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Peyronie's Disease Agents

Collagenase clostridium histolyticum (CCH / Xiaflex) is the only FDA-approved pharmacologic treatment for Peyronie's disease (PD). Interferon α-2b has moderate guideline support for intralesional use, while intralesional verapamil has weak and conflicting evidence. The AUA PD Guideline hierarchy places CCH as a Moderate Recommendation (Grade B), IFN α-2b as a supported option with counseling for flu-like side effects (Clinical Principle), and verapamil as having "substantial uncertainty regarding its efficacy."[1] Multiple oral agents (vitamin E, tamoxifen, procarbazine, omega-3, vitamin E + L-carnitine) are explicitly recommended against by the AUA, while PRP and hyaluronic acid are emerging intralesional therapies under active investigation.

For broader context, see the clinical Peyronie's disease article and Intracavernosal injection agents for the injection technique context. For ED in PD, see PDE5 inhibitors.

Collagenase clostridium histolyticum (CCH / Xiaflex) — FDA-approved​

Mechanism​

CCH is a mixture of two bacterial collagenases — AUX-I (Class I) and AUX-II (Class II) — derived from Clostridium histolyticum. These enzymes enzymatically degrade collagen types I and III, the primary structural components of Peyronie's plaques, disrupting the fibrotic architecture and allowing mechanical remodeling of the tunica albuginea.[2][3]

FDA-approved indication and dosing[4]​

  • Indication: adult men with PD with a palpable plaque and curvature deformity ≥30° at the start of therapy
  • Dose: 0.58 mg per injection into the plaque
  • Treatment cycle: 2 injections, 1–3 days apart, followed by a penile modeling procedure 1–3 days after the second injection
  • Maximum: up to 4 treatment cycles at ~6-week intervals (total: 8 injections, 4 modeling procedures)
  • Stopping rule: stop if curvature is <15° or if any further therapy is judged clinically inappropriate
  • REMS program required — available only through the XIAFLEX REMS

Injection technique[4]​

  1. Induce erection (intracavernosal alprostadil 10–20 µg) to identify the point of maximum concavity
  2. Mark the target area
  3. Allow the penis to return to flaccid before injection
  4. 27-gauge ½-inch needle inserted from the side of the plaque, advanced transversely through the width — do not advance beneath the plaque or perpendicularly toward the corpora
  5. Confirm proper needle position by resistance to plunger depression
  6. Slowly inject 0.25 mL of reconstituted solution

Penile modeling performed by the clinician 1–3 days after the second injection of each cycle. Patients perform home modeling 3 times daily between cycles and attempt to straighten the penis painlessly during spontaneous erections once daily.[1]

Efficacy — IMPRESS I/II pivotal trials​

Two identical Phase III, double-blind, placebo-controlled RCTs (n = 832 combined):[1][4]

OutcomeCCHPlaceboDifference
Mean % change in curvature (Study 1 / 2)−35.0% / −33.2%−17.8% / −21.8%−17.2% / −11.4% (p < 0.01)
Absolute curvature reduction~17°~9.3°7.7° net benefit
PDQ Bother domainSignificantly improvedLess improvementp < 0.05

The AUA Guideline explicitly frames this as a "modest difference of 7.7°" vs placebo, while acknowledging the absolute 17° reduction in the treated arm is clinically meaningful.[1]

Real-world effectiveness​

Hellstrom 2019 multi-institutional analysis (n = 918):[5]

  • Curvature 48.2° → 32.9° (30.1% improvement; p < 0.001)
  • Confirms IMPRESS magnitude translates outside the trial population

Zhang 2022 meta-analysis (prospective studies) corroborates the ~30% curvature-reduction signal across the contemporary literature.[6]

Incremental benefit by cycle — complete the course​

Ziegelmann 2023 pooled analysis of the IMPRESS trials — each additional cycle produces incremental benefit:[7]

Group≥20% curvature reduction
After cycle 1 only29.9%
Among cycle 1 non-responders, across all 4 cycles60.8%
Among cycle 1–2 non-responders, by cycle 442.7%
Among cycle 1–3 non-responders, by cycle 423.5%

Counsel patients to complete all 4 cycles even when early response is modest.

Patient-reported outcomes​

Ziegelmann 2016 clinical-practice cohort (n = 69) after 4 series:[8]

  • 57% — CCH negated the need for surgery
  • 52% — restoration of penetration
  • 81% — perceived treatment as meaningful
  • 88% — subjective improvement

Long-term durability — 5-year data​

Goldstein 2020 Phase 4 (n = 280) followed CCH-treated patients for 5 years without additional treatment:[9][10]

  • Baseline of the follow-up already reflected a mean curvature improvement of 20.9° (39.5%) from CCH therapy
  • Additional 9.1% improvement occurred by year 5 (4.3° further reduction; p < 0.001)
  • Durable response without retreatment

Adverse events and safety​

CCH carries an FDA boxed warning for corporal rupture and serious penile injury.[4]

Adverse eventCCHPlaceboNotes
Any AE92%61%Most mild–moderate; 79% resolved within 14 days
Penile hematoma≥25%—Most common AE
Penile swelling≥25%—
Penile pain≥25%—
Severe penile hematoma3.7% (39/1,044)—May require intervention
Confirmed corporal rupture0.5% (5/1,044)—Surgical emergency
Corporal rupture cannot be excluded0.9% (9/1,044)—"Popping" + ecchymosis + detumescence

Zucker 2024 VA study (n = 1,541) — 0.7% corporal rupture rate (11/1,541); most fractures occurred within 2 weeks of injection, associated with intercourse or spontaneous erections. Six required surgical repair; five managed conservatively.[11]

Contraindications and precautions​

  • Do NOT inject into the urethra, corpora cavernosa, or penile vasculature
  • Avoid sexual intercourse and vigorous penile activity for ~2 weeks after each injection
  • Not studied in ventral plaques — IMPRESS enrolled only dorsal and lateral plaques[12]

Market availability​

CCH remains FDA-approved and available in the US through the REMS program. It has been discontinued in Canada and Europe due to cost and poor market uptake, shifting practice toward surgical management in those regions.[13]

Interferon α-2b​

Mechanism​

Antifibrotic, antiproliferative, and immunomodulatory cytokine. In PD:[12][14][1]

  • Reduces fibroblast proliferation
  • Decreases collagen synthesis and ECM deposition
  • Increases collagenase activity
  • Modulates TGF-β signaling

FDA status: not FDA-approved for PD — all use is off-label.

Dosing[12][15][1]​

  • 5 million units (MU) per injection (some centers use 2 MU)
  • Every 2 weeks
  • 6–24 injections (median 12 in the largest series)
  • Intralesional injection directly into the plaque

Efficacy​

Hellstrom multicenter placebo-controlled RCT (n = 103 with stable PD >12 mo, curvature ≥30°):[1]

OutcomeIFN α-2bPlacebo
Curvature reduction13.5°4.5°
Plaque size reduction2.6 cm²0.9 cm²
Penile pain resolution67.7%28.1%
Peak systolic velocityImprovedNo change
Mean resistive indexImprovedNo change

Cochrane 2023 review rated certainty of evidence as very low, downgrading for study limitations, indirectness (patients with >1 plaque excluded), and imprecision (MD −10.0°; 95% CI −15.95 to −4.05; single trial, 103 participants).[16]

Tulane retrospective series (Stewart 2015 / Trost 2013, n = 127–131):[12][15]

  • Median 12 biweekly injections
  • 54% responded (≥20% curvature improvement); overall mean improvement 9.0° (p < 0.001)
  • Duration of PD did not affect response
  • Independent of plaque location — notably effective for ventral plaques that are outside the CCH IMPRESS evidence base
  • No change in penile vascular parameters on duplex

Adverse effects[1]​

  • Flu-like symptoms (myalgias, fevers, chills) — most common; typically last <24 h; ameliorated by NSAIDs and hydration
  • Mild injection-site reactions
  • No systemic hematologic toxicity at intralesional doses

The European Urology systematic review (Russo 2018) concluded that CCH and IFN α-2b are the only two intralesional agents with evidence supporting a clinically significant effect on penile curvature.[14]

Intralesional verapamil​

Mechanism​

Calcium channel blocker with in-vitro effects on plaque matrix:[16]

  • Inhibits synthesis / secretion of ECM molecules (collagen, GAGs, fibronectin)
  • Increases collagenase activity
  • Modifies TGF-β activity

FDA status: not FDA-approved for PD — all use is off-label.

Dosing — Levine protocol[17]​

  • 10 mg diluted to 10 mL (some centers use 10 mg in 4–5 mL)
  • Multiple-puncture technique to distribute drug throughout the plaque
  • Every 2 weeks × 12 injections (6-month course)

Efficacy — conflicting evidence​

Supportive uncontrolled data:

  • Levine 1997 (n = 38 completers) — pain resolved in 97%; subjective curvature decrease in 76%; objective decrease in 54%; improved coital ability in 72%[17]
  • Sadagopan 2019 meta-analysis of 7 study groups — significant improvement in sexual function (p < 0.05)[18]

Controlled-trial data:

  • Cochrane 2023 — very low certainty; MD −1.86° (95% CI −10.39 to 6.67; 1 study, 14 participants) — CI crosses the clinically meaningful threshold[16]
  • Electromotive verapamil RCT — minimal benefit; groups statistically indistinguishable[1]
  • Cochrane excluded several verapamil studies for data-integrity concerns (single-author data falsification)[16]

Guideline divergence​

  • AUA — "The evidence for intralesional verapamil is weak; clinicians should carefully consider whether use of this treatment is appropriate given the substantial uncertainty regarding its efficacy and the availability of other treatments that are clearly more effective."[1]
  • EAU — recommends against intralesional verapamil[16]
  • ISSM — sees a potential role[16]

Adverse effects[1]​

Penile bruising, dizziness, nausea, injection-site pain; no systemic cardiovascular effects reported at intralesional doses.

Oral agents​

Agents the AUA recommends AGAINST[1]​

The AUA PD Guideline (Moderate Recommendation; Grade B/C) explicitly states clinicians should not offer oral therapy with:

  • Vitamin E
  • Tamoxifen
  • Procarbazine
  • Omega-3 fatty acids
  • Vitamin E + L-carnitine combination

"There is no convincing evidence for the efficacy of any of the listed therapies"; using ineffective treatments delays effective therapy and constitutes a moderate risk/burden.

Pentoxifylline — optional adjunct, thin evidence​

Methylxanthine with antioxidant, antifibrotic, anti-inflammatory, and vasorelaxant effects; inhibits TGF-β signaling.[19]

  • AUA lists pentoxifylline among "other treatments" without formal recommendation
  • Cochrane 2023 excluded pentoxifylline studies for data-integrity concerns[16]
  • Paulis 2025 narrative review (20 studies) argued clinical experience demonstrates benefit, but systematic reviews do not show consistent evidence; further RCTs are needed[19]

Practical use: 400 mg PO TID as an acute-phase adjunct, often layered with other therapies. Not a primary treatment.

Tadalafil 5 mg daily​

Spirito 2024 retrospective comparative analysis (n = 191) in acute-phase PD:[20]

  • Curvature-progression rate significantly lower on tadalafil at 12 weeks (25.9% vs 39.7%; p = 0.042)
  • IIEF-5 improved significantly (19.3 vs 11.2; p < 0.001)

See PDE5 inhibitors for the broader antifibrotic-synergy and ED-management case.

Emerging intralesional therapies​

Platelet-rich plasma (PRP)​

Autologous blood product rich in growth factors; modulates inflammation and promotes tissue remodeling.

  • Ledesma 2024 Phase 2 RCT (n = 41) — safe, no serious AEs; PRP-first group showed curvature 40° → 25° at 6 mo (p = 0.047), suggesting a delayed treatment effect[21]
  • Dachille 2025 prospective cohort (n = 72) — 3 injections 2 wk apart; median curvature 50° → 40° (p < 0.001) with improved sexual function[22]
  • Zugail 2024 percutaneous needle tunneling + PRP (n = 54, 6 sessions) — median −44.4% curvature correction (45° → 30°; p = 0.001)[23]

Not yet guideline-recommended; lacks large RCTs. One of the most actively investigated emerging therapies.

Hyaluronic acid (HA)​

Cilio 2024 retrospective intraplaque HA (n = 62 stable PD, 3 injections 2 wk apart with concurrent vacuum / stretching) — curvature 52.7° → 40.3° (p < 0.001).[24] No RCT data; reasonable as an adjunct in stable-phase PD where CCH is unavailable or contraindicated.

Onabotulinum toxin A​

Investigated based on smooth-muscle-relaxing and fibrosis-modulating activity. Russo 2018 EU review found significant curvature improvements in single-arm / case-control studies only, with no RCT data supporting routine use.[14]

Comparative summary​

AgentFDAAUA stanceTypical curvature reductionEvidence qualityKey advantageKey limitation
CCH (Xiaflex)ApprovedModerate / Grade B17° absolute; ~35%Moderate (2 Phase III RCTs)Only FDA-approved agent; durable 5-y dataCorporal-rupture boxed warning; REMS; high cost; not studied in ventral plaques[1][4]
IFN α-2bOff-labelClinical Principle9–13.5° (RCT)Very low (Cochrane, 1 RCT)Effective for ventral and dorsal plaques; improves pain and hemodynamicsFlu-like symptoms; 6–24 biweekly injections[1][12]
VerapamilOff-labelWeak evidence; use with caution0–54% (conflicting)Very low (Cochrane)Inexpensive; locally well toleratedWeak / conflicting evidence; data-integrity concerns; EAU recommends against[1][16]
PRPOff-labelNot yet recommended10–20° (early)Low (Phase 2 RCT + cohorts)Autologous; safePreliminary; no large RCTs; not standardized[21][22]
Hyaluronic acidOff-labelInsufficient evidence~12° (retrospective)LowTolerable; plaque-size reductionNo RCTs; limited stable-phase data[24]
Tadalafil 5 mg dailyApproved for ED/LUTSEmerging role in acute-phase PDLower progression rateLow–moderate (retrospective)Oral; treats concomitant EDDisease-modifying claim exploratory[20]
PentoxifyllineOff-label"Other"; optional adjunctNot quantifiableLow / mixedInexpensive oralCochrane excluded for data integrity[19]

Treatment algorithm per AUA framework​

Acute / active phase (pain, evolving curvature)​

  • Observation with counseling about natural history
  • NSAIDs for pain management (Expert Opinion)
  • Consider daily tadalafil 5 mg to reduce curvature progression[20]
  • Consider pentoxifylline 400 mg TID as adjunct[19]
  • Do NOT offer vitamin E, tamoxifen, procarbazine, omega-3, or vitamin E + L-carnitine[1]

Stable phase (≥3–6 months of stability)​

  • First-line intralesional: CCH for curvature 30–90° with palpable plaque and intact erectile function (AUA Moderate)[1]
  • Alternative intralesional: IFN α-2b — particularly for ventral plaques (excluded from IMPRESS) or when CCH is unavailable / unaffordable[12]
  • Verapamil only after careful discussion of weak evidence and better alternatives[1]
  • Mechanical adjunct: penile traction therapy with or without intralesional therapy[25]
  • Surgery (plication, grafting, prosthesis) for injection failure, severe curvature, or concomitant ED — see the clinical Peyronie's disease article[1]

Evidence Summary​

IndicationAgentEvidence levelKey source
Peyronie's plaque — FDA-approved treatmentCCHLevel 1 (2 Phase III RCTs)IMPRESS I/II[4]; AUA 2015[1]
CCH 5-year durabilityCCHLevel 3Goldstein 2020[9]
CCH incremental benefit by cycleCCHLevel 1 (pooled RCT)Ziegelmann 2023[7]
CCH real-world effectivenessCCHLevel 3Hellstrom 2019[5]; Zhang 2022[6]
Interferon α-2b — RCTIFNLevel 1 (single RCT; Cochrane very low)AUA-cited Hellstrom RCT[1]; Cochrane 2023[16]
IFN α-2b — ventral-plaque effectivenessIFNLevel 3Stewart 2015[12]
VerapamilVerapamilVery low (Cochrane)Cochrane 2023[16]
Oral therapies (vitamin E, tamoxifen, procarbazine, omega-3, vitamin E + L-carnitine)VariousLevel 1–2 (negative)AUA 2015[1]
Daily tadalafil in acute PDTadalafil 5 mgLevel 3Spirito 2024[20]
PRPPRPLevel 2 (Phase 2 RCT + cohort)Ledesma 2024[21]; Dachille 2025[22]

Clinical Positioning​

  • CCH is the only FDA-approved pharmacologic PD treatment — curvature 30–90°, palpable plaque, intact erectile function, REMS program, up to 4 cycles.[1][4]
  • Complete the full 4-cycle course even in early non-responders. Ziegelmann 2023 shows 60.8% of cycle-1 non-responders eventually reach ≥20% curvature reduction.[7]
  • Counsel explicitly about the 0.5–0.7% corporal-rupture risk and the mandatory 2-week sexual-activity restriction after each injection. Zucker 2024 VA data show most fractures occur in the 2 weeks after injection.[4][11]
  • CCH net benefit over placebo is modest (~7.7°); absolute reduction (~17°) is clinically meaningful. Set realistic expectations before treatment.[1][4]
  • IFN α-2b is the best option for ventral plaques and where CCH is unavailable/unaffordable. Premedicate for flu-like symptoms with NSAIDs and hydration.[12][1]
  • Verapamil is not a first-line agent. The Cochrane CI crosses the clinically meaningful threshold, the EAU recommends against, and several studies were excluded for data-integrity concerns.[16]
  • Do not offer vitamin E, tamoxifen, procarbazine, omega-3, or vitamin E + L-carnitine. The AUA recommends against these agents, and prescribing them postpones effective treatment.[1]
  • Consider daily tadalafil 5 mg in acute-phase PD — treats concomitant ED and may reduce curvature progression per Spirito 2024. Cochrane framed PDE5i primarily as ED management rather than disease-modifying, but the signal is reasonable to layer in.[20]
  • PRP is promising but not yet guideline-endorsed — reasonable in patients seeking alternatives in trial settings, with counseling that large-RCT data do not yet exist.[21][22]
  • CCH cost is a real access issue — a full 4-cycle course approaches $30,000–$40,000+ before insurance. In Europe and Canada, discontinuation has shifted practice toward surgery.[13]
  • Intralesional therapy does not treat pain or ED — address pain with NSAIDs in the acute phase; manage concomitant ED with PDE5 inhibitors or beyond.[1]

See Also​

References​

1. Nehra A, Alterowitz R, Culkin DJ, et al. "Peyronie's disease: AUA guideline." J Urol. 2015;194(3):745–753. doi:10.1016/j.juro.2015.05.098

2. Dhillon S. "Collagenase clostridium histolyticum: a review in Peyronie's disease." Drugs. 2015;75(12):1405–1412. doi:10.1007/s40265-015-0441-7

3. Hoy SM. "Collagenase clostridium histolyticum: a review in Peyronie's disease." Clin Drug Investig. 2020;40(1):83–92. doi:10.1007/s40261-019-00867-5

4. US Food and Drug Administration. XIAFLEX (collagenase clostridium histolyticum) — prescribing information. Updated 2024-04-05.

5. Hellstrom WJG, Tue Nguyen HM, Alzweri L, et al. "Intralesional collagenase clostridium histolyticum causes meaningful improvement in men with Peyronie's disease: results of a multi-institutional analysis." J Urol. 2019;201(4):777–782. doi:10.1097/JU.0000000000000032

6. Zhang F, Xiong Y, Wang W, et al. "The efficacy and safety of intralesional injection of collagenase for Peyronie's disease: a meta-analysis of published prospective studies." Front Pharmacol. 2022;13:973394. doi:10.3389/fphar.2022.973394

7. Ziegelmann M, Hu Y, Xiang Q, et al. "Incremental treatment response by cycle with collagenase clostridium histolyticum for Peyronie's disease: a pooled analysis of two Phase 3 trials." Urology. 2023;175:126–131. doi:10.1016/j.urology.2023.02.019

8. Ziegelmann MJ, Viers BR, McAlvany KL, et al. "Restoration of penile function and patient satisfaction with intralesional collagenase clostridium histolyticum injection for Peyronie's disease." J Urol. 2016;195(4 Pt 1):1051–1056. doi:10.1016/j.juro.2015.10.065

9. Goldstein I, Lipshultz LI, McLane M, et al. "Long-term safety and curvature deformity characterization in patients previously treated with collagenase clostridium histolyticum for Peyronie's disease." J Urol. 2020;203(6):1191–1197. doi:10.1097/JU.0000000000000743

10. Goldstein I, McLane MP, Xiang Q, et al. "Long-term curvature deformity characterization in men previously treated with collagenase clostridium histolyticum for Peyronie's disease, subgrouped by penile plaque calcification." Urology. 2020;146:145–151. doi:10.1016/j.urology.2020.08.045

11. Zucker I, Nackeeran S, Mirza S, Masterson TA. "Risk factors for penile fracture after intralesional collagenase clostridium histolyticum in Peyronie's disease." Urology. 2024;183:117–120. doi:10.1016/j.urology.2023.10.019

12. Stewart CA, Yafi FA, Knoedler M, et al. "Intralesional injection of interferon-α2b improves penile curvature in men with Peyronie's disease independent of plaque location." J Urol. 2015;194(6):1704–1707. doi:10.1016/j.juro.2015.06.096

13. Mann U, Shiff B, Jain K, et al. "Canadian provider perspectives on collagenase clostridium histolyticum for the treatment of Peyronie's disease and the impact of its discontinuation." Int J Impot Res. 2022;34(6):599–602. doi:10.1038/s41443-021-00458-z

14. Russo GI, Milenkovic U, Hellstrom W, et al. "Clinical efficacy of injection and mechanical therapy for Peyronie's disease: a systematic review of the literature." Eur Urol. 2018;74(6):767–781. doi:10.1016/j.eururo.2018.07.005

15. Trost LW, Ates E, Powers M, Sikka S, Hellstrom WJ. "Outcomes of intralesional interferon-α2b for the treatment of Peyronie disease." J Urol. 2013;190(6):2194–2199. doi:10.1016/j.juro.2013.05.022

16. Rosenberg JE, Ergun O, Hwang EC, et al. "Non-surgical therapies for Peyronie's disease." Cochrane Database Syst Rev. 2023;7:CD012206. doi:10.1002/14651858.CD012206.pub2

17. Levine LA. "Treatment of Peyronie's disease with intralesional verapamil injection." J Urol. 1997;158(4):1395–1399.

18. Sadagopan A. "A snapshot of intralesional verapamil injection in the treatment of Peyronie's disease today." Andrologia. 2019;51(10):e13388. doi:10.1111/and.13388

19. Paulis G, Paulis A. "Oxidative mechanism of Peyronie's disease and effectiveness of pentoxifylline in the therapeutic management: a narrative review." Antioxidants (Basel). 2025;14(2):208. doi:10.3390/antiox14020208

20. Spirito L, Manfredi C, La Rocca R, et al. "Daily low-dose tadalafil may reduce the penile-curvature progression rate in patients with acute Peyronie's disease: a retrospective comparative analysis." Int J Impot Res. 2024;36(2):129–134. doi:10.1038/s41443-022-00651-8

21. Ledesma BR, Velasquez DA, Egemba C, et al. "A Phase 2 randomized, placebo-controlled crossover trial to evaluate safety and efficacy of platelet-rich plasma injections for Peyronie's disease: clinical trial update." Int J Impot Res. 2024;36(8):813–817. doi:10.1038/s41443-024-00844-3

22. Dachille G, Panunzio A, Bizzotto L, et al. "Platelet-rich plasma intra-plaque injections rapidly reduce penile curvature and improve sexual function in Peyronie's disease patients: results from a prospective large-cohort study." World J Urol. 2025;43(1):306. doi:10.1007/s00345-025-05691-5

23. Zugail AS, Alshuaibi M, Lombion S, Beley S. "Safety and feasibility of percutaneous needle tunneling with platelet-rich plasma injections for Peyronie's disease in the outpatient setting: a pilot study." Int J Impot Res. 2024;36(2):140–145. doi:10.1038/s41443-023-00744-y

24. Cilio S, Rocca R, Celentano G, et al. "Intraplaque injections of hyaluronic acid for the treatment of stable-phase Peyronie's disease: a retrospective single-center experience." Asian J Androl. 2024;26(3):268–271. doi:10.4103/aja202371

25. Minore A, Cacciatore L, Presicce F, et al. "Intralesional and topical treatments for Peyronie's disease: a narrative review of current knowledge." Asian J Androl. 2025;27(2):156–165. doi:10.4103/aja202460