By Nat Jones

Originally designed to treat cardiovascular diseases, phosphodiesterase-5 (PDE5) inhibitors made a major splash on the pharmaceutical market in 1998 with the approval of Viagra®. By far, it was the blockbuster drug of the decade. Other PDE5 inhibitors were soon to follow, and patent expiration dates have been an interesting phenomenon to watch, with multiple extensions involved. The good news is that tadalafil is now free of patents, and compounding pharmacies have some opportunities to use this drug in various customized medications.

Current Uses and Further Research
Tadalafil has labeled uses for benign prostatic hyperplasia, erectile dysfunction (ED) (including patients with diabetes mellitus or following radical prostatectomy), and improvement in exercise ability for patients with World Health Organization Group I pulmonary hypertension. There is a sub-group combination for benign prostatic hyperplasia and ED as well. Off-label uses include altitude-sickness prophylaxis (specifically prevention of high-altitude pulmonary edema), and treatment of sexual dysfunction in males receiving antidepressant therapy.¹

Researchers have looked at or are currently looking at tadalafil in many other areas of interest as well. These include treatment for fetal growth restriction, Duchenne and Becker muscular dystrophies, male reproduction (increase in semen quality), improved endothelial function, passage of distal ureteral stones, treatment of myocardial ischemia/reperfusion injury and heart failure along with bladder ischemia, and aging bladder dysfunction.^2,3,4,5

It is rare and also very exciting when compounders get such a new, widely researched and proven option for our tool boxes. With the current indications and potential uses, we will be able to use this ingredient in many ways with a variety of dosage forms to meet patient needs.

Potential Compounding Options with Tadalafil
The obvious compounding use for this ingredient is in various dosage forms for ED in men. For patients whose needs are not met with commercial products, we have created a variety of formulas (oral, sublingual/buccal, rapid dissolve, and nasal) of different strengths, following the FDA essential-copy guidance document, with dosages compliant in the potency differences from manufactured products where appropriate for individual patients.

Additional options include interesting combinations of ingredients. For example, activated vitamin B6 (pyridoxal 5 phosphate) can help decrease pituitary secretions, including prolactin, and excess prolactin is associated with decreased arousal in both men and women.^6,7,8 Apomorphine has shown to be effective and well tolerated in the treatment of ED.⁹ There is an interesting link with vitamin B6 deficiency and increased risk of cardiovascular disease as well as high homocysteine levels linked to ED, suggesting that folate and vitamin B12 could also be beneficial.^10,11  

We have also received anecdotal reports of patients experiencing benefit with a combination of sildenafil and tadalafil.* It is important to understand that many of these formulas can be used for multiple reasons. Also, please note that this drug is not without adverse events, contraindications/precautions and drug-drug interactions, etc., when given percutaneously (transdermal or vaginal), because if it is absorbed, it can have an effect and must be excreted in some way.

 PCCA has many related formulations with tadalafil in a variety of strengths and dosage forms. PCCA members can access them here.

Apart from sexual aversion, vaginal pain and vaginal atrophy, there are four main problematic aspects to female sexual dysfunction caused by multiple factors: desire, arousal, orgasm and sexual satisfaction. Tadalafil orally may be effective for sexual desire, sexual arousal, sexual orgasm and sexual satisfaction. Not only does it increase nitric oxide in the corpus cavernosum of men, but in women, it also results in the relaxation of clitoral and vaginal smooth muscle and increased blood flow in these sites, a normal step in arousal and necessary to achieve orgasm.¹² This mechanism makes it likely to improve the arousal aspect, possibly leading to improved orgasmic outcome. There are also case studies showing improved libido and anorgasmia from oral use in patients on serotonin reuptake inhibitors.¹³

Wound care is another logical use for tadalafil. With the exception of exudative types (e.g., venous stasis), most wounds benefit from increased nitric oxide availability to help improve blood flow.¹⁴ A formulation with Spira-Wash® Gel would be a potential option for patients with wounds, but may also be considered for those with female sexual dysfunction and applied externally or vaginally.

Tadalafil has also been studied in patients with ED when applied transdermally with nanoparticles.15 We obviously can’t compound nanoparticle size emulsions, but we can deliver it transdermally with Lipoderm®.  PCCA Formula #13276 in Lipoderm is one potential option. This formula could also be clinically appropriate for patients with scleroderma, which is another possible use for tadalafil.16 For patients with ED and premature ejaculation, PCCA Formula #13277 in Lipoderm may be applicable. (PCCA members can access these formulas here.)

PCCA’s formulas are a great way to start using tadalafil for a variety of your patients. If PCCA members have other formula ideas or any questions, they can contact our Clinical Services Department at 800.331.2498.

Nat Jones, RPh, FIACP, is a Clinical Compounding Pharmacist at PCCA. He has over 30 years of experience in hospital and community pharmacy, and he owned and operated independent pharmacies for almost 20 years before joining PCCA in 2012. Nat is also a fellow of the International Academy of Compounding Pharmacists. He has delivered presentations at professional seminars for over 15 years on topics including general pharmacy compounding, wound care, pain management, hormone replacement therapy for men and women, dermatology and cosmetics, among others.

A version of this article was originally published the winter 2019 issue of the Apothagram, PCCA’s members-only magazine.

References
1.    Tadalafil – Drug Summary. (n.d.). In Prescribers’ Digital Reference. Retrieved from https://www.pdr.net/drug-summary/Adcirca-tadalafil-2115 
2.    Umekawa, T., Maki, S., Kubo, M., Tanaka, H., Nii, M., Tanaka, K., . . . Ikeda, T. (2018). TADAFER II: Tadalafil treatment for fetal growth restriction - A study protocol for a multicenter randomised controlled phase II trial. BMJ Open, 8(10).  http://dx.doi.org/10.1136/bmjopen-2017-020948 
3.    Amano, T., Earle, C., Imao, T., Matsumoto, Y., & Kishikage, T. (2018). Administration of daily 5 mg tadalafil improves endothelial function in patients with benign prostatic hyperplasia. Aging Male, 21(1), 77-82. https://doi.org/10.1080/13685538.2017.1367922 
4.    Bai, Y., Yang, Y., Wang, X., Tang, Y., Han, P., & Wang, J. (2017). Tadalafil facilitates the distal ureteral stone expulsion: A meta-analysis. Journal of Endourology, 31(6), 557–563. https://doi.org/10.1089/end.2016.0837
5.    Andersson, K.-E., Boedtkjer, D. B., & Forman, A. (2017). The link between vascular dysfunction, bladder ischemia, and aging bladder dysfunction. Therapeutic Advances in Urology, 9(1), 11–27. https://dx.doi.org/10.1177%2F1756287216675778
6.    Moretti, C., Fabbri, A., Gnessi, L., Bonifacio, V., Fraioli, F., & Isidori, A. (1982). Pyridoxine (B6) suppresses the rise in prolactin and increases the rise in growth hormone induced by exercise. The New England Journal of Medicine, 307(7), 444-445. https://doi.org/10.1056/NEJM198208123070719
7.    Krysiak, R., Drosdzol-Cop, A., Skrzypulec-Plinta, V., & Okopien, B. (2016). Sexual function and depressive symptoms in young women with elevated macroprolactin content: A pilot study. Endocrine, 53(1), https://doi.org/10.1007/s12020-016-0898-5  
8.    Buvat, J. (2003). Hyperprolactinemia and sexual function in men: A short review. International Journal of Impotence Research, 15(5), 373-377. https://doi.org/10.1038/sj.ijir.3901043
9.    Mullhall, J. P., Bukofzer, S., Edmonds, A. L., & George, M. (2001). An open-label, uncontrolled dose-optimization study of sublingual apomorphine in erectile dysfunction. Clinical Therapeutics, 23(8), 1260–1271. 
10.    Baghdadi, H. H., Allam, A., & Sheweita, S. A. (2013). Erectile dysfunction medication induced-changes in plasma levels of homocysteine and antioxidant enzyme activities as risk factors for cardiovascular disease. Journal of Taibah University Medical Sciences, 8(3), 151–156. https://doi.org/10.1016/j.jtumed.2013.04.003
11.    Friso, S., Lotto, V., Corrocher, R., & Choi, S. W. (2012). Vitamin B6 and cardiovascular disease. In J. R. Harris (Ed.), Subcellular Biochemistry (Vol. 56, pp. 265–290). https://doi.org/10.1007/978-94-007-2199-9_14  
12.    Borghi, C., & Dell'Atti, L. (2017). Tadalafil once daily: Narrative review of a treatment option for female sexual dysfunctions (FSD) in midlife and older women. Archivio Italiano di Urologia e Andrologia, 89(1), 7–11. https://doi.org/10.4081/aiua.2017.1.7
13.    Ashton, A. K., & Weinstein, W. (2006). Tadalafil reversal of sexual dysfunction caused by serotonin enhancing medications in women. Journal of Sex Marital Therapy, 32(1), 1–3. https://doi.org/10.1080/00926230500229079  
14.    Davenport, C., & Dubin, A. (2015). Tadalafil therapy and severe chronic foot wound resolution. International Wound Journal, 12(6), 733–736. https://doi.org/10.1111/iwj.12378
15.    Han, G., Tar, M., Kuppam, D. S., Friedman, A., Melman, A., Friedman, J., & Davies, K. P. (2010). Nanoparticles as a novel delivery vehicle for therapeutics targeting erectile dysfunction. The Journal of Sexual Medicine, 7(1), 224–233. https://doi.org/10.1111/j.1743-6109.2009.01507.x
16.    Patel, R. M., & Nagle, D. J. (2012). Nonoperative management of scleroderma of the hand with tadalafil and subatmospheric pressure wound therapy: Case report. The Journal of Hand Surgery, 37(4), 803–806. https://doi.org/10.1016/j.jhsa.2011.12.030

*As of this publication, sildenafil is still patented in the United States.

These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The information contained herein is not intended to replace or substitute for conventional medical care, or encourage its abandonment.