II. Indications
- Metastatic Basal Cell Cancer (not amenable to surgery)
- Vismodegib (Erivedge)
- Sonidegib (Odomzo)
-
Acute Myeloid Leukemia (new onset, or age >75 years and not candidate for induction Chemotherapy)
- Glasdegib (Daurismo)
III. Mechanism
- Sonic Hedgehog (Shh) Signaling Pathway
- Hedgehog (Hh) family of signaling Proteins
- Key role in human development (as well as many other species, including Drosophila)
- Regulates tissue and organ morphogenesis, as well as stem cell proliferation in adults
- Many cancers involve aberrant activation of the Hh pathway
- Components
- Signal cascade
- Sonic Hedgehog (SHh) family factors bind PTC (patched)
- PTC binding releases SMO (smoothened) as a signal
- SMO activates transcription of target genes via the GLI family of Proteins
- Hedgehog (Hh) family of signaling Proteins
- SHH Pathway Inhibitor
IV. Medications
- Vismodegib (Erivedge)
- Highly Teratogenic (see below)
- Risk of myalgias, severe cutaneous reactions, prematurely fuses Growth Plates (children)
- Sonidegib (Odomzo)
- Highly Teratogenic (see below)
- Risk of myalgias, prematurely fuses Growth Plates (children)
- Avoid with moderate to strong CYP3A Inhibitors and Inducers
- Glasdegib (Daurismo)
- Highly Teratogenic (see below)
- Risk of Prolonged QTc
- Avoid with moderate to strong CYP3A Inhibitors and Inducers
V. Dosing
- See other references for disease specific dosing protocols
VI. Adverse Effects
-
Teratogenic (Vismodegib, Sonidegib)
- See safety below
- Premature Growth Plate closure in children (Vismodegib, Sonidegib)
- Not approved for use in children
- Severe Cutaneous Reactions (Vismodegib)
- QTc Prolongation (Glasdegib)
- Other common adverse effects
- Arthralgias, myalgias and Muscle spasms, and Fatigue
- Weight loss, decreased appetite, Dysgeusia, Nausea, Vomiting and Constipation
VII. Safety
- Avoid in Lactation
- Avoid in pregnancy (all trimesters, pregnancy category X and )
- Use reliable Contraception
- Boxed Warning for Vismodegib, Sonidegib and
- Highly Teratogenic (severe midline defects, irreversible malformations and missing digits)
- Continue reliable Contraception for at least 1 month Glasdegib, 20 months Sonidegib, 24 months after Vismodegib
- Men should use Condoms to prevent transmission of agent via semen
- Do not donate semen for 1 month after Glasdegib, 3 months after Vismodegib and 8 months after Sonidegib
- Avoid donation of blood or Blood Products for 24 months after Vismodegib, 20 months after Sonidegib
VIII. Safety
- Avoid in pregnancy (all trimesters)
- Use reliable Contraception
- Shh Pathway is key to Embryo Development
- Monitoring
- Serum Creatinine
- Serum Creatine Kinase
- Electrocardiogram (Glasdegib)
IX. Drug Interactions
-
CYP3A Inhibitors
- Avoid Sonidegib, Glasdegib with strong CYP3A Inhibitors overall
- Avoid Sonidegib with moderate CYP3A Inhibitors for >14 days
-
CYP3A Inducers
- Avoid Sonidegib, Glasdegib with moderate to strong CYP3A Inducers
-
Medication Causes of QTc Prolongation
- Avoid with Glasdegib
X. Resources
- Vismodegib (DailyMed)
- Sonidegib (DailyMed)
- Glasdegib (DailyMed)