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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.1

  • In females of reproductive potential, a pregnancy test must be obtained prior to treatment initiation.1

  • Pregnancy must be prevented by use of reliable contraception in females of reproductive potential and sexually mature males.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • Men must not donate semen during and for at least 8 months after therapy.1

Introduction

Antineoplastic agent; a hedgehog signaling pathway inhibitor.1 2 3 4 5

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.1 2

Sonidegib Dosage and Administration

General

Pretreatment Screening

Patient Monitoring

Administration

Oral Administration

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

Dosage

Adults

Basal Cell Carcinoma
Oral

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

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.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, sex, or ethnicity.9

Hepatic Impairment

Mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C): No dosage adjustment required.1 9

Renal Impairment

Mild to moderate renal impairment (Clcr 30–89 mL/minute): No dosage adjustment required.1 9

Geriatric Patients

No specific dosage recommendations.1

Cautions for Sonidegib

Contraindications

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryofetal toxicity and teratogenicity demonstrated in animals.1 (See Boxed Warning.)

Avoid pregnancy during therapy.1 Females of reproductive potential should use effective contraception during treatment and for at least 20 months following drug discontinuance.1

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.1 Men must not donate semen during and for at least 8 months after therapy.1

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.1

Obtain a pregnancy test prior to initiating therapy in females of reproductive potential.1

If pregnancy occurs in a female patient or female partner of male patient receiving sonidegib, apprise of potential fetal hazard.1 Report any suspected fetal exposure to the manufacturer at 800-406-7984.1

Other Warnings and Precautions

Musculoskeletal Effects

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

Most common musculoskeletal effects include muscle spasms, musculoskeletal pain, myalgia.1 Musculoskeletal pain and myalgia usually precede increased CK concentrations.1 Some patients experienced musculoskeletal effects requiring medical intervention with magnesium supplementation, muscle relaxants, analgesics, IV hydration, and/or hospitalization.1

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

Monitor CK and Scr concentrations at baseline, periodically during therapy, and as clinically indicated.1 If musculoskeletal symptoms and elevations in CK concentrations of >2.5 times ULN occur, monitor CK and Scr concentrations at least weekly until resolution.1 Temporary interruption, dosage reduction, or discontinuance of drug may be necessary depending on severity of musculoskeletal symptoms.1

Premature Fusion of the Epiphyses

May cause epiphyseal disorders, including premature fusion of the epiphyses, in pediatric patients.1

Infertility

May impair female fertility based on animal findings.1

Specific Populations

Pregnancy

May cause fetal harm.1

Verify pregnancy status in females of reproductive potential prior to initiating therapy.1

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 800-406-7984.1

Lactation

Not known whether distributed into milk.1 Discontinue breast-feeding during therapy and for at least 20 months after drug discontinuance.1 10

Effects of sonidegib on breast-fed infants or human milk production unknown.1

Pediatric Use

Safety and efficacy not established.1

Epiphyseal disorders reported in pediatric patients exposed to sonidegib in a clinical trial.1

Geriatric Use

No overall differences in efficacy in geriatric patients (≥65 years of age) compared with younger adults.1 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.1

No specific dosage recommendations.1

Hepatic Impairment

In population pharmacokinetic analyses, systemic exposure not altered by mild, moderate, or severe hepatic impairment; no dosage adjustment necessary in such patients.1 9 14

Renal Impairment

In a population pharmacokinetic analysis, systemic exposure not altered by mild (Clcr 60–89 mL/minute) or moderate (Clcr of 30–59 mL/minute) renal impairment; dosage adjustment not necessary in such patients.1 9

Common Adverse Effects

Adverse effects reported in ≥10% of patients receiving sonidegib: Muscle spasms,1 2 alopecia,1 2 dysgeusia,1 2 fatigue,1 2 nausea,1 2 diarrhea,1 2 musculoskeletal pain,1 weight loss,1 2 decreased appetite,1 2 myalgia,1 2 abdominal pain,1 headache,1 2 pain,1 vomiting,1 pruritus,1 arthralgia.2

Laboratory abnormalities (≥15%): Increased Scr,1 increased CK,1 hyperglycemia,1 increased lipase,1 anemia,1 lymphopenia,1 elevated AST and ALT concentrations,1 increased amylase.1

Amenorrhea lasting at least 18 months reported in 2 of 14 premenopausal women receiving sonidegib (200 or 800 mg once daily).1

Drug Interactions

Metabolized principally by CYP3A.1

Inhibitor of CYP2B6 and 2C9; does not induce CYP1A2, 2B6, or 3A.1

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 OATP1B3.1 In vitro, not a substrate of P-gp, MRP2, or BCRP.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible pharmacokinetic interaction (increased concentrations and systemic exposure of sonidegib).1 Avoid concomitant use.1 (See Specific Drugs under Interactions.)

Moderate CYP3A inhibitors: Possible pharmacokinetic interaction (increased concentrations and systemic exposure of sonidegib).1 Avoid concomitant use.1 (See Specific Drugs under Interactions.) If concomitant short-term therapy (≤14 days) cannot be avoided, monitor for adverse musculoskeletal effects and other toxicities.1

Moderate or potent CYP3A inducers: Possible pharmacokinetic interaction (decreased concentrations and systemic exposure of sonidegib).1 Avoid concomitant use.1 (See Specific Drugs under Interactions.)

Specific Drugs

Drug

Interaction

Comments

Efavirenz

Possible decreased sonidegib exposure1

Decrease in sonidegib AUC of 56 or 69% expected after concomitant use for 14 days or 4 months, respectively1

Avoid concomitant use1

Erythromycin

Possible increased sonidegib exposure1

1.8- or 2.8-fold increase in sonidegib AUC expected after concomitant use for 14 days or 4 months, respectively1

Avoid concomitant use; if concomitant short-term therapy (<14 days) cannot be avoided, monitor for adverse effects1

Ketoconazole

Possible increased sonidegib exposure1

Increased sonidegib AUC and peak concentrations by 2.2- and 1.5-fold, respectively1

Avoid concomitant use1

Rifampin

Possible decreased sonidegib exposure1

Decreased sonidegib AUC and peak concentrations by 72 and 54%, respectively1

Avoid concomitant use1

Sonidegib Pharmacokinetics

Absorption

Bioavailability

<10% absorbed.1 4 5

Systemic exposure and peak plasma concentrations increase in a dose-proportional manner following administration of sonidegib 100–400 mg.1 3

Peak plasma sonidegib concentrations are attained about 2–4 hours after oral administration under fasting conditions.1

Steady-state concentrations are achieved within approximately 4 months.1

Estimated systemic accumulation is 19-fold.1

Food

Administration with a high-fat meal increased AUC and peak plasma concentrations by 7.4- to 7.8-fold.1 Fivefold increase in bioavailability reported after administration with a high-fat meal in a population pharmacokinetic analysis.9

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.1 9 14

Mild (Clcr 60–89 mL/minute) or moderate (Clcr 30–59 mL/minute) renal impairment: Systemic exposure was similar to that in patients with normal renal function.1 9

Age, sex, body weight, or ethnicity: No clinically important effects on sonidegib pharmacokinetics.1 9 Systemic exposure following administration of sonidegib (single 200-mg dose) increased by 1.7-fold in healthy Japanese individuals versus those from Western countries.1

Distribution

Extent

Not known whether distributed into human milk or semen.1

Plasma Protein Binding

>97%.1

Elimination

Metabolism

Metabolized mainly by CYP3A.1

Elimination Route

Eliminated mainly in feces (70%) and to a lesser extent in urine (30%).1

Half-life

Estimated terminal half-life: 28–29.6 days.1 9

Stability

Storage

Oral

Capsules

25°C (excursions permitted between 15–30°C).1

Actions

Advice to Patients

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.16 Consult manufacturer's website for additional information.16

Sonidegib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

200 mg

Odomzo

Sun Pharmaceutical Industries Inc

AHFS DI Essentials™. © Copyright 2024, Selected Revisions January 1, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Sun Pharmaceutical Industries Inc. Odomzo (sonidegib) capsules prescribing information. Cranbury, NJ; 2019 May. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=028312dc-d155-4fd5-8abd-6bb9f011d3cc

2. Migden MR, Guminski A, Gutzmer R et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015; 16:716-28. http://www.ncbi.nlm.nih.gov/pubmed/25981810?dopt=AbstractPlus

3. Rodon J, Tawbi HA, Thomas AL et al. A phase I, multicenter, open-label, first-in-human, dose-escalation study of the oral smoothened inhibitor Sonidegib (LDE225) in patients with advanced solid tumors. Clin Cancer Res. 2014; 20:1900-9. http://www.ncbi.nlm.nih.gov/pubmed/24523439?dopt=AbstractPlus

4. Zollinger M, Lozac'h F, Hurh E et al. Absorption, distribution, metabolism, and excretion (ADME) of 14C-sonidegib (LDE225) in healthy volunteers. Cancer Chemother Pharmacol. 2014; 74:63-75. http://www.ncbi.nlm.nih.gov/pubmed/24817600?dopt=AbstractPlus

5. Burness CB. Sonidegib: First Global Approval. Drugs. 2015; 75:1559-66. http://www.ncbi.nlm.nih.gov/pubmed/26323341?dopt=AbstractPlus

6. Wahid M, Jawed A, Mandal RK et al. Vismodegib, itraconazole and sonidegib as hedgehog pathway inhibitors and their relative competencies in the treatment of basal cell carcinomas. Crit Rev Oncol Hematol. 2016; 98:235-41. http://www.ncbi.nlm.nih.gov/pubmed/26614022?dopt=AbstractPlus

7. Gupta S, Takebe N, Lorusso P. Targeting the Hedgehog pathway in cancer. Ther Adv Med Oncol. 2010; 2:237-50. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3126020&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/21789137?dopt=AbstractPlus

8. Genentech. Erivedge (vismodegib) capsules prescribing information. South San Francisco, CA; 2015 May.

9. Goel V, Hurh E, Stein A et al. Population pharmacokinetics of sonidegib (LDE225), an oral inhibitor of hedgehog pathway signaling, in healthy subjects and in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2016; 77:745-55. http://www.ncbi.nlm.nih.gov/pubmed/26898300?dopt=AbstractPlus

10. Novartis Pharmaceuticals Corporation. East Hanover, NJ: Personal communication.

11. Dummer R, Guminski A, Gutzmer R et al. The 12-month analysis from Basal Cell Carcinoma Outcomes with LDE225 Treatment (BOLT): A phase II, randomized, double-blind study of sonidegib in patients with advanced basal cell carcinoma. J Am Acad Dermatol. 2016; 75:113-125.e5. http://www.ncbi.nlm.nih.gov/pubmed/27067394?dopt=AbstractPlus

12. Lear JT, Migden MR, Lewis KD et al. Long-term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30-month analysis of the randomized phase 2 BOLT study. J Eur Acad Dermatol Venereol. 2018; 32:372-381. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=PMC5873455&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/28846163?dopt=AbstractPlus

13. Dummer R, Guminksi A, Gutzmer R et al. Long-term efficacy and safety of sonidegib in patients with advanced basal cell carcinoma: 42-month analysis of the phase II randomized, double-blind BOLT study. Br J Dermatol. 2020; 182:1369-1378. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=PMC7318253&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/31545507?dopt=AbstractPlus

14. Horsmans Y, Zhou J, Liudmila M et al. Effects of Mild to Severe Hepatic Impairment on the Pharmacokinetics of Sonidegib: A Multicenter, Open-Label, Parallel-Group Study. Clin Pharmacokinet. 2018; 57:345-354. http://www.ncbi.nlm.nih.gov/pubmed/28577129?dopt=AbstractPlus

15. Zhou J, Quinlan M, Glenn K et al. Effect of esomeprazole, a proton pump inhibitor on the pharmacokinetics of sonidegib in healthy volunteers. Br J Clin Pharmacol. 2016; 82:1022-9. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=PMC5137827&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/27277189?dopt=AbstractPlus

16. Sun Pharmaceutical Industries Inc. Odomzo (sonidegib): Access and resources. Accessed 8 Feb 2022. https://www.odomzo.com/hcp/financial-assistance

Frequently asked questions