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Clostridium Histolyticum (Xiaflex[R]) for the Treatment Of Peyronie's Disease.

Peyronie's disease is a progressive wound-healing disorder highlighted by excessive collagen deposition in the tunica albuginea of the penile corpora. Its precise etiology is unclear; it has been connected to a history of penile trauma characterized by microvascular insults. It is characterized by penile pain, curvature with erection, possible other deformities with erection, and potential erectile dysfunction. The psychological impact of this condition is high, with many men feeling they are deformed and suffering from psychosocial stress. Collagenase clostridium histolyticum (Xiaflex[R]) was approved on December 6, 2013, by the United States Food and Drug Administration (FDA) for use with patients with Peyronie's disease. Prior to FDA approval of Xiaflex, the primary treatment for Peyronie's disease was surgical, owing to limited trials and unreliable results of other medical treatments, resulting in a very limited evidence base.

Background

There is no well-established epidemiology for Peyronie's disease; its true prevalence in the population is unknown due to inconsistent methodology used to measure curvature and the particular sample under study. This results in a prevalence rate that ranges from 0.5% to 20.3% (American Urological Association [AUA], 2015). The disease itself has two recognized states. The initial acute phase consists of an inflammatory response and development of chronic fibrotic plaques. This is when men are most likely to complain of penile pain, and it is suspected that this is the optimal time to intervene. But many patients do not present during this initial development of symptoms. Stable Peyronie's disease describes a lack of pain and a plaque that does not change for at least three months. The most common place for this plaque is the dorsal aspect of the penile shaft, with the plaque noted midshaft.

Psychosocial effects are present with Peyronie's disease as well, including an increased incidence in depression, decreased self-esteem, and a change in relationship dynamics that can include self-isolation (Nelson & Mulhall, 2013). While there has been no proven causal relationship, men with Peyronie's disease more commonly have risk factors for arterial disease, such as diabetes mellitus and obesity dyslipidemia, smoking, and hypertension. There is a well-established correlation between the presence of Dupuytren's contracture and Peyronie's disease, suggesting a genetic factor in some men.

Diagnostic evaluation includes a focused clinical history and examination. There is no international standard for evaluation of men who present with this condition, but examination should include a full examination, with the phallus gently stretched, and determination of plaque size and location. Further evaluation can include a photograph of the erect penis provided by the patient or in-office intracavernosal injection of a vasoactive agent to promote erection.

Description and Indications

Xiaflex is purified collagenase clostridium histolyticum, isolated and purified from the fermentation of Clostridium histolyticum bacteria (Endo Pharmaceuticals, Inc., 2017). It is supplied as a single-use dose of sterile lyophilized powder (white cake) intended for reconstitution prior to intralesional injection into a Peyronie's plaque. The supplied sterile diluent is 0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride, with 0.5 mg of hydrochloric acid, 18.5 mg of sucrose, and 1.1 mg of tromethamine. It is supplied in single use glass vials; in this form, it is stable for up to two years when kept refrigerated at 2[degrees] to 8[degrees]C (36[degrees] to 46[degrees]F). Reconstituted solution can be kept at room temperature for up to 60 minutes or refrigerated for up to four hours prior to administration.

Xiaflex can only be administered by a healthcare provider who has met the requirements of the company and completed required training for use of Xiaflex in the treatment of Peyronie's disease via their Risk Evaluation and Mitigation Strategy (REMS) program.

Only adult men with Peyronie's disease demonstrating a palpable plaque and curvature at least 30[degrees] are candidates for this therapy. This medication is also used to treat Dupuytren's contracture, the only other indication for this product.

Clinical Trials

Two large, multicenter, double-blind, randomized, placebo-controlled, phase 3 clinical studies demonstrated that the use of collagenase is appropriate in Peyronie's disease when the following criteria were met: stable disease, curvature between 30[degrees] and 90[degrees], no hourglass deformity, no calcified plaque, plaque is not proximally located at the base of the penis, and normal erectile function (Gelbard et al., 2013; Levine et al, 2015). In total, 832 men were enrolled in the Investigation for Maximal Peyronie's Reduction Efficacy and Safety Studies, I and II (IMPRESS) trials that demonstrated use of intralesional collagenase injections were associated with a decrease in penile curvature, plaque volume, and patient bother scores. Average duration of Peyronie's disease was from 46 to 57 months in these cohorts, with subsequent improvement of up to 32.4%, with modeling done by a clinician in conjunction with collagenase injections. Safety data from these trials showed this treatment was well-tolerated; penile hematomas were reported in up to 50% of men enrolled in the trial. Treatment with collagenase did not prevent subsequent surgery when indicated. These trials did not include men with hourglass deformities, ventral curvature, calcified plaques, or plaques that were located more proximal to the base of the penis. Collagenase injections were not investigated as treatment for penile pain or underlying erectile dysfunction associated with Peyronie's disease. Average curvature reduction can be expected to be up to 17[degrees].

Two trials predate the IMPRESS trials (Gelbard, James, Riach, & Dorey, 1993; Gelbard et al., 2012) that also support the use of collagenase with men who have Peyronie's disease.

Level of Evidence Supporting Use for Peyronie's Disease

Xiaflex is the only FDA-approved nonsurgical treatment for Peyronie's disease. As explained in the AUA (2015) guidelines:
   The Panel notes that intralesional collagenase is a therapy for
   curvature; it does not treat pain or ED. The best evidence for the
   use of intralesional collagenase in combination with modeling to
   treat curvature is provided by four RCTs [randomized controlled
   trials] (Gelbard et al., 1993, 2012, 2013; Levine et al., 2015).
   Body of evidence strength is Grade B.


These guidelines are tempered by the fact that to date, these studies have not been replicated, and the results may not be generalizable. Ongoing follow up aims to answer the question of whether or not the results seen in these randomized controlled trials are sustained over time. Overall reduction in curvature is modest, keeping in mind the concomitant low risk of adverse events.

Dosage/Administration

Xiaflex is available only from providers who have been approved for the Endo Pharmaceuticals, Inc., REMS program, and facilities must also be certified for this program because the medication is shipped directly to a pharmacy or office. To reconstitute the medication, 0.39 mL of the diluent supplied is injected into the vial containing the cake of lyophilized powder. When reconstituted, the solution should be clear. Dosing for each possible injection in the series is precisely the same: 0.58 mg of Xiaflex in 0.25 mL of dilutent. Patients may receive a total of four series of injections; each series consists of two injections separated by 48 to 72 hours. This is a total of eight injections, with each series separated by six weeks. The injection is administered with a 1 mL hubless syringe with 0.01 mL graduations with a 27-gauge half-inch needle to ensure proper dosing.

The injection should be targeted toward the area of maximum concavity in the bend of the penis. A pharmacologic injection can be induced to establish the target area for the injection. The penis must be flaccid prior to the injection, and the needle is advanced through the width of the plaque without passing completely through it. As the needle is withdrawn from the plaque, the plunger is depressed to dispense the medication. Once the needle is removed, gentle pressure is applied to the injection site. Some providers may choose to gently wrap the penis for a few hours afterward to minimize swelling and bruising. A penile modeling procedure (as described in the package handout, online, and in patient information provided by the company) is performed one to three days after the second injection of each series.

Pharmacology

Collagenase clostridium histolyticum is a proteinase that hydrolyzes collagen, resulting in destruction of collagen deposits. Injection into a Peyronie's plaque may result in disruption of the plaque, leading to a reduction in pain and penile curvature for men with Peyronie's disease. There is no evidence of accumulation of the drug in the tissue 30 minutes after administration (Endo Pharmaceuticals, Inc., 2017). To date, there is no evidence for impact on fertility or early embryonic development when tested in rats. This medication has not been tested in patients younger than 18 years.

Drug Interactions

Xiaflex was not tested in men who were anticoagulated.

Contraindications/Precautions

Xiaflex injections for penile curvature have a risk for corporal rupture or penile fracture. Corporal rupture was reported as an adverse reaction in 5 of 1,044 (0.5%) treated patients (Endo Pharmaceuticals, Inc., 2017). Men must avoid any manner of sexual activity for at least 14 days after the second injection in the series. Penile ecchymosis or hematoma are also potential side effects of this medication. Men may report deep indigo bruising several hours after the injection, penile swelling, or penile pain. This will usually resolve less than 14 days after the injection and tends to follow tissue planes.

Cost and Billing

The cost of Xiaflex varies by facility, but Endo Pharmaceuticals, Inc., offers both reimbursement and copay assistance for patients through local pharmaceutical representatives and its website. Not all insurance covers this medication; it may be a covered benefit only after failure of other options that are determined by the specific insurance company. Currently, it is a covered benefit under Medicare. Regardless of insurance, the injection series is billed as a two-part staged procedure, and documentation must include the need for a second injection 48 to 72 hours after the first.

Nursing Considerations and Teaching Points

Men must be aggressively counseled prior to beginning treatment regarding the potential adverse events that may occur with the administration of Xiaflex and their role in preventing the side effect of penile fracture. All men undergoing treatment with Xiaflex should be given the patient guide that details the process of injection administration, discusses potential side effects, and describes the penile modeling procedure provided by the company.

* Men must be reminded to avoid sexual activity of any type, beginning after the first injection and extending to a minimum of 14 days after the second injection, as long as any pain and swelling have ended. This mitigates the risk of penile fracture.

* Patients should be told that their penis may appear swollen and/or bruised, and it may be painful after the injection.

* Men need to contact their urology provider if they are unable to urinate or have a sudden loss of the ability to maintain an erection.

* Other side effects may include changes to the color of the skin of the penis, a lump at the injection site, or itching of the penis or scrotum.

* Consistent penile modeling promotes better results.

* The penis may be loosely wrapped after the injection to help decrease subsequent penile swelling and bruising. The wrap should not cause pain or prevent urination, and may be left on for several hours.

Conclusion

Treatment with Xiaflex offers men a medical treatment option for Peyronie's disease that does not prevent them from being candidates for future surgical procedures to correct remaining penile curvature. Whereas surgical procedures will straighten the penis, treatment with Xiaflex offers the potential for some recovery of penile length and girth, while also straightening the curvature.

Key Words: Peyronie's disease, penile corpora, penile pain, erectile dysfunction, clostridium histolyticum (Xiaflex[R]).

doi:10.7257/1053-816X.2017.37.5.270

References

American Urological Association (AUA). (2015). Peyronie's disease: AUA guideline. Retrieved from http://www.auanet. org/guidelines/peyronies-disease-(2015)

Endo Pharmaceuticals, Inc. (2017). Xiaflex - Collagenase Clostridium histolyticum. Retrieved July 31, 2017, from http://www. endo.com/File%20Library/Products/Prescribing%20Infor mation/Xiaflex_prescribing_information.htmI#section-12

Gelbard, M.K., James, K., Riach, P., & Dorey, F. (1993). Collagenase versus placebo in the treatment of Peyronie's disease: A double-blind study. The Journal of Urology, 149(1), 156-158.

Gelbard, M., Lipshultz, L.I., Tursi, J., Smith, T., Kaufman, G., & Levine, L.A. (2012). Phase 2b study of the clinical efficacy and safety of collagenase Clostridium histolyticum in patients with Peyronie disease. The Journal of Urology, 187(6), 2268-2274.

Gelbard, M., Goldstein, I., Hellstrom, W.J., McMahon, C.G., Smith, T., Tursi, J., ... Carson, C.C., 3rd. (2013). Clinical efficacy, safety and tolerability of collagenase Clostridium histolyticum for the treatment of Peyronie disease in 2 large double-blind, randomized, placebo controlled phase 3 studies. The Journal of Urology, 190(1), 199-207.

Levine, L.A., Cuzin, B., Mark, S., Gelbard, M.K., Jones, N.A., Liu, G., ... Ralph, D.J. (2015). Clinical safety and effectiveness of collagenase clostridium histolyticum injection in patients with Peyronie's disease: A phase 3 open-label study. The Journal of Sexual Medicine, 12(1), 248-258.

Nelson, C.J., & Mulhall, J.P. (2013). Psychological impact of Peyronie's disease: A review. The Journal of Sexual Medicine, 10(3), 653-660.

Susanne A. Quallich, PhD, ANP-BC, NP-C, CUNP, FAANP, is a Andrology Nurse Practitioner, Division of Andrology and Urologic Health, Department of Urology, University of Michigan Health System, Ann Arbor, MI, and a Member of the Urologic Nursing Editorial Board.
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Title Annotation:Medication Minute
Author:Quallich, Susanne A.
Publication:Urologic Nursing
Article Type:Report
Date:Sep 1, 2017
Words:2223
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