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U.S. Food & Drug Administration (FDA) Clinical Pharmacology Corner Update: FDA Approves Odomzo (Sonidegib)

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FDA Approves Odomzo® (Sonidegib) for the Treatment of Locally Advanced Basal Cell Carcinoma

On July 24, 2015, the United States Food and Drug Administration (FDA) approved Odomzo (sonidegib) oral capsules for the treatment of adult patients with locally advanced basal cell carcinoma that has recurred following surgery or radiation therapy or that is not amenable to curative surgery or radiation therapy. The recommended dose is 200 mg administered once daily under fasted conditions (i.e., at least one hour before or 2 hours after a meal).

Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD) of Sonidegib

  • MOA: Inhibitor of the Hedgehog pathway.
  • Dose proportionality: Exhibited dose-proportional increases in systemic exposure over the dose range of 100 mg (i.e., half the recommended dosage) to 400 mg (i.e., twice the recommended dosage), but less than dose-proportional increases at doses greater than 400 mg.
  • Accumulation: 19-fold at steady state (time to steady state is approximately 4 months).
  • Absorption: Less than 10% is absorbed (Tmax of 2 to 4 hours) in patients.
  • Food effect: A 7.4- to 7.8-fold increase in sonidegib exposure was observed following the administration of Odomzo with a high-fat meal (1000 calories with 50% from fat) to healthy subjects.
  • Plasma protein binding: Greater than 97%, independent of the drug concentration.
  • Terminal half-life (mean): Approximately 28 days in patients.
  • Metabolism: Metabolized to inactive metabolites by CYP3A.
  • Excretion: Of the absorbed dose, approximately 70% was eliminated in the feces and 30% was eliminated in the urine. Unchanged sonidegib was not detectable in the urine.
  • Exposure-safety: At a dose of 800 mg once daily, sonidegib did not prolong the QTc interval. The probability of Grade 3 or 4 creatine kinase elevation increased with higher sonidegib trough concentrations in clinical studies at Odomzo dosages of 200 mg or 800 mg (i.e., four times the recommended dosage) once daily.

Drug Interaction Potential

  • Avoid strong and moderate CYP3A inhibitors. Coadministration of a strong (e.g., ketoconazole) or moderate (e.g., erythromycin) CYP3A4 inhibitor for 14 days could increase sonidegib exposure by 2.2-fold and 1.8- fold, respectively. If a moderate CYP3A inhibitor must be used, the inhibitor should be administered for less than 14 days and patients should be closely monitored for adverse reactions, particularly musculoskeletal adverse reactions.
  • Avoid strong and moderate CYP3A inducers. Coadministration of a strong (e.g., rifampicin) or moderate (e.g., efavirenz) CYP3A4 inducer for 14 days could decrease sonidegib exposure by 72% and 56%, respectively.
  • Sonidegib is a weak base that demonstrates pH dependent solubility. An exploratory analysis suggests that sonidegib steady state exposure is 34% lower in patients concurrently taking a gastric acid-reducing agent (e.g., proton pump inhibitor or histamine-2 receptor antagonist) compared to patients taking Odomzo alone. The clinical relevance of this finding is unknown.

Use in Specific Populations

No dose adjustment is recommended in patients with renal impairment or mild hepatic impairment. Mild hepatic impairment (defined as either total bilirubin less than or equal to the upper limit of normal (ULN) and aspartate aminotransferase (AST) greater than the ULN or total bilirubin greater than 1.0 to 1.5 times the ULN) or mild (creatinine clearance (CLcr) 60 to 89 mL/min) to moderate (CLcr 30 to 59 mL/min) renal impairment had no effect on sonidegib steady state exposure as compared to patients with normal organ function. The effect of moderate to severe hepatic impairment on sonidegib exposure is unknown.

Safety and Efficacy

The safety and effectiveness of Odomzo were evaluated in a single, randomized, placebo-controlled, double-blind, multiple cohort clinical trial conducted in 230 patients. The major efficacy outcome measure was objective response rate (ORR) and a supportive efficacy outcome measure was duration of response. In the 66 patients with locally advanced disease randomized to a 200 mg dose, the ORR was 58% (95% confidence interval: 45, 70). Among the 38 patients with an objective response, 7 (18%) patients experienced subsequent disease progression with 4 of these 7 patients having maintained a response of 6 months or longer. The remaining 31 patients (82%) had ongoing responses ranging from to 1.9+ to 18.6+ months. In the 79 patients treated with Odomzo 200 mg daily, the most common grade 3 or 4 adverse events were musculoskeletal, including elevation of serum creatine kinase, muscle spasms, musculoskeletal pain and myalgia, which occurred in 9% of patients.


Full prescribing information is available at http://go.usa.gov/3A4km.

The Office of Clinical Pharmacology (OCP) regulatory reviews for new drugs or biologics are often available for viewing shortly following approval at the Agency's Drugs@FDA website (http://go.usa.gov/3A48Y).

We always welcome your thoughts regarding the format, content, and utility of information you receive via this Burst email initiative. Comments may be sent via email to ocp@fda.hhs.gov.

This burst was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.


FDA/Center for Drug Evaluation and Research (CDER)
Office of Translational Sciences
Office of Clinical Pharmacology
Email: ocp@fda.hhs.gov


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