You have just graduated pharmacy school. The journey was long, but it was such a life-changing experience filled with so many new and exciting opportunities. What if, shortly thereafter, you were told this professional pursuit was not to be. How would you feel? Disappointment? Heartache? All appropriate responses following dreams not made possible. The same, perhaps on an even grander scale, is the reality of our patients with cystic fibrosis that develop a significant rash or systemic reaction after starting on a highly effective potentially life-altering cystic fibrosis transmembrane conductance regulator (CFTR) modulator. Envision this - the patient started CFTR treatment, takes a deep breath that fills their lungs triggering a wonderous new outlook on life but, in an instant, the patient's dream of a sustained improvement in their quality of life is stripped away due to an adverse drug reaction. Did we mention that all of this plays out during a pandemic? As the pharmacist, you are in a unique position to come to the rescue. Dusting off our pharmaceutical calculation skills, partnering with a local allergist and/or immunologist and coordinating with the cystic fibrosis care team, this patient-experienced tragedy can be turned into fortune.
With the approval of highly effective CFTR modulators, thinking of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) specifically, rash has been reported in 10.9% of patients started on therapy1. Posing a unique challenge, ELX/TEZ/IVA contains three active ingredients. This creates a clinical conundrum, as it is difficult to virtually impossible to identify the offending agent(s). Many patients develop a self-limiting rash that often abates in a week or so, sometimes requiring pharmacologic interventions with antihistamines or topical steroids. However, many Centers have reported one or two patients who develop a more severe reaction that warrants discontinuation and often treatment with systemic glucocorticosteroids and antihistamines. Recognizing the spectrum of the ELX/TEZ/IVA drug rash, the potential risk of a drug rechallenge may outweigh any benefit. Case reports have described strategies at reintroducing CFTR modulator therapy, with the first documented case of ivacaftor desensitization by Patterson and colleagues2
Included in this issue are two pragmatic approaches to desensitization to ELX/TEZ/IVA. Diseroad and her colleagues constructed a 23-day tablet splitting approach with initial exposure to ivacaftor only. 3 On day 8, quarter tablet titrations start the journey to full dose, reached at day 23. Loyd and his team rechallenged their patient, starting with half dose and in three days increasing to full dose ELX/TEZ/IVA4. All the while, the patient was maintained on an antihistamine premedication regimen. With these described approaches, patients were able to tolerate their modulator. The approaches described were deemed practical but are a far cry from a true escalating dose desensitization regimen. It is important to note that tablet splitting does introduce potential dosing errors. The USP standard for oral dosage forms are + 20% with assurance of uniformity in the setting of subdivision of scored tablets5. Today's modern methods of formulation, dosage forms are much more precise than this allowance but still, it adds variability. What about a dosage form that is not scored? ELX/TEZ/IVA happens to fall within this category. In addition, tablet splitting can be done with a kitchen knife or a new tablet splitting device. And what about a quarter tablet? Splitting a tablet to ¼ of its original size is imprecise at best. Are there other alternatives or considerations? Is this the best we can do to make sure our patients get their chance at success with this new potentially life-changing therapy? What if this does not work?
see related articles on page 463 and 467
For decades, pharmacists have been involved with their allergy/immunology colleagues in the design of desensitization protocols and then compounding the precise preparations for antibiotic desensitization regimens in the hospital setting. Remember the infamous sequential order of 1:1000 the dose, 1:100 the dose, and so forth for 10 to 12 different increasing doses for our patients who needed a critical drug at a critical time. Why not use this same proven approach for our ELX/TEZ/IVA patients? Impractical and challenging, yes, but certainly possible.
One of the biggest challenges to this approach is acquisition of the drug and professional payment. Exceeding $200,000 per year, ELX/TEZ/IVA comes with a hefty price tag coupled with the limited distribution of this therapy. We want to help, but due to the distribution channels local compounding pharmacies are not able to obtain ELX/TEZ/IVA. The manufacturer is legally limited to provide any assistance (easily a topic for another editorial) and therefore we have almost no data on stability. Finally, the expertise provided by the cystic fibrosis team and an allergist is essential to help stratify the approach pursued. Would the approach of Diseroad et al3 or Loyd et al4 work? Would the patient be better suited for a true desensitization protocol? Leonhardt and colleagues describes this approach, and it is not easy6. At least four to five hours of work in experienced hands preparing serial triturations (when was the last time you heard that word? Pharmacy school?) has been successful in at least six cases. Desensitization is started at home without pre-treatment with antihistamines or glucocorticosteroids. Yet, payment for the pharmacist is still a challenge. A patient referred to our center from another state was going to be charged in excess of $21,000 dollars for their initial prescription. At our Center, we do this without additional charge since we feel this is part of our total care approach for our patients. Obviously, other pharmacies may not be able to “comp” their professional time.
Pharmacists can come to the rescue and remembering our unique skill in “extemporaneous preparation,” we can offer many options for our patients. Not every patient will have a dramatic response to this new therapy, but all patients can have the opportunity for such benefit with our help.
ABBREVIATIONS
- CF
cystic fibrosis
- CFTR
cystic fibrosis transmembrane conductance regulator
- ELX/TEZ/IVA
elexacaftor/tezacaftor/ivacaftor
Footnotes
Disclosure. The authors declare no conflicts or financial interest in any product or service mentioned in this manuscript. Drs. Kuhn and Autry have received financial support for clinical research from Vertex Pharmaceuticals
References
- 1.Middleton PG, Mall MA, Previnek P, et al. Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. New Engl J Med . 2019;381:1809–1819. doi: 10.1056/NEJMoa1908639. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Patterson A, Autry E, Kuhn R, Wurth M. Ivacaftor Drug Desensitization. Pediatr Pulmonol . 2019;54(6):672–674. doi: 10.1002/ppul.24319. [DOI] [PubMed] [Google Scholar]
- 3.Diseroad ER, Mogayzel PJ, Pan A. Rechallenge of Elexacaftor/Tezacaftor/Ivacaftor After Skin Rash in Two Pediatric Patients Rechallenge of Elexacaftor/Tezacaftor/Ivacaftor. J Pediatr Pharmacol Ther . 2022;27(5):463–466. doi: 10.5863/1551-6776-27.5.463. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Loyd I, Papac N, Hirshburg J, Levin J, Dannelley et al. If at first you don't succeed, Triafta again. J Pediatr Pharmacol Ther . 2022;27(5):467–469. doi: 10.5863/1551-6776-27.5.467. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Green G, Berg C, Polli J et al. Pharmacopeial Standards for Subdivision of Characteristics of Scored Tablets. Pharmacopeial Form . 2009;35(6):1592–1612. [Google Scholar]
- 6.Leonhardt K, Autry E, Kuhn R, Wurth M. CFTR Modulator Drug Desensitization: Preserving the Hope of Long Term Improvement. Pediatric Pulmonol . 2021;56(8):2546–2552. doi: 10.1002/ppul.25437. [DOI] [PubMed] [Google Scholar]