sonidegib (Rx)

All grades of severity listed unless otherwise indicated

>10% (All Grades)

Increased serum creatinine (92%)

Increased serum creatine kinase (61%)

Muscle spasms (54%)

Alopecia (53%)

Hyperglycemia (51%)

Dysgeusia (46%)

Increased lipase (43%)

Fatigue (41%)

Nausea (39%)

Diarrhea (32%)

Anemia (32%)

Musculoskeletal pain (32%)

Decreased weight (30%)

Lymphopenia (28%)

Decreased appetite (23%)

Myalgia (19%)

Increased ALT or AST (19%)

Abdominal pain (18%)

Increased amylase (16%)

Headache (15%)

Pain (14%)

Vomiting (11%)

>10% (Grade 3-4)

Increased lipase (13%)

1-10% (All Grades)

Pruritus (10%)

1-10% (Grade 3)

Increased serum creatine kinase (8%)

Hyperglycemia (4%)

Increased ALT/AST (4%)

Muscle spasms (3%)

Decreased weight (3%)

Lymphopenia (3%)

Decreased appetite (1%)

Musculoskeletal pain (1%)

Nausea (1%)

Diarrhea (1%)

Vomiting (1%)

Increased amylase (1%)

Contraindications

None

Cautions

Can cause embryo-fetal death or severe birth defects when administered to a pregnant woman (see Black Box Warnings and Pregnancy sections)

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

Musculoskeletal adverse reactions, which may be accompanied by serum creatine kinase elevations, occur with Hedgehog (Hh) pathway inhibitors

Premature fusion of the epiphyses has been reported in pediatric patients exposed to sonidegib and other Hh pathway inhibitors; cases of progressive of epiphyseal fusion reported in pediatric patients receiving other Hh pathway inhibitors; not indicated for use in pediatric patients

Avoid coadministration with moderate/strong CYP3A inhibitors or inducers

Pregnancy

Based on sonidegib’s mechanism of action, can cause fetal harm when administered to a pregnant woman

There are no available data on the use 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)

Verify pregnancy status of females of reproductive potential prior to initiating

Advise females of reproductive potential to use effective contraception during treatment and for at least 20 months after the last dose

Do not donate blood for at least 20 months after the last dose

Males

• Unknown 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 and for at least 8 months after the last dose
• Do not donate semen for at least 8 month or blood for at least 20 months

Lactation

Unknown if distributed in human breast milk

Because of the potential for serious adverse reactions in breastfed infants from sonidegib, advise a nursing woman not to breastfeed during treatment and for 20 months after the last dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Hedgehog (Hh) pathway inhibitor; the Hh signaling pathway is important in embryogenesis, but in adults, it is mostly inactive; signaling is relayed by key proteins, including smoothened (SMO)

Hh ligand-expressing cancerous epithelial cells that are activated by the Hh signaling pathway may cause growth promotion; sonidegib binds to and inhibits SMO, a transmembrane protein involved in Hedgehog signal transduction

Absorption

<10% of oral dose is absorbed

Peak plasma time: 2-4 hr (fasting)

Peak plasma concentration: 1030 ng/mL

Minimum plasma concentration: 890 ng/mL

AUC: 22 mcg·h/mL

Distribution

Protein bound: >97%

Vd (Vss/F): 9,166 L

Metabolism

Primarily metabolized by CYP3A

The main circulating compound was unchanged sonidegib (36% of circulating radioactivity)

Elimination

Half-life: 28 days

Excretion: 70% feces; 30% urine

Instructions

Swallow capsule on an empty stomach, at least 1 hr before or 2 hr after a meal

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

Storage

Store at controlled room temperature (25°C [77°F]); excursions permitted to 15-30°C (59-86°F)