To the Editor: The Hedgehog pathway inhibitors (HPIs), sonidegib and vismodegib, are indicated for locally advanced BCC or metastatic BCC but have a high incidence of adverse effects (AE) resulting in therapy interruption or discontinuation. We conducted a literature review according to the Preferred Items for Systematic Review and Meta-Analysis (PRISMA) guidelines on the management of AEs to improve knowledge gaps in therapy. Combined with our own 5-year experience,1Simone P.D. Schwarz J.M. Strasswimmer J.M. Four-year experience with vismodegib hedgehog inhibitor therapy.J Am Acad Dermatol. 2016; 74: 1264-1265Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar we identified the major AEs leading to management challenges: alopecia, dysgeusia, weight loss, elevated creatine phosphokinase (CPK), muscle spasms, ovarian dysfunction, and new onset squamous cell carcinoma. Myopathies and elevations of CPK are the most common AEs. Ally et al,2Ally M.S. Tang J.Y. Lindgren J. et al.Effect of calcium channel blockade on vismodegib-induced muscle cramps.JAMA Dermatol. 2015; 151: 1132-1134Crossref PubMed Scopus (23) Google Scholar in a small clinical trial (n = 17), noted that patients experienced a modest improvement in symptoms within 2 weeks of amlodipine treatment. A study is in progress to evaluate levocarnitine in alleviating HPI-associated muscle spasms (NCT01893892). Elevated CPK has been described for both sonidegib and vismodegib, with monitoring for required for sonidegib but not vismodegib. Significantly, CPK levels were not monitored during vismodegib trials. HPI patients at risk for CPK abnormalities or myopathies, such as those concurrently using a statin, may benefit from periodic monitoring. Alopecia is the second most common AE. Unlike with chemotherapy, alopecia usually involves less than 50% of the scalp.3Macdonald J.B. Macdonald B. Golitz L.E. LoRusso P. Sekulic A. Cutaneous adverse effects of targeted therapies: Part II: Inhibitors of intracellular molecular signaling pathways.J Am Acad Dermatol. 2015; 72: 221-228Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar MacDonald et al3Macdonald J.B. Macdonald B. Golitz L.E. LoRusso P. Sekulic A. Cutaneous adverse effects of targeted therapies: Part II: Inhibitors of intracellular molecular signaling pathways.J Am Acad Dermatol. 2015; 72: 221-228Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar recommend concealment measures and minoxidil 2-5% continued for 6 months after therapy. Dysgeusia is the third most common AE. Le Moigne et al4Le Moigne M. Saint-Jean M. Jirka A. et al.Dysgeusia and weight loss under treatment with vismodegib: benefit of nutritional management.Support Care Cancer. 2016; 24: 1689-1695Crossref PubMed Scopus (10) Google Scholar demonstrated a benefit of early nutritional screening for those taking vismodegib, with less weight loss in the intervention group that received nutritional counseling. Significantly, a greater than 5% weight loss can occur without dysgeusia, possibly due to diarrhea, nausea, xerostomia, oral thrush, or abdominal pain.4Le Moigne M. Saint-Jean M. Jirka A. et al.Dysgeusia and weight loss under treatment with vismodegib: benefit of nutritional management.Support Care Cancer. 2016; 24: 1689-1695Crossref PubMed Scopus (10) Google Scholar Addressing oral hygiene, reflux disease, low-grade oral infection, and postnasal drip are reported to improve taste sensation in non-HPI patients.3Macdonald J.B. Macdonald B. Golitz L.E. LoRusso P. Sekulic A. Cutaneous adverse effects of targeted therapies: Part II: Inhibitors of intracellular molecular signaling pathways.J Am Acad Dermatol. 2015; 72: 221-228Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar While patients who undergo HPI therapy are generally older adults, premenopausal women of childbearing age may experience amenorrhea likely due to reversible follicle-stimulating hormone receptor inhibition.1Simone P.D. Schwarz J.M. Strasswimmer J.M. Four-year experience with vismodegib hedgehog inhibitor therapy.J Am Acad Dermatol. 2016; 74: 1264-1265Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar It is essential to counsel primary care physicians on both the teratogenicity and sequelae of ovarian failure because non-dermatologists are largely unfamiliar with the side effects of HPIs. As use of HPIs for basal cell nevus syndrome expands to a younger population, a larger number of patients may experience amenorrhea. Recently, new onset squamous cell carcinomas have been reported during HPI therapy. Zhu et al5Zhu G.A. Sundram U. Chang A.L. Two different scenarios of squamous cell carcinoma within advanced basal cell carcinomas: cases illustrating the importance of serial biopsy during vismodegib usage.JAMA Dermatol. 2014; 150: 970-973Crossref PubMed Scopus (47) Google Scholar recommend that a new or persistent ulceration, nodule or erythema in the BCC tumor site should be biopsied if present after 3 months of HPI therapy. We recommend that total body skin exams be conducted during therapy and non-BCC lesions comprehensively treated, because we have identified synchronous occult amelanotic melanoma in 3 of 12 patients considered for HPI therapy.1Simone P.D. Schwarz J.M. Strasswimmer J.M. Four-year experience with vismodegib hedgehog inhibitor therapy.J Am Acad Dermatol. 2016; 74: 1264-1265Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar We have successfully maintained 2 patients on continuous daily therapy for more 5 years by judicious attention to management of AEs.1Simone P.D. Schwarz J.M. Strasswimmer J.M. Four-year experience with vismodegib hedgehog inhibitor therapy.J Am Acad Dermatol. 2016; 74: 1264-1265Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Alternate dosage regimens to mitigate AEs are promising and a clinical trial is underway (NCT01815840).