CROSPOVIDONE, UNSPECIFIED (UNII: 2S7830E561)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • POLOXAMER 188 (UNII: LQA7B6G8JG)
  • SODIUM LAURYL SULFATE (UNII: 368GB5141J)
  • GELATIN, UNSPECIFIED (UNII: 2G86QN327L)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • AMMONIA (UNII: 5138Q19F1X)
  • FERROSOFERRIC OXIDE (UNII: XM0M87F357)
  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
  • SHELLAC (UNII: 46N107B71O)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Hedgehog Pathway Inhibitor - [EPC] (Established Pharmacologic Class)
  • Smoothened Receptor Antagonists - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Sun Pharmaceutical Industries, Inc.
Labeler Code: 47335
FDA Application Number: NDA205266 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 09-21-2017 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Odomzo Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Warning: Embryo-Fetal Toxicity

  • ODOMZO can cause embryo-fetal death or severe birth defects when administered to a pregnant woman.
  • ODOMZO is embryotoxic, fetotoxic, and teratogenic in animals [see Warnings and Precautions (5.1) and Use in Specific Populations (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 [see Warnings and Precautions (5.1) and Use in Specific Populations (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 [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3)].

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.

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 forSevere 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 forSerum 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 (equivalent to 281 mg of diphosphate salt of sonidegib).

4 Contraindications

None.

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 PotentialVerify 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)].MalesAdvise 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 DonationAdvise 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 33.5months). 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 1a No Grade 4 adverse reactions were reported.Adverse ReactionODOMZO 200 mg(N=79)All Gradesa %Grade 3%Musculoskeletal and connective tissue disorders    Muscle spasms543    Musculoskeletal pain321    Myalgia190Skin and subcutaneous tissue disorder    Alopecia530    Pruritus100Nervous system disorders    Dysgeusia460    Headache151General disorders and administration site conditions    Fatigue414    Pain141Gastrointestinal disorders    Nausea391    Diarrhea321    Abdominal pain180    Vomiting111Investigations    Decreased weight303Metabolism and nutrition disorders    Decreased appetite231Table 2: Key Laboratory Abnormalitiesaa 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.Laboratory TestODOMZO 200 mg(N=79)All Grades %Grades 3-4%Chemistry    Increased serum creatinine92b0    Increased serum creatine kinase (CK)618    Hyperglycemia514    Increased lipase4313    Increased alanine aminotransferase194    Increased aspartate aminotransferase194    Increased amylase161Hematology    Anemia320    Lymphopenia283AmenorrheaAmenorrhea lasting for at least 18 months occurred in two of 14 pre-menopausal women treated with ODOMZO 200 mg
or 800 mg once daily.

7.1 Effects Of Other Drugs On Sonidegib

Strong and Moderate CYP3A InhibitorsAvoid 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 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 [see Clinical Pharmacology (12.3)].Strong and Moderate CYP3A InducersAvoid 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)].

8.1 Pregnancy

Risk SummaryBased 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 Sun Pharmaceutical
Industries, Inc. at 1-800-406-7984.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.DataAnimal DataDaily 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 TestingVerify the pregnancy status of females of reproductive potential prior to initiating ODOMZO treatment.ContraceptionFemalesAdvise females of reproductive potential to use effective contraception during treatment with ODOMZO and for at least
20 months after the last dose.MalesIt 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.InfertilityBased 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 DataIn 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.

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 (equivalent to 281 mg of diphosphate
salt of sonidegib) 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.

12.1 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 ElectrophysiologyAt a dose of 800 mg once daily, sonidegib does not prolong the QTc interval.

12.3 Pharmacokinetics

AbsorptionLess 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)].DistributionThe 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.EliminationThe elimination half-life (t1/2) of sonidegib estimated from population pharmacokinetic (PK) modeling was approximately 28 days.MetabolismSonidegib is primarily metabolized by CYP3A. The main circulating compound was unchanged sonidegib (36% of circulating radioactivity).ExcretionSonidegib 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 PopulationsHepatic ImpairmentMild (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 ImpairmentMild (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 RaceAge, 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 ODOMZO.Drug Interaction StudiesEffects of CYP3A Inhibitors on SonidegibStrong CYP3A inhibitor: The geometric mean sonidegib AUC0-10d increased by 2.2-fold and the Cmax increased by 1.5-fold when ODOMZO at a dose of 800 mg was taken with ketoconazole compared to ODOMZO alone [see Drug Interactions (7.1)]. 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: 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 SonidegibStrong CYP3A inducer: The geometric mean sonidegib AUC0-10d decreased by 72% and the Cmax decreased by 54% when ODOMZO at a dose of 800 mg was taken with rifampicin compared to ODOMZO alone [see Drug Interactions (7.1)].Moderate CYP3A inducer: 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 TransportersIn 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 SonidegibNo clinically meaningful effect on sonidegib exposure was observed when ODOMZO at dose of 200 mg was coadministered with esomeprazole, a proton pump inhibitor.

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 30 months unless
discontinued earlier. The ORR was 56% (95% confidence interval: 43, 68), consisting of 3 (5%) complete responses and
34 (52%) 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 21%. The median duration of response was 26.1 months (95% CI:10.1, not 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 30 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 47335-303-83Store 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 Sun Pharmaceutical Industries Inc. at 1-800-406-7984.Blood DonationAdvise patients not to donate blood or blood products while taking ODOMZO and for 20 months after stopping treatment.Musculoskeletal Adverse ReactionsAdvise 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)].Administration InstructionsAdvise patients to take ODOMZO on an empty stomach, at least 1 hour before or 2 hours after a meal [see Dosage and Administration (2.1)].LactationAdvise women not to breastfeed during treatment with ODOMZO and for up to 20 months after the last dose [see Use in Specific Populations (8.2)].Manufactured for Sun Pharma Global FZE by:Patheon Inc.Mississauga, Ontario L5N 7K9, CanadaDistributed by:Sun Pharmaceutical Industries, Inc.Cranbury, NJ 08512ODOMZO is a registered trademark of Sun Pharma Global FZE.

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