Sonidegib

Black Box Warnings

Based on sonidegib’s mechanism of action, can cause embryo-fetal death or severe birth defects when administered to a pregnant woman

Sonidegib is embryotoxic, fetotoxic, and teratogenic in animals

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

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

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 pathway inhibitors

Avoid coadministration with moderate/strong CYP3A inhibitors or inducers

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

Before taking sonidegib, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to sonidegib or any of its ingredients
• have muscle pain or spasms, or have a history of a muscle disorder called rhabdomyolysis or myopathy
• have any other medical conditions
• are pregnant or plan to become pregnant.
• are breastfeeding or plan to breastfeed. It is not known if sonidegib passes into your breast milk. Do not breastfeed during treatment and for 20 months after your final dose of sonidegib. Talk to your healthcare provider about the best way to feed your baby during this time.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

WARNING: EMBRYO-FETAL TOXICITY

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. 

Sonidegib is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Sonidegib is used to treat basal cell carcinoma (a type of skin cancer).

Sonidegib is usually given when surgery or radiation cannot be used, or have been used without success.

Sonidegib may also be used for purposes not listed in this medication guide.

Basal Cell Carcinoma

Treatment of locally advanced basal cell carcinoma that has recurred following surgery or radiation therapy or in those who are not candidates for surgery or radiation therapy.1 2

General

• Women of childbearing potential must be tested for pregnancy prior to initiation of the drug.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

• Monitor serum CK and Scr concentrations at baseline, periodically during therapy, and as clinically indicated.1 More frequent monitoring is indicated in patients who develop musculoskeletal effects during therapy.1 (See Musculoskeletal Effects under Cautions.)

Administration

Oral Administration

Administer orally once daily at least 1 hour before or 2 hours after a meal.1

Dosage

Adults

200 mg once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

For first occurrence of serum CK concentrations of 2.5–10 times ULN or first occurrence of severe or intolerable adverse musculoskeletal effects, interrupt therapy until resolution; resume dosage of 200 mg once daily.1

If recurrent CK concentrations of 2.5–5 times ULN occur, interrupt therapy until resolution; resume dosage of 200 mg once daily.1

For CK concentrations >2.5 times ULN with worsening renal function or >10 times ULN, permanently discontinue drug.1

If recurrent CK concentrations >5 times ULN or recurrent severe or intolerable adverse musculoskeletal effects occur, permanently discontinue drug.1

Special Populations

No dosage adjustment recommended based on age, body weight, gender, or ethnicity.9

Hepatic Impairment

Mild hepatic impairment (total bilirubin concentrations not exceeding ULN with AST concentrations exceeding ULN, or total bilirubin concentrations exceeding ULN, but ≤1.5 times ULN): No dosage adjustment required.1 9 (See Special Populations under Pharmacokinetics.)

Moderate or severe hepatic impairment: Not studied; no dosage recommendations at this time.1 9

Renal Impairment

No dosage adjustment required.1 9 (See Special Populations under Pharmacokinetics.)

Geriatric Patients

No specific dosage recommendations.1 (See Geriatric Use under Cautions.)

Take sonidegib exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

sonidegib should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

Take sonidegib on an empty stomach, at least 1 hour before or 2 hours after a meal.

Swallow the capsule whole. Do break, crush, or open it.

Dosing

The dose of sonidegib will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of sonidegib. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (capsules):
  • For advanced basal cell carcinoma:
    • Adults—200 milligrams (mg) once a day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of sonidegib, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Following a single 200 mg dose, exposure (AUCinf) is 1.7-fold higher in Japanese healthy subjects as compared to Western healthy subjects.

Basal cell carcinoma, locally advanced: 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 are no contraindications listed in the manufacturer’s labeling.

Note: Verify pregnancy status of females of reproductive potential prior to therapy initiation. Measure serum creatine kinase (CK) levels and renal function tests in all patients prior to starting treatment.

Basal cell carcinoma, locally advanced: Oral: 200 mg once daily until disease progression or unacceptable toxicity (Migden, 2015)

Missed doses: If a dose is missed, skip the missed dose and resume dosing with the next scheduled dose.

Refer to adult dosing.

Mild, moderate, or severe impairment (Child-Pugh classes A, B, and C): There are no dosage adjustments provided in the manufacturer's labeling; however, hepatic impairment had no clinically meaningful effect on sonidegib exposure (compared to patients with normal hepatic function).

Serum creatine kinase (CK) and serum creatinine (baseline, periodically during treatment, and at least weekly with musculoskeletal toxicity and CK elevations >2.5 times ULN until resolution), liver function, pregnancy status, signs/symptoms of musculoskeletal toxicity.