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Figure.
Mean Change in Cramp Frequency, Cramp Severity, Cramp Duration, and Night Awakenings Over Time From Baseline With Amlodipine Treatment in 8 Patients
Mean Change in Cramp Frequency, Cramp Severity, Cramp Duration, and Night Awakenings Over Time From Baseline With Amlodipine Treatment in 8 Patients

Mean values at each time point refer to the 2-week period preceding the respective telephone-administered questionnaire. Arrowheads indicate the point at which amlodipine treatment was initiated. Patients who experienced a reduction in cramp frequency noted efficacy within 2 weeks of starting amlodipine treatment, and the benefits were maintained throughout the 8-week trial.

Table.  
Mean (SD) Change in Muscle Cramp Characteristics Over Time With Amlodipine Treatment
Mean (SD) Change in Muscle Cramp Characteristics Over Time With Amlodipine Treatment
1.
Epstein  EH.  Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8(10):743-754.
PubMedArticle
2.
Sekulic  A, Migden  MR, Oro  AE,  et al.  Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171-2179.
PubMedArticle
3.
Tang  JY, Mackay-Wiggan  JM, Aszterbaum  M,  et al.  Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med. 2012;366(23):2180-2188.
PubMedArticle
4.
Teperino  R, Amann  S, Bayer  M,  et al.  Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat. Cell. 2012;151(2):414-426.
PubMedArticle
5.
ClinicalTrials.gov. The Purpose of This Study Is to Determine The Efficacy and Safety of a Systemic Hedgehog Pathway Antagonist (GDC-0449) in Patients With Basal Cell Nevus Syndrome (BCNS).https://clinicaltrials.gov/ct2/show/NCT00957229. Accessed June 1, 2015.
6.
ClinicalTrials.gov. Trial Comparing the Effects of Intermittent Vismodegib Versus Photodynamic Therapy in Patients With Multiple Basal Cell Carcinomas. https://clinicaltrials.gov/ct2/show/NCT01556009. Accessed June 1, 2015.
7.
Ozkul  Y.  Influence of calcium channel blocker drugs in neuromuscular transmission. Clin Neurophysiol. 2007;118(9):2005-2008.
PubMedArticle
Research Letter
October 2015

Effect of Calcium Channel Blockade on Vismodegib-Induced Muscle Cramps

Author Affiliations
  • 1Department of Dermatology, Stanford University, Stanford, California
  • 2Children’s Hospital Oakland Research Institute, Oakland, California
JAMA Dermatol. 2015;151(10):1132-1134. doi:10.1001/jamadermatol.2015.1937

Aberrant hedgehog (HH) pathway signaling is the pivotal molecular abnormality in all basal cell carcinomas whether occurring sporadically or as part of the rare autosomal dominant disease basal cell nevus (Gorlin) syndrome (OMIM 109400).1 Vismodegib (Erivedge, GDC-0449), an oral HH pathway inhibitor, is approved by the Food and Drug Administration for the treatment of locally advanced and metastatic basal cell carcinomas.2

One of the major adverse effects of vismodegib is severe muscle cramps.2,3 Currently, there is no treatment for this adverse effect, often resulting in drug therapy discontinuation.3 Teperino et al4 suggested that vismodegib acts not only to antagonize canonical HH signaling but also to agonize noncanonical HH signaling, causing cell membrane calcium channel activation and inducing muscle cramps. These investigators proposed that calcium channel blockers might abrogate this adverse event.4 Our objective was to evaluate the course of muscle cramps in our cohort of vismodegib-treated patients and to investigate whether the calcium channel blocker amlodipine besylate would alter the self-reported severity and frequency of these cramps.

Methods

This was an ancillary study of 43 patients enrolled in 2 clinical trials testing vismodegib, 150 mg/d, for basal cell carcinoma prevention.5,6 We treated 9 patients with basal cell nevus syndrome with amlodipine, 10 mg/d, for 8 weeks based on their willingness to take a daily medication for cramps. We queried them using telephone-administered questionnaires at –4 weeks, baseline, and 2, 4, and 8 weeks after amlodipine therapy initiation about cramp frequency, severity (scale of 0 [none] to 10 [severe]), and duration (minutes); frequency of night awakenings due to muscle cramps; and common adverse effects associated with amlodipine. We excluded 34 patients from amlodipine treatment who had completed the study (n = 3), were not currently using vismodegib (n = 11), were expected to stop taking vismodegib within the ensuing 4 weeks (n = 7), were already using amlodipine at baseline (n = 2), were unwilling to take amlodipine or had contraindications to its use (n = 9), or were unavailable to complete baseline questionnaires (n = 2). This study was approved by the Children’s Hospital Oakland Research Institute Institutional Review Board. Oral informed consent was received from all patients.

Our primary end point was the percentage change in muscle cramp frequency from baseline to week 8 of amlodipine treatment. Our secondary outcomes were changes in muscle cramp severity, cramp duration, and frequency of night awakenings. On the basis of an effect size of 30% reduction in muscle cramp frequency (SD, 20%) at week 8 from baseline and a power of 80%, a sample size of 6 patients would be required to detect a statistically significant (α = .05) difference before and after amlodipine treatment.

Results

We included 8 amlodipine-treated patients in the analysis; one patient was excluded because of incomplete questionnaires after baseline. Study participants included 5 men and 3 women with a mean (SD) age of 54 (11) years who were treated with a mean (SD) of 14 (11) months of vismodegib at baseline.

During a period of 8 weeks, the percentage change in cramp frequency was significantly reduced by −5.81% per week (95% CI, −10.15% to −1.48%; P = .009) with amlodipine treatment (Table and Figure). There was no significant change in muscle cramp severity (P = .48), cramp duration (P = .85), or frequency of night awakenings (P = .47) over time (Figure).

As a comparison, we followed up 9 patients who did not take amlodipine but who were taking vismodegib and answered regular telephone questionnaires about muscle cramps. During a period of 8 weeks, there was a nonsignificant increase in cramp frequency by 5.13% per week (95% CI, −7% to 17%; P = .42) in control patients. There was no change in muscle cramp severity (P = .37), cramp duration (P = .42), or frequency of night awakenings (P = .43) over time.

One patient reported mild intermittent dizziness, one noted new grade 1 peripheral edema, and none reported increased headaches or hypotension with amlodipine treatment.

Discussion

We found that in a subset of patients with basal cell nevus syndrome, amlodipine, 10 mg daily, reduced the frequency of vismodegib-induced muscle cramps after 8 weeks compared with baseline. In contrast, patients who did not take amlodipine did not have a decrease in muscle cramps during the 8-week observation period. Amlodipine may be effective in vismodegib-induced muscle cramps because it blocks voltage-gated calcium channels and inhibits the transport of extracellular calcium into muscle that is required for contraction.7

Conclusions

In our study, the therapeutic benefit of amlodipine was evident within 2 weeks; therefore, we recommend a 2-week trial of amlodipine treatment for vismodegib-related muscle cramps with continued use if successful. Further study with a larger randomized clinical trial is warranted.

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Article Information

Accepted for Publication: May 19, 2015.

Corresponding Author: Ervin H. Epstein Jr, MD, Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609 (eepstein@chori.org).

Published Online: July 22, 2015. doi:10.1001/jamadermatol.2015.1937.

Author Contributions: Drs Ally and Tang had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Ally, Tang, Epstein.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Ally, Tang, Lindgren, Acosta-Raphael, Rezaee.

Critical revision of the manuscript for important intellectual content: Ally, Tang, Lindgren, Rezaee, Chanana, Epstein.

Statistical analysis: Ally, Tang, Rezaee.

Obtained funding: Lindgren, Epstein.

Administrative, technical, or material support: Ally, Lindgren, Acosta-Raphael, Rezaee, Chanana.

Study supervision: Tang, Lindgren, Epstein.

Conflict of Interest Disclosures: The funding of the clinical trials from which these data were abstracted was supported in large part by Genentech. Dr Epstein reported owning stock in Curis and Infinity. No other disclosures were reported.

Funding/Support: This investigator-initiated trial was supported in part by Children’s Hospital Oakland Research Institute, Genentech, Clinical and Translational Science Award UL1RR02413 from the National Institutes of Health, grant 1K23AR056736 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Dr Tang), grant R01CA109584 from the National Cancer Institute (Dr Epstein), Damon Runyon Cancer Research Foundation Clinical Investigator Award CI-54-11 (Dr Tang), and funding from the Swim Across America Foundation and the Michael J. Rainen Family Foundation.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data, and preparation of the manuscript. The funding source had a role in reviewing and approving the manuscript and in the decision to submit the manuscript for publication.

Additional Contributions: Shufeng Li, MS, helped with statistical analysis. We thank the enrollees and the University of California, San Francisco, Clinical and Translational Science Institute.

References
1.
Epstein  EH.  Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8(10):743-754.
PubMedArticle
2.
Sekulic  A, Migden  MR, Oro  AE,  et al.  Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171-2179.
PubMedArticle
3.
Tang  JY, Mackay-Wiggan  JM, Aszterbaum  M,  et al.  Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med. 2012;366(23):2180-2188.
PubMedArticle
4.
Teperino  R, Amann  S, Bayer  M,  et al.  Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat. Cell. 2012;151(2):414-426.
PubMedArticle
5.
ClinicalTrials.gov. The Purpose of This Study Is to Determine The Efficacy and Safety of a Systemic Hedgehog Pathway Antagonist (GDC-0449) in Patients With Basal Cell Nevus Syndrome (BCNS).https://clinicaltrials.gov/ct2/show/NCT00957229. Accessed June 1, 2015.
6.
ClinicalTrials.gov. Trial Comparing the Effects of Intermittent Vismodegib Versus Photodynamic Therapy in Patients With Multiple Basal Cell Carcinomas. https://clinicaltrials.gov/ct2/show/NCT01556009. Accessed June 1, 2015.
7.
Ozkul  Y.  Influence of calcium channel blocker drugs in neuromuscular transmission. Clin Neurophysiol. 2007;118(9):2005-2008.
PubMedArticle
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