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
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Potential risk of teratogenicity and embryofetal toxicity.1
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In females of reproductive potential, a pregnancy test must be obtained prior to treatment initiation.1
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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.)
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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
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Verify pregnancy status in females of reproductive potential prior to initiation of the drug.1
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Evaluate serum creatine kinase (CK, creatine phosphokinase, CPK) and Scr concentrations prior to initiation of therapy.1
Patient Monitoring
-
Monitor serum CK and Scr concentrations periodically during therapy, and as clinically indicated.1 More frequent monitoring may be necessary if toxicity occurs.1
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
OralFor 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
-
Manufacturer states none known.1
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
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
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Inhibits the hedgehog pathway by binding to and inhibiting Smoothened, a transmembrane protein involved in hedgehog signal transduction.1
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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.3 4 6 7
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Aberrant activation of the hedgehog pathway implicated in development of several malignancies (e.g., basal cell carcinoma).3 4 5 6 7
Advice to Patients
-
Importance of advising patients to take the drug at least 1 hour before or 2 hours after a meal.1 If a dose is missed, take the next dose at the regularly scheduled time.1
-
Risk of adverse musculoskeletal effects.1 Importance of monitoring CK and Scr concentrations before and during therapy.1 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.1
-
Risk of premature fusion of the epiphyses in pediatric patients.1 Importance of advising patients that safety and efficacy of sonidegib have not been established in pediatric patients.1
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Risk of fetal harm.1 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.1 Female patients and female partners of men receiving sonidegib should contact clinician if pregnancy is suspected or confirmed.1 Advise pregnant females potentially exposed to the drug of potential fetal risk.1
-
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.1
-
Risk of serious adverse reactions in breast-fed infants.1 Importance of advising women to avoid breast-feeding while receiving sonidegib and for at least 20 months after discontinuance.1 10
-
Importance of advising men to avoid donating semen while receiving sonidegib and for at least 8 months after discontinuance.1
-
Importance of advising patients to avoid donating blood or blood products while receiving sonidegib and for at least 20 months after discontinuance.1
-
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.1
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Importance of informing patients of other important precautionary information.1
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
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
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