Sonidegib, a hedgehog signaling pathway inhibitor, is an antineoplastic agent.1, 2, 3, 4, 5
Sonidegib is used for the treatment of locally advanced basal cell carcinoma in adults whose disease recurred following surgery or radiation therapy, and in those who are not candidates for surgery or radiation therapy.1, 2
The current indication for sonidegib in the treatment of locally advanced basal cell carcinoma is based principally on the results of a randomized, double-blind, noncomparative phase 2 study (BOLT) in patients with locally advanced or metastatic basal cell carcinoma.1, 2 The primary measure of efficacy was objective response rate (as evaluated by a blinded independent central review committee).1, 2 Tumor response was evaluated in patients with locally advanced disease using a modification of the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in addition to radiographic assessment of target lesions, digital clinical photography, and tumor biopsy.1, 2 Complete response in locally advanced disease was defined as the absence of tumor in all modalities used for assessment.1 Response by digital clinical photography was evaluated using World Health Organization (WHO) adapted criteria; partial response was defined as a 50% or greater reduction in lesion size (i.e., sum of the product of perpendicular diameters of lesions) and complete response was defined as disappearance of all lesions.1
In this study, the median age of patients was 67 years (range: 25-92 years); 3 patients had a diagnosis of nevoid basal cell carcinoma syndrome (also known as Gorlin syndrome).1 Most of the patients (76%) had received prior therapy for basal cell carcinoma, including surgery (73%), radiation therapy (18%), and topical or photodynamic therapy (21%).1 Approximately half of the patients had aggressive histology (micronodular, infiltrative, multifocal, basosquamous, or sclerosing basal cell carcinoma).1, 2 In this study, 66 patients with locally advanced basal cell carcinoma received sonidegib 200 mg orally once daily.1 Treatment was continued until disease progression, death, or unacceptable toxicity occurred or treatment was discontinued for other reasons.1, 2 Patients enrolled in the study with locally advanced basal cell carcinoma were required to have lesions for which radiation therapy was contraindicated or inappropriate (e.g., diagnosis of nevoid basal cell carcinoma syndrome or limitations due to location of tumor), had disease recurrence following surgery or radiation therapy, or had unresectable disease.1
After at least 30 months of follow-up (unless discontinued earlier), the objective response rate was 56% in patients with locally advanced basal cell carcinoma receiving sonidegib 200 mg once daily; 5% of these patients achieved a complete response.1, 12 The median duration of response was 26.1 months.1, 12, 13 These results were sustained in the final 42-month analysis.13 Objective response rates were similar between patients with locally advanced basal cell carcinoma receiving sonidegib 200 or 800 mg once daily.1, 2, 11, 12, 13 Results of a subgroup analysis (based on histology and geographic region) suggested that the drug's effect on objective response was consistent among these subgroups.2, 11, 12
Sonidegib is administered orally once daily on an empty stomach, at least 1 hour before or 2 hours after a meal.1
For the treatment of locally advanced basal cell carcinoma following failure of prior surgery or radiation therapy, the recommended dosage of sonidegib in adults is 200 mg once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
For the first occurrence of elevations in serum CK concentrations of 2.5-10 times the upper limit of normal (ULN) or first occurrence of severe or intolerable adverse musculoskeletal effects, sonidegib therapy should be withheld until the toxicity has resolved.1 Sonidegib may then be resumed at a dosage of 200 mg once daily.1
If recurrent elevations in serum CK concentrations of 2.5-5 times the ULN occur, sonidegib therapy should be withheld until the toxicity has resolved.1 Sonidegib may then be resumed at a dosage of 200 mg once daily.1
If elevations in serum CK concentrations exceeding 2.5 times the ULN with worsening renal function or exceeding 10 times the ULN occur, sonidegib therapy should be permanently discontinued.1
For recurrent elevations in serum CK concentrations exceeding 5 times the ULN or for recurrent severe intolerable adverse musculoskeletal effects, sonidegib therapy should be permanently discontinued.1
No dosage adjustment is recommended based on age, body weight, sex, or ethnicity.9
No dosage adjustment is necessary in patients with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C).1, 9, 14
No dosage adjustment is necessary in patients with mild to moderate renal impairment (creatinine clearance 30-89 mL/minute).1, 9
The manufacturer makes no specific dosage recommendations for geriatric patients.1
The manufacturer states that there are no known contraindications to the use of sonidegib.1
Fetal/Neonatal Morbidity and Mortality
There are no adequate and well-controlled studies of sonidegib in pregnant women; however, based on its mechanism of action and animal findings, sonidegib may cause fetal harm.1 The drug has been shown to cause embryofetal toxicity (i.e., abortion, fetal resorption) and teratogenic effects (i.e., severe midline defects, absent digits, severe craniofacial anomalies, other irreversible malformations) in rabbits receiving sonidegib at exposure levels of approximately 0.05 times the human exposure at the recommended dosage.1
Pregnancy should be avoided during sonidegib therapy.1 Females of reproductive potential should be advised to use an effective method of contraception while receiving sonidegib and for at least 20 months after discontinuance of therapy.1 Patients should be apprised of the potential hazard to the fetus if the drug is used during pregnancy.1 While receiving sonidegib and for at least 8 months after discontinuing the drug, sexually mature males (including those who have successfully undergone vasectomy) must use a condom each time they have sexual contact with a pregnant female or female of reproductive potential and must not donate semen while receiving sonidegib and for at least 8 months after discontinuing the drug.1
Because sonidegib may cause fetal harm and because of the possibility that the drug may be present in blood and be transfused into a female who is pregnant, patients receiving sonidegib must not donate blood or blood products during therapy and for at least 20 months following discontinuance of the drug.1
All females of reproductive potential must be tested for pregnancy prior to initiation of sonidegib therapy.1 If a female patient or female partner of a male patient receiving sonidegib therapy becomes pregnant during therapy or within 20 or 8 months, respectively, after discontinuance of the drug, the clinician should notify the manufacturer at 800-406-7984.1
Other Warnings and Precautions
Musculoskeletal effects, possibly accompanied by elevations of serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations, commonly occur during treatment with inhibitors of the hedgehog pathway, including sonidegib.1, 8 In clinical studies evaluating sonidegib (dosage range of 100 mg to 3 g) in 571 patients with advanced malignancies, rhabdomyolysis (defined as serum CK concentrations exceeding 10 times the baseline value and serum creatinine concentrations of 1.5 or more times the baseline value) occurred in 1 patient receiving sonidegib 800 mg.1 In the BOLT study, musculoskeletal effects or increased serum CK concentrations occurred in 68% (grade 3 or 4 in 9%) or 61% (grade 3 or 4 in 8%), respectively, of patients receiving sonidegib 200 mg daily.1 The most common musculoskeletal effects reported in this study included muscle spasms, musculoskeletal pain, and myalgia; musculoskeletal pain and myalgia usually preceded elevations in serum CK concentrations.1 The median time to occurrence of grade 2 or greater elevations in serum CK concentrations was 12.9 weeks (range: 2-39 weeks) and the median time for resolution of toxicity to grade 1 or less was 12 days (range: 8-14 days).1 Adverse musculoskeletal effects requiring medical intervention, including magnesium supplementation, muscle relaxants, and/or opiates or other analgesics, occurred in 29% of patients receiving sonidegib 200 mg daily; 5% of patients receiving this dosage of the drug required IV hydration or hospitalization.1
Serum CK and creatinine concentrations should be evaluated at baseline, periodically during sonidegib therapy, and as clinically indicated; patients who develop musculoskeletal symptoms and elevations in CK concentrations exceeding 2.5 times the upper limit of normal (ULN) should be monitored at least weekly until the toxicity has resolved.1 Temporary interruption, dosage reduction, or discontinuance of sonidegib may be necessary depending on severity of musculoskeletal symptoms during therapy with the drug.1
Premature Fusion of the Epiphyses
Epiphyseal disorders, including premature fusion of the epiphyses may occur in pediatric patients exposed to hedgehog pathway inhibitors, including sonidegib.1 Progression of epiphyses fusion has occurred despite discontinuation of the hedgehog pathway inhibitor.1 Sonidegib is not FDA-labeled for use in pediatric patients.1
Results of animal studies suggest that sonidegib may impair female fertility.1 Infertility was observed in female rats receiving sonidegib at dosages of 20 mg/kg or more daily (dosages approximately 1.3 times the human exposure at the recommended dosage).1 A reduced incidence of pregnancy, increased number of early resorptions, and decreased incidence of viable fetuses also were observed in female rats receiving the drug at dosages approximately 0.12 times the human exposure at the recommended dosage.1 In a repeat-dose toxicity study, degeneration of reproductive organs (i.e., uterus, ovaries) was observed in female rats receiving sonidegib at exposure levels of approximately 2 or more times the human exposure at the recommended dosage.1
Sonidegib may cause fetal harm if administered to pregnant females based on its mechanism of action and animal findings.1
Verify pregnancy status in all females of reproductive potential prior to initiation of sonidegib therapy.1 If a female patient or female partner of a male patient receiving sonidegib therapy becomes pregnant during therapy or within 20 or 8 months, respectively, after discontinuance of the drug, the clinician should notify the manufacturer at 800-406-7984.1
It is not known whether sonidegib is distributed into milk.1 Because of the potential for serious adverse reactions to sonidegib in breast-fed infants, women should be advised to discontinue breast-feeding while receiving sonidegib and for at least 20 months after discontinuance of therapy.1, 10 The effects of the drug on breast-fed infants or on milk production are unknown.1
Safety and efficacy of sonidegib have not been established in pediatric patients.1
Data in animals suggest possible adverse effects on bone, teeth, reproductive tissues, and nerve fibers in juvenile rats receiving sonidegib at exposure levels of approximately 1.2 times the human exposure at the recommended dosage.1
Epiphyseal disorders were reported in pediatric patients exposed to sonidegib in a clinical trial.1
In the BOLT study, 54% of patients receiving sonidegib (200 or 800 mg once daily) were 65 years of age or older and 28% were 75 years of age or older.1 No overall differences in efficacy were observed between geriatric and younger adults; however, grade 3 or 4 adverse effects, serious adverse effects, or adverse effects requiring interruption or discontinuance of therapy occurred more frequently in patients 65 years of age or older compared with younger adults.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Hepatic impairment (Child-Pugh class A, B, and C) has no meaningful effect on systemic exposure to sonidegib.1, 9, 14 In a population pharmacokinetic analysis, no clinically important differences in systemic exposure of sonidegib were observed between patients with mild hepatic impairment (i.e., total bilirubin concentrations not exceeding the ULN with AST concentrations exceeding the ULN, or total bilirubin concentrations exceeding the ULN, but no more than 1.5 times the ULN) and those with normal hepatic function.9 In another pharmacokinetic analysis, total sonidegib exposure was similar in patients with mild to severe hepatic impairment (Child-Pugh class A, B, and C) and those with normal hepatic function.14 Peak plasma concentrations were decreased in patients with severe hepatic impairment.14
No dosage adjustment is necessary in patients with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, and C).1, 9, 14
In a population pharmacokinetic analysis, no clinically important differences in systemic exposure of sonidegib were observed between patients with mild (creatinine clearance of 60-89 mL/minute) or moderate (creatinine clearance of 30-59 mL/minute) renal impairment and those with normal renal function.1, 9
No dosage adjustment is necessary in patients with mild to moderate renal impairment (creatinine clearance 30-89 mL/minute).1, 9
Adverse effects reported in 10% or more of patients with advanced basal cell carcinoma receiving sonidegib in the principal efficacy study include 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 and arthralgia.2
Laboratory abnormalities reported in more than 15% of patients receiving sonidegib include elevated concentrations of serum creatinine,1 elevated concentrations of serum CK,1, 2 hyperglycemia,1 elevated concentrations of lipase,1 anemia,1 lymphopenia,1 elevated concentrations of aminotransferases (i.e., AST, ALT),1 and elevated concentrations of amylase.1
Amenorrhea lasting at least 18 months also has been reported in 2 of 14 premenopausal women receiving sonidegib (200 or 800 mg once daily).1
Sonidegib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A.1 In vitro studies indicate that sonidegib inhibits CYP isoenzymes 2B6 and 2C9, but does not induce CYP 1A2, 2B6, or 3A.1
In vitro studies indicate that sonidegib inhibits breast cancer resistance protein (BCRP, ABCG2), but 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 studies also indicate that the drug is not a substrate of P-gp, MRP2, or BCRP.1
Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of sonidegib with moderate or potent inhibitors of CYP3A may result in increased peak plasma concentrations and systemic exposure of sonidegib.1 When the potent CYP3A inhibitor ketoconazole (200 mg twice daily for 14 days) was administered concomitantly with sonidegib (single 800-mg dose) in healthy individuals, peak plasma concentrations and area under the plasma concentration-time curve (AUC) of sonidegib were increased by 1.5- and 2.2-fold, respectively.1 Simulations using physiologically based pharmacokinetic models suggest that a similar increase in AUC would occur in cancer patients receiving concomitant administration of sonidegib (200 mg once daily) and a potent CYP3A inhibitor for 14 days.1 Simulations using physiologically based pharmacokinetic models suggest that concomitant administration of erythromycin, a moderate CYP3A inhibitor, and sonidegib (200 mg once daily) for 14 days or 4 months may increase AUC of sonidegib by 1.8- or 2.8-fold, respectively.1
Concomitant use of sonidegib with potent or moderate inhibitors of CYP3A should be avoided.1 If concomitant short-term (less than 14 days) therapy with a moderate CYP3A inhibitor cannot be avoided, the manufacturer recommends monitoring for adverse musculoskeletal effects and other toxicities.1
Concomitant use of sonidegib with moderate or potent inducers of CYP3A may result in decreased peak plasma concentrations and AUC of sonidegib.1 When the potent CYP3A inducer rifampin (600 mg daily for 14 days) was administered concomitantly with sonidegib (single 800-mg dose) in healthy individuals, the peak plasma concentrations and AUC of sonidegib were decreased by 54 and 72%, respectively.1 Simulations using physiologically based pharmacokinetic models suggest that concomitant administration of efavirenz, a moderate CYP3A inducer, and sonidegib (200 mg once daily) for 14 days or 4 months may decrease AUC of sonidegib by 56 or 69%, respectively, in cancer patients.1
Concomitant use of sonidegib with moderate or potent inducers of CYP3A should be avoided.1
Drugs Affecting Gastric Acidity
Several population pharmacokinetic analyses have indicated that concomitant administration of a proton-pump inhibitor and sonidegib decreased systemic exposure of sonidegib by approximately 30%.9, 14, 15 This decrease in exposure is not considered clinically meaningful and is unlikely to impact sonidegib therapy.1, 15
Sonidegib is an antineoplastic agent that inhibits the hedgehog pathway by binding to and selectively inhibiting Smoothened, a transmembrane protein involved in hedgehog signal transduction.1, 2, 3, 4, 5 The hedgehog signaling pathway plays an important role during embryonic organ and tissue development and is a key regulator of bone development and maintenance of tissues and stem cells in adults and during postnatal development.3, 4, 6, 7 However, genetic mutations that allow for aberrant activation of the hedgehog pathway have been implicated in the development of several malignancies such as basal cell carcinoma.3, 4, 5, 6, 7 Inhibition of Smoothened by sonidegib results in inhibition of the hedgehog pathway.1, 4
Following oral administration, less than 10% of sonidegib is absorbed.1, 4, 5 Area under the serum concentration-time curve (AUC) and peak plasma concentrations of sonidegib are dose proportional over a dosage range of 100-400 mg.1, 3 Peak plasma concentrations of sonidegib are achieved 2-4 hours following oral administration of a single dose of sonidegib (100 mg to 3 g) under fasting conditions in cancer patients.1 Following administration of sonidegib, steady-state concentrations of the drug are achieved in approximately 4 months and the estimated accumulation is 19-fold.1 Administration of sonidegib with a high-fat meal (approximately 1000 calories with 50% of calories from fat) increased systemic exposure (AUC and peak plasma concentrations) of sonidegib by 7.4- to 7.8-fold.1 In a population pharmacokinetic analysis, administration of sonidegib with a high-fat meal increased bioavailability of the drug fivefold.9 Sonidegib is metabolized in the liver principally by cytochrome P-450 (CYP) isoenzyme 3A.1 In vitro, sonidegib is more than 97% bound to plasma proteins.1 Following oral administration of sonidegib, approximately 70% of the absorbed dose is recovered in feces and 30% is recovered in urine; unchanged drug is not excreted in urine.1, 4 The estimated plasma elimination half-life of the drug is 28-29.6 days.1, 9
Population pharmacokinetic analyses indicate that age, sex, body weight, and ethnicity generally do not have clinically important effects on the exposure of sonidegib.1, 9 A cross-study comparison indicates that systemic exposure following administration of sonidegib (single 200-mg dose) is increased by 1.7-fold in healthy Japanese individuals compared with individuals from Western countries.1
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
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 | Sun Pharmaceutical Industries Inc. |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions February 11, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Sun Pharmaceutical Industries Inc. Odomzo® (sonidegib) capsules prescribing information. Cranbury, NJ; 2019 May. [Web]
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. [PubMed 25981810]
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. [PubMed 24523439]
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. [PubMed 24817600]
5. Burness CB. Sonidegib: First Global Approval. Drugs . 2015; 75:1559-66. [PubMed 26323341]
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. [PubMed 26614022]
7. Gupta S, Takebe N, Lorusso P. Targeting the Hedgehog pathway in cancer. Ther Adv Med Oncol . 2010; 2:237-50. [PubMedCentral][PubMed 21789137]
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. [PubMed 26898300]
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. [PubMed 27067394]
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. [PubMedCentral][PubMed 28846163]
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. [PubMedCentral][PubMed 31545507]
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. [PubMed 28577129]
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. [PubMedCentral][PubMed 27277189]
16. Sun Pharmaceutical Industries Inc. Odomzo® (sonidegib): Access and resources. Accessed 8 Feb 2022. [Web]