Sonidegib (Monograph)

Brand name: Odomzo
Drug class: Antineoplastic Agents
Chemical name: Rel-N-[6-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-3-pyridinyl]-2-methyl-4′-(trifluoromethoxy)-[1,1′-Biphenyl]-3-carboxamide
Molecular formula: C₂₆H₂₆F₃N₃O₃
CAS number: 956697-53-3

Warning

Fetal/Neonatal Morbidity and Mortality

Potential risk of teratogenicity and embryofetal toxicity.
In females of reproductive potential, a pregnancy test must be obtained prior to treatment initiation.
Pregnancy must be prevented by use of reliable contraception in females of reproductive potential and sexually mature males. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Men must not donate semen during and for at least 8 months after therapy.

Introduction

Antineoplastic agent; a hedgehog signaling pathway inhibitor.

Uses for Sonidegib

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.

Sonidegib Dosage and Administration

General

Pretreatment Screening

Verify pregnancy status in females of reproductive potential prior to initiation of the drug.
Evaluate serum creatine kinase (CK, creatine phosphokinase, CPK) and S_cr concentrations prior to initiation of therapy.

Patient Monitoring

Monitor serum CK and S_cr concentrations periodically during therapy, and as clinically indicated. More frequent monitoring may be necessary if toxicity occurs.

Administration

Oral Administration

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

Dosage

Adults

Basal Cell Carcinoma

Oral

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

Dosage Modification for Toxicity

Musculoskeletal Effects

Oral

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.

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

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

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

Special Populations

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

Hepatic Impairment

Mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C): No dosage adjustment required.

Renal Impairment

Mild to moderate renal impairment (Cl_cr 30–89 mL/minute): No dosage adjustment required.

Geriatric Patients

No specific dosage recommendations.

Cautions for Sonidegib

Contraindications

Manufacturer states none known.

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryofetal toxicity and teratogenicity demonstrated in animals. (See Boxed Warning.)

Avoid pregnancy during therapy. Females of reproductive potential should use effective contraception during treatment and for at least 20 months following drug discontinuance.

Because it is not known whether drug distributes into semen, sexually mature males (including those who have undergone successful vasectomy) must use a condom each time during sexual contact with a pregnant female or female of reproductive potential during and for at least 8 months after therapy. Men must not donate semen during and for at least 8 months after therapy.

Patients must not donate blood or blood products during and for at least 20 months after therapy, because of potential for any sonidegib present in blood to be transfused into a pregnant female.

Obtain a pregnancy test prior to initiating therapy in females of reproductive potential.

If pregnancy occurs in a female patient or female partner of male patient receiving sonidegib, apprise of potential fetal hazard. Report any suspected fetal exposure to the manufacturer at 800-406-7984.

Other Warnings and Precautions

Musculoskeletal Effects

Musculoskeletal effects, possibly accompanied by increased CK concentrations, occur frequently. Rhabdomyolysis (i.e., serum CK concentrations >10 times baseline value; S_cr concentrations ≥1.5-fold baseline value) reported in 1 patient receiving sonidegib 800 mg.

Most common musculoskeletal effects include muscle spasms, musculoskeletal pain, myalgia. Musculoskeletal pain and myalgia usually precede increased CK concentrations. Some patients experienced musculoskeletal effects requiring medical intervention with magnesium supplementation, muscle relaxants, analgesics, IV hydration, and/or hospitalization.

Median time to onset of grade 2 or greater elevations in CK concentrations: 12.9 weeks. Median time to resolution of increased CK concentrations to grade 1 or less: 12 days.

Monitor CK and S_cr concentrations at baseline, periodically during therapy, and as clinically indicated. If musculoskeletal symptoms and elevations in CK concentrations of >2.5 times ULN occur, monitor CK and S_cr concentrations at least weekly until resolution. Temporary interruption, dosage reduction, or discontinuance of drug may be necessary depending on severity of musculoskeletal symptoms.

Premature Fusion of the Epiphyses

May cause epiphyseal disorders, including premature fusion of the epiphyses, in pediatric patients.

Infertility

May impair female fertility based on animal findings.

Specific Populations

Pregnancy

May cause fetal harm.

Verify pregnancy status in females of reproductive potential prior to initiating therapy.

If pregnancy occurs in a female patient or female partner of male patient receiving sonidegib during therapy or within 20 or 8 months, respectively, after the last dose, notify manufacturer at 800-406-7984.

Lactation

Not known whether distributed into milk. Discontinue breast-feeding during therapy and for at least 20 months after drug discontinuance.

Effects of sonidegib on breast-fed infants or human milk production unknown.

Pediatric Use

Safety and efficacy not established.

Epiphyseal disorders reported in pediatric patients exposed to sonidegib in a clinical trial.

Geriatric Use

No overall differences in efficacy in geriatric patients (≥65 years of age) compared with younger adults. Increased incidence of grade 3 or 4 adverse effects, serious adverse effects, or adverse effects requiring interruption or discontinuance of therapy in geriatric patients compared with younger adults.

No specific dosage recommendations.

Hepatic Impairment

In population pharmacokinetic analyses, systemic exposure not altered by mild, moderate, or severe hepatic impairment; no dosage adjustment necessary in such patients.

Renal Impairment

In a population pharmacokinetic analysis, systemic exposure not altered by mild (Cl_cr 60–89 mL/minute) or moderate (Cl_cr of 30–59 mL/minute) renal impairment; dosage adjustment not necessary in such patients.

Common Adverse Effects

Adverse effects reported in ≥10% of patients receiving sonidegib: Muscle spasms, alopecia, dysgeusia, fatigue, nausea, diarrhea, musculoskeletal pain, weight loss, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, pruritus, arthralgia.

Laboratory abnormalities (≥15%): Increased S_cr, increased CK, hyperglycemia, increased lipase, anemia, lymphopenia, elevated AST and ALT concentrations, increased amylase.

Amenorrhea lasting at least 18 months reported in 2 of 14 premenopausal women receiving sonidegib (200 or 800 mg once daily).

Drug Interactions

Metabolized principally by CYP3A.

Inhibitor of CYP2B6 and 2C9; does not induce CYP1A2, 2B6, or 3A.

Inhibitor of breast cancer resistance protein (BCRP, ABCG2); does not inhibit P-glycoprotein (P-gp, ABCB1), multidrug resistance protein 2 (MRP2, ABCC2), organic cation transporter (OCT) 1, OCT2, organic anion transporter (OAT) 1, OAT3, organic anion transport protein (OATP) 1B1, and OATP1B3. In vitro, not a substrate of P-gp, MRP2, or BCRP.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible pharmacokinetic interaction (increased concentrations and systemic exposure of sonidegib). Avoid concomitant use. (See Specific Drugs under Interactions.)

Moderate CYP3A inhibitors: Possible pharmacokinetic interaction (increased concentrations and systemic exposure of sonidegib). Avoid concomitant use. (See Specific Drugs under Interactions.) If concomitant short-term therapy (≤14 days) cannot be avoided, monitor for adverse musculoskeletal effects and other toxicities.

Moderate or potent CYP3A inducers: Possible pharmacokinetic interaction (decreased concentrations and systemic exposure of sonidegib). Avoid concomitant use. (See Specific Drugs under Interactions.)

Specific Drugs

Drug	Interaction	Comments
Efavirenz	Possible decreased sonidegib exposure Decrease in sonidegib AUC of 56 or 69% expected after concomitant use for 14 days or 4 months, respectively	Avoid concomitant use
Erythromycin	Possible increased sonidegib exposure 1.8- or 2.8-fold increase in sonidegib AUC expected after concomitant use for 14 days or 4 months, respectively	Avoid concomitant use; if concomitant short-term therapy (<14 days) cannot be avoided, monitor for adverse effects
Ketoconazole	Possible increased sonidegib exposure Increased sonidegib AUC and peak concentrations by 2.2- and 1.5-fold, respectively	Avoid concomitant use
Rifampin	Possible decreased sonidegib exposure Decreased sonidegib AUC and peak concentrations by 72 and 54%, respectively	Avoid concomitant use

Sonidegib Pharmacokinetics

Absorption

Bioavailability

<10% absorbed.

Systemic exposure and peak plasma concentrations increase in a dose-proportional manner following administration of sonidegib 100–400 mg.

Peak plasma sonidegib concentrations are attained about 2–4 hours after oral administration under fasting conditions.

Steady-state concentrations are achieved within approximately 4 months.

Estimated systemic accumulation is 19-fold.

Food

Administration with a high-fat meal increased AUC and peak plasma concentrations by 7.4- to 7.8-fold. Fivefold increase in bioavailability reported after administration with a high-fat meal in a population pharmacokinetic analysis.

Special Populations

Mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C): Systemic exposure was similar to that in patients with normal hepatic function.

Mild (Cl_cr 60–89 mL/minute) or moderate (Cl_cr 30–59 mL/minute) renal impairment: Systemic exposure was similar to that in patients with normal renal function.

Age, sex, body weight, or ethnicity: No clinically important effects on sonidegib pharmacokinetics. Systemic exposure following administration of sonidegib (single 200-mg dose) increased by 1.7-fold in healthy Japanese individuals versus those from Western countries.

Distribution

Extent

Not known whether distributed into human milk or semen.

Plasma Protein Binding

>97%.

Elimination

Metabolism

Metabolized mainly by CYP3A.

Elimination Route

Eliminated mainly in feces (70%) and to a lesser extent in urine (30%).

Half-life

Estimated terminal half-life: 28–29.6 days.

Stability

Storage

Oral

Capsules

25°C (excursions permitted between 15–30°C).

Actions

Inhibits the hedgehog pathway by binding to and inhibiting Smoothened, a transmembrane protein involved in hedgehog signal transduction.
Hedgehog signaling pathway plays important role during embryonic organ and tissue development; also key regulator of bone development and maintenance of tissues and stem cells in adults and during postnatal development.
Aberrant activation of the hedgehog pathway implicated in development of several malignancies (e.g., basal cell carcinoma).

Advice to Patients

Importance of advising patients to take the drug at least 1 hour before or 2 hours after a meal. If a dose is missed, take the next dose at the regularly scheduled time.
Risk of adverse musculoskeletal effects. Importance of monitoring CK and S_cr concentrations before and during therapy. Importance of immediately reporting dark urine, decreased urine output, inability to urinate, or new or worsening unexplained muscle pain, tenderness, or weakness that occurs during therapy or persists following discontinuance.
Risk of premature fusion of the epiphyses in pediatric patients. Importance of advising patients that safety and efficacy of sonidegib have not been established in pediatric patients.
Risk of fetal harm. Necessity of advising females of reproductive potential to use effective contraception during therapy and for at least 20 months after discontinuance; importance of obtaining pregnancy tests prior to initiation of therapy. Female patients and female partners of men receiving sonidegib should contact clinician if pregnancy is suspected or confirmed. Advise pregnant females potentially exposed to the drug of potential fetal risk.
Necessity of advising men (including those who have successfully undergone vasectomy) to use a condom during sexual encounters with females of reproductive potential during therapy and for at least 8 months after discontinuance.
Risk of serious adverse reactions in breast-fed infants. Importance of advising women to avoid breast-feeding while receiving sonidegib and for at least 20 months after discontinuance.
Importance of advising men to avoid donating semen while receiving sonidegib and for at least 8 months after discontinuance.
Importance of advising patients to avoid donating blood or blood products while receiving sonidegib and for at least 20 months after discontinuance.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses.
Importance of informing patients of other important precautionary information.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Sonidegib can only be obtained through a limited network of specialty pharmacies or distributors. Consult manufacturer's website for additional information.