Sonidegib (Odomzo - Novartis) is a Hedgehog signaling pathway inhibitor that has been approved for the treatment of basal cell carcinoma.

Sonidegib (Odomzo) Uses:

• Locally advanced basal cell carcinoma:

  • With locally advanced basal cell carcinoma (BCC), treatment of adult patients, that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy.

Vismodegib is another hedgehog pathway inhibitor used to treat skin cancer.

Sonidegib Dose in Adults

Note:

• Prior to therapy initiation, verify the pregnancy status of females of reproductive potential.
• Prior to starting treatment, measure serum creatine kinase (CK) levels and renal function tests in all patients.

Sonidegib Dose in the treatment of locally advanced Basal cell carcinoma:

P/O:

• Until disease progression or unacceptable toxicity, 200 mg once every 24 hours (Migden 2015)

Missed doses:

• Skip the missed dose and resume dosing with the next scheduled dose, if a dose is missed.

Sonidegib Use in Children:

The safety and efficacy of the drug in children have not been established.

Sonidegib Pregnancy Risk  Category: D

• [US Boxed Warning]:

• When administered to a pregnant woman, Sonidegib can cause embryo-fetal death or severe birth defects.
• Sonidegib is embryotoxic, fetotoxic & teratogenic in animals.
• Prior to initiating therapy, verify the pregnancy status of females of reproductive potential.
• During treatment with sonidegib & for at least 20 months after the last dose, advise females of reproductive potential to use effective contraception.
• Advise males of the potential risk of exposure through semen and to use condoms with a pregnant partner or a female partner of reproductive potential during treatment with sonidegib and for at least 8 months after the last dose.
• It is not known if sonidegib is present in semen or not.
• Even following a vasectomy, males with female partners of reproductive potential should use condoms.
• During sonidegib treatment, advise male patients not to donate sperm and for at least 8 months after the last sonidegib dose.
• Following exposure to sonidegib, health care providers should notify the manufacturer of pregnancies which may occur (888-669-6682).

Sonidegib use during breastfeeding:

• It is not known if sonidegib is secreted in breast milk or not.
• During therapy and for at least 20 months after treatment, due to the potential for serious adverse reactions in the breast-feeding infant, breast-feeding is not recommended by the manufacturer.

Sonidegib Dose in Kidney Disease:

CrCl 30 to 89 mL/minute:

• In the manufacturer's labeling, there are no dosage adjustments provided.
• However, mild or moderate impairment had no clinically meaningful effect on sonidegib exposure (compared to patients with normal renal function).

CrCl <30 mL/minute:

• In the manufacturer's labeling, there are no dosage adjustments provided.

Sonidegib Dose in Liver disease:

Mild, moderate, or severe impairment (Child-Pugh classes A, B, and C):

• In the manufacturer's labeling, there are no dosage adjustments provided.
• However, hepatic impairment had no clinically meaningful effect on sonidegib exposure (compared to patients with normal hepatic function).

Common Side Effects of Sonidegib (Odomzo):

• Central Nervous System:

  • Fatigue
  • Headache
  • Pain

• Dermatologic:

  • Alopecia

• Endocrine & Metabolic:

  • Hyperglycemia
  • Weight Loss
  • Increased Serum ALT
  • Increased Serum AST
  • Increased Amylase

• Gastrointestinal:

  • Dysgeusia
  • Increased Serum Lipase
  • Nausea
  • Diarrhea
  • Decreased Appetite
  • Abdominal Pain
  • Vomiting

• Hematologic & Oncologic:

  • Anemia
  • Lymphocytopenia

• Neuromuscular & Skeletal:

  • Increased Creatine Phosphokinase
  • Muscle Spasm
  • Musculoskeletal Pain
  • Myalgia

• Renal:

  • Increased Serum Creatinine

Less Common Side Effects of Sonidegib (Odomzo):

• Dermatologic:

  • Pruritus

Contraindications to Sonidegib (Odomzo):

• In the manufacturer's labeling, there are no contraindications listed.

Warnings and Precautions

• Amenorrhea:

  • In women of reproductive potential, Amenorrhea lasting for at least 18 months was observed.

• Musculoskeletal toxicity:

  • In more than two-thirds of patients treated with sonidegib, Musculoskeletal toxicity occurred (including grade 3 and 4 events).
  • Muscle spasms, musculoskeletal pain, and myalgia were the most frequently reported musculoskeletal adverse reactions.
  • Increased serum creatine kinase (CK) levels were also commonly observed (some events were grade 3 or 4).
  • By musculoskeletal pain and myalgia, CK elevations were usually preceded.
  • When CK elevations were grade 2 or higher, the median time to symptom onset was ~13 weeks (range: 2-39 weeks), and the median time to resolution (to ≤ grade 1) was 12 days.
  • More than one-quarter of patients needed medical management for musculoskeletal toxicity (eg, magnesium supplementation, muscle relaxants, and analgesics/opioids).
  • Several patients needed intravenous hydration or hospitalization.
  • Rhabdomyolysis was observed in one patient in clinical trials (at a dose higher than the FDA-approved dose).
  • During therapy, examine serum CK levels & serum creatinine at baseline and periodically  (more frequently if muscle symptoms are reported or if clinically indicated).
  • Advise patients to promptly report new unexplained muscle pain, tenderness, or weakness (either occurring during therapy or persisting after discontinuation).
  • May need therapy interruption or discontinuation.

• Renal impairment:

  • Although the measurement remained within the normal range in more than 75 percent of patients, increased serum creatinine was observed in the majority of patients receiving sonidegib.
  • Examine serum creatinine at baseline and periodically, while dosage adjustment is not required in patients with renal impairment, particularly if patients present with musculoskeletal toxicity.

Sonidegib: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Serum creatine kinase (CK) & serum creatinine (baseline, periodically during treatment, and at least weekly with musculoskeletal toxicity and CK elevations >2.5 times ULN until resolution)
• Liver function
• Pregnancy status
• Signs/symptoms of musculoskeletal toxicity.

How to administer Sonidegib (Odomzo)?

P/O:

• Administer on an empty stomach at least 1 hour before or 2 hours after a meal.

Mechanism of action of Sonidegib (Odomzo):

• Basal cell carcinoma is linked to mutations in Hedgehog pathway component components.
• Hedgehogs regulate cell growth and differentiation in embryogenesis.
• Although the pathway is not normally active in adult tissue (Von Hoff 2009), Hedgehog mutations that are associated with basal cell carcinoma can activate it. This causes an unrestricted proliferation of basal cells.
• Sonidegib, a selective Hedgehog pathway inhibitor, binds to and inhibits Smoothened homologs (SMO), transmembrane proteins involved in Hedgehog signal transduction.

Absorption:

• 10%
• AUC & C increase by 7.4-7.8-fold when taken with a high-fat meal (1,000 calories with 50% fat content).

Distribution:

• 9,166 L.

Protein binding:

• >97 percent.

Metabolism:

• Primarily hepatic through CYP3A

Bioavailability:

• <10 percent of an oral dose is absorbed.

Half-life elimination:

• ~28 days.

Time to peak:

• 2-4 hours.

Excretion:

• Feces (~70 percent).
• Urine (30 percent).

International Brands of Sonidegib:

• Odomzo
• Odomo

Sonidegib Brand Names in Pakistan:

No Brands Available in Pakistan.