DRUG INTERACTIONS-(summary)

 CYP3A inhibitors: Avoid strong CYP3A inhibitors. Avoid long-term (greater than 14 days) use of moderate CYP3A inhibitors. (7.1) ? CYP3A inducers: Avoid strong and moderate CYP3A inducers

DRUG INTERACTIONS -(details)

1. Effects of Other Drugs on Sonidegib Strong and Moderate CYP3A Inhibitors Avoid concomitant administration of ODOMZO with strong CYP3A inhibitors, including but not limited to saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole and nefazodone 

Avoid concomitant administration of ODOMZO with moderate CYP3A inhibitors, including but not limited to atanzavir, diltiazem, and fluconazole. If a moderate CYP3A inhibitor must be used, administer the moderate CYP3A inhibitor for less than 14 days and monitor closely for adverse reactions particularly musculoskeletal adverse reactions 

Strong and Moderate CYP3A Inducers Avoid concomitant administration of ODOMZO with strong and moderate CYP3A inducers, including but not limited to carbamazepine, efavirenz, modafinil, phenobarbital, phenytoin, rifabutin, rifampin and St. John’s Wort (Hypericum perforatum) 

Novel Drug Approvals for 2015

1.Name       -  ODOMZO

2. Active Ingredient-     Sonidegib

3. Indication-      To treat patients with locally advanced basal carcinom

Date of Approval     July  2015

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use ODOMZO safely and effectively. See full prescribing information for ODOMZO. ODOMZO® (sonidegib) capsules, for oral use

Initial U.S. Approval: 2015

WARNING:

EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning.

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

 • 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. 

• 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.

INDICATIONS AND USAGE-

 ODOMZO is a hedgehog pathway inhibitor indicated for the treatment of adult patients with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy. 

ADVERSE REACTIONS-

 The most common adverse reactions occurring in =10% of patients are muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus.

CONTRAINDICATIONS--

 None. 

WARNINGS AND PRECAUTIONS-

 Blood donation: Advise patients not to donate blood or blood products during treatment with ODOMZO and for at least 20 months after the last dose.

 Musculoskeletal adverse reactions: Obtain serum creatine kinase (CK) and creatinine levels prior to initiating therapy, periodically during treatment, and as clinically indicated. Temporary dose interruption or discontinuation of ODOMZO may be required based on the severity of musculoskeletal adverse reactions.

DOSAGE AND ADMINISTRATION-

 Recommended dose: 200 mg orally once daily taken on an empty stomach, at least 1 hour before or 2 hours after a meal.

DOSAGE FORMS AND STRENGTHS-

 200 mg capsules 

PATIENT COUNSELING INFORMATION -

Advise the patient to read the FDA-approved patient labeling (Medication Guide). 

 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 dos

 Advise males, even those with prior vasectomy, to use condoms, to avoid potential drug exposure in both pregnant partners and female partners of reproductive potential during treatment with ODOMZO and for at least 8 months after the last dose.

 Advise female patients and female partners of male patients to contact their healthcare provider with a known or suspected pregnancy.

 Advise females who may have been exposed to ODOMZO during pregnancy, either directly or through seminal fluid, to contact the Novartis Pharmaceuticals Corporation 

Advise patients not to donate blood or blood products while taking ODOMZO and for 20 months after stopping treatment.

Musculoskeletal Adverse Reactions Advise patients to contact their healthcare provider immediately for new or worsening signs or symptoms of muscle toxicity, dark urine, decreased urine output, or the inability to urinate

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

Lactation Advise women not to breastfeed during treatment with OD

Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2015-XX July 2015

CLINICAL PHARMACOLOGY

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.

2. Pharmacodynamics Cardiac Electrophysiology At a dose of 800 mg once daily, sonidegib does not prolong the QTc interval. Reference ID: 3797098

3 Pharmacokinetics Absorption Less than 10% of an oral dose of ODOMZO is absorbed.

Following the administration of a single ODOMZO dose (100 mg to 3000 mg) under fasted conditions in patients with cancer, the median time-to-peak concentration (Tmax) was 2 to 4 hours.

Sonidegib exhibited dose-proportional increases in the area under the curve (AUC) and the maximal concentration (Cmax) over the dose range of 100 mg to 400 mg, but less than dose-proportional increases at doses greater than 400 mg.

Steady-state was reached approximately 4 months after starting ODOMZO and the estimated accumulation at steady-state was 19-fold.

Following a dose of 200 mg once daily, the estimated mean steady-state Cmax is 1030 ng/mL, AUC0-24h is 22 µg*h/mL and minimal concentration (Cmin) is 890 ng/mL.

A high-fat meal (approximately 1000 calories with 50% of calories from fat) increased exposure to sonidegib (geometric mean AUCinf and Cmax) by 7.4- to 7.8-fold 

Distribution -                                                                                                                    The estimated apparent steady-state volume of distribution (Vss/F) was 9,166 L. Sonidegib was highly bound to human plasma proteins in vitro (>97%) and the binding was concentration independent. In vitro studies suggested that sonidegib is not a substrate of ABCB1 (P-glycoprotein), ABCC2 (MRP2, cMOAT) or ABCG2 (BCRP).

Elimination-                                                                                                                     The elimination half-life (t1/2) of sonidegib estimated from population pharmacokinetic (PK) modeling was approximately 28 days.

Metabolism-                                                                                                                      Sonidegib is primarily metabolized by CYP3A. The main circulating compound was unchanged sonidegib (36% of circulating radioactivity).

Excretion-                                                                                                                     Sonidegib and its metabolites are eliminated primarily by the hepatic route. Of the absorbed dose, approximately 70% was eliminated in the feces and 30% was eliminated in the urine. Unchanged sonidegib was not detectable in the urine.

Specific Populations -                                                                                               Hepatic Impairment -                                                                                                      Based on the population PK analyses, mild hepatic impairment (total bilirubin = upper limit of normal (ULN) and aspartate aminotransferase (AST) >ULN or total bilirubin >1.0 to 1.5 times ULN, n=35) had no effect on sonidegib steady-state exposure as compared to patients with normal hepatic function (total bilirubin =ULN and AST =ULN, n=315) [see Use in Specific Populations (8.6)]

 Renal Impairment-                                                                                                    Based on the population PK analyses, mild (CLcr 60 to 89 mL/min, n=129) and moderate (CLcr 30 to 59 mL/min, n=60) renal impairment had no effect on sonidegib steady-state exposure as compared to patients with normal renal function (CLcr =90 mL/min, n=161)

Age, Sex, Weight and Race-                                                                                           Based on population PK analyses, age, body weight, or sex has no clinically meaningful effect on sonidegib exposure.

A cross study comparison suggests that geometric mean AUCinf of sonidegib is 1.7-fold higher in Japanese healthy subjects compared to Western healthy subjects (Whites and Blacks) following a single 200 mg dose of ODOMZO. 

Drug Interaction Studies-                                                                                                  Effects of CYP3A Inhibitors on Sonidegib Strong CYP3A inhibitor: Healthy subjects received a single 800 mg dose of ODOMZO alone (n=16) or 5 days after starting oral ketoconazole (200 mg twice daily for 14 days) (n=15). The geometric mean sonidegib AUC0-10d increased by 2.2-fold and the Cmax increased by 1.5-fold when ODOMZO was taken with ketoconazole compared to ODOMZO alone [see Drug Interactions (7.1)].

Based on physiologic based pharmacokinetics (PBPK) simulations, the geometric mean sonidegib steady-state AUC0-24h would similarly increase in cancer patients taking ODOMZO 200 mg once daily when coadministered with a strong CYP3A inhibitor for 14 days.

Moderate CYP3A inhibitor:                                                                                              Based on PBPK simulations, the geometric mean sonidegib steady-state AUC0-24h would increase 1.8-fold when ODOMZO 200 mg once daily is coadministered with a moderate CYP3A inhibitor (erythromycin) for 14 days and would increase 2.8-fold when ODOMZO 200 mg once daily is coadministered with a moderate CYP3A inhibitor (erythromycin) for 4 months.

Effects of CYP3A Inducers -                                                                                           on Sonidegib Strong CYP3A inducer: Healthy subjects received a single 800 mg dose of ODOMZO alone (n=16) or 5 days after starting oral rifampicin (600 mg daily for 14 days) (n=16). The geometric mean sonidegib AUC0-10d decreased by 72% and the Cmax decreased by 54% when ODOMZO was taken with rifampicin compared to ODOMZO alone [see Drug Interactions 

Moderate CYP3A inducer:                                                                                                Based on PBPK simulations, the geometric mean sonidegib steady-state AUC0-24h would decrease 56% in cancer patients taking ODOMZO 200 mg once daily when coadministered with a moderate CYP3A inducer (efavirenz) for 14 days and would decrease 69% when coadministered with a moderate CYP3A inducer (efavirenz) for 4 months.

Effect of Sonidegib- on Cytochrome P450 Enzymes and Transporters In vitro studies suggested that sonidegib inhibits CYP2B6 and CYP2C9 and it does not induce CYP1A2, CYP2B6 or CYP3A expression or activity. In vitro studies suggested that sonidegib inhibits ABCG2, but it does not inhibit ABCB1, ABCC2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2.

Effect of Acid Reducing Agents on Sonidegib Based on population PK analysis, concomitant administration of a proton pump inhibitor or a histamine-2-recep

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary -                                                                                               Based on its mechanism of action and data from animal reproduction studies, ODOMZO can cause fetal harm when administered to a pregnant woman

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 

. 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 effect onyoung  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. 

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.

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 

Pregnancy Testing -Verify the pregnancy status of females of reproductive potential prior to initiating ODOMZO treatment.

Contraception  during treatment with ODOMZO and for at least 20 months after the last dose. Males It is not known if sonidegib is present in semen.

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

Advise males not to donate semen during treatment with ODOMZO and for at least 8 months after the last dose. Infertility Based on findings from animal studies, female fertility may be compromised with ODOMZO [see Nonclinical Toxicology (13.1)]

4. Pediatric Use -The safety and effectiveness of ODOMZO have not been established in pediatric patients. Juvenile Animal Data In a 5-week juvenile rat toxicology study, effects of sonidegib were observed in bone, teeth, reproductive tissues, and nerves at doses =10 mg/kg/day (approximately 1.2 times the recommended human dose based on AUC).

Bone findings included thinning/closure of bone growth plate, decreased bone length and width, and hyperostosis. Findings in teeth included missing or fractured teeth, and atrophy. Reproductive tissue toxicity was evidenced by atrophy of testes, ovaries, and uterus, partial development of the prostate gland and seminal vesicles, and inflammation and aspermia of the epididymis. Nerve degeneration was also noted

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. Reference ID: 3797098

6. Hepatic Impairment- No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin = upper limit of normal (ULN) and aspartate aminotransferase (AST) >ULN or total bilirubin >1.0 to 1.5 times ULN). ODOMZO has not been studied in patients with moderate or severe hepatic impairment 

7. Renal Impairment-  No dose adjustment is recommended for patients with renal impairment 

 OVERDOSAGE There are no recommendations regarding management of overdosage