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Peyronie's Disease Agents

Collagenase clostridium histolyticum (CCH; Xiaflex) is the only FDA-approved medication for Peyronie's disease (PD).[75] See the clinical PD page for assessment and treatment selection.[1][2]

The 2026 EAU guideline and the Fifth ICSM recommendations (published December 2025/January 2026) update the context around the still-current 2015 AUA PD guideline.[2][3][4]

Collagenase clostridium histolyticum​

Indication and selection​

The US indication is an adult man with a palpable plaque and curvature at least 30° at treatment initiation. The label does not itself impose the narrower AUA selection criteria of stable disease, greater than 30° and less than 90°, and erections sufficient for intercourse with or without medication. AUA 2015 frames CCH as a Moderate Recommendation (Evidence Strength Grade B) for that selected population, given in combination with clinician and patient modeling, with a separate Clinical Principle to counsel on ecchymosis, swelling, pain and corporal rupture before starting it.[1][2]

IMPRESS excluded ventral curvature, isolated hourglass deformity and calcification that interfered with injection. A ventral curve is not synonymous with a plaque involving the urethra: urethral involvement is a label contraindication, whereas ventral curvature was a trial exclusion.[1] Use outside the pivotal population requires explicit discussion of the more limited evidence.[1][2] CCH targets plaque collagen.[1][2]

The EAU 2026 guideline strongly recommends CCH for men with dorsal or lateral curvature above 30° who request non-surgical treatment, and separately advises operating only when the disease is stable and intercourse is compromised by the deformity (stability defined as 3–6 months without change, or more than 9–12 months from onset). Candidate factors that predict a better response are covered under predictors of response.[3]

Use outside the pivotal trial population. Two practice series describe CCH treatment in men with ventral curvature or acute-phase PD, groups excluded from the pivotal trials but not, on those features alone, outside the US label indication.[1][69][70] In a later single-center prospective database using protocols modified over time, 560 CCH-treated men (85 ventral, 475 nonventral) had median curvature changes of −25° and −24°, respectively (p = 0.08), with no urethral injuries in either cohort.[76] In a single-institution registry of 228 CCH-treated men (329 curvature measures: 83% dorsal, 50% lateral and 11% ventral, with overlap), ventral curvature had the greatest relative improvement (29.5°, 49%) compared with lateral (11.4°, 38%) and dorsal (15.0°, 25%), with adverse events similar across directions and no urethral complications.[69] A separate multi-institutional analysis of 918 men treated with CCH found 134 (14.6%) were within 6 months of PD onset (acute phase); curvature improvement did not differ significantly from the 784 stable-phase men (13.5° versus 15.6°, p = 0.09), nor did treatment-related adverse events (11.9% versus 9.8%, p = 0.44).[70] A single-arm 74-patient acute-phase series using one injection reported a similar curvature reduction (mean −19.3°) with improvement in IIEF-5 and PDQ subscores at 3 and 6 months.[71]

Mechanism​

Xiaflex combines two clostridial collagenases, AUX-I and AUX-II, which act synergistically in vitro to hydrolyze native triple-helical collagen. In studies of explanted Peyronie's plaques the enzymes disrupt the predominant plaque collagens, types I and III. At higher doses and longer incubation, type IV collagen in small veins was also affected, but arteries, nerves and large veins were not structurally damaged in the in vitro and in vivo studies summarized in the label. There are no clinical data on the relative contribution of each enzyme.[1]

US labeled preparation and course​

ItemInstruction
Dose0.58 mg into the plaque responsible for the curvature[1]
ReconstitutionAdd 0.39 mL of the supplied diluent; inject 0.25 mL of the reconstituted solution. The whole vial contains 0.9 mg and is not the labeled PD dose.[1]
CycleTwo injections 1–3 days apart, then clinician modeling 1–3 days after the second injection
Interval/courseAbout 6 weeks between cycles, up to 4 cycles / 8 injections
StoppingOmit subsequent cycles if curvature becomes less than 15° or further treatment is clinically inappropriate; safety of more than one course is unknown.
DeliveryREMS-certified prescriber and healthcare site; follow the complete current preparation/injection instructions.[1]

EAU 2026 describes the same 0.58 mg two-injection cycle every six weeks for up to four cycles, and separately a modified short protocol (one 0.9 mg vial per cycle, spread along three lines around the point of maximum curvature, up to three cycles at four-week intervals, with home stretching, modeling and vacuum use in place of office modeling).[3] Reported results are comparable to IMPRESS but come from small, largely uncontrolled series; the short protocol is not the US labeled regimen.[3]

Injection and modeling considerations​

The label sequence is below. It does not replace REMS training.[1]

  1. Mark the target. Before each cycle, induce an erection (a single intracavernosal injection of alprostadil 10 or 20 mcg may be used), find the plaque at the point of maximum concavity and mark it with a surgical marker.[1]
  2. Prepare the dose. The reconstituted solution should be clear; do not inject it if it is cloudy, discolored or contains particles. It may stand at room temperature for up to 1 hour or be refrigerated for up to 4 hours (allow about 15 minutes to warm). Discard unused solution and diluent after each injection.
  3. Inject with the penis flaccid. Apply antiseptic, and local anesthetic if desired. Draw 0.25 mL into a hubless syringe with 0.01 mL graduations and a fixed 27-gauge, half-inch needle.[1] Place the needle tip on the side of the plaque in line with the point of maximal concavity, enter at the plaque edge and advance from the side, transversely across the plaque toward the opposite side without passing completely through it. Do not advance beneath the plaque or perpendicularly toward the corpora cavernosa. Resistance to minimal plunger pressure confirms placement.
  4. Deposit along the track. Inject steadily and withdraw slowly so that the full dose lies within the plaque; for a plaque only a few millimeters wide the withdrawal distance is very small. Apply gentle pressure and a dressing if needed.[72] A full-shaft gauze-and-wrap dressing from glans to base, left in place up to 24 hours and applied loosely enough to avoid restricting blood or urine flow, has been described by one center to limit bruising, hematoma and edema.[72]
  5. Second injection. Give the second injection of the cycle 1–3 days later, about 2–3 mm from the first.

Avoid the urethra, nerves, vessels and corpora cavernosa throughout: injection into these collagen-containing structures is what risks corporal rupture.[1]

In-office modeling takes place 1–3 days after the second injection, on the flaccid penis, with local anesthetic if desired. Grip the shaft about 1 cm proximal and distal to the injection site without pressing on the site, and use the plaque as a fulcrum. Apply firm, steady pressure with both hands to bend the penis opposite to its curvature to the point of moderate resistance. Hold 30 seconds, rest 30 seconds, and repeat for three attempts in total.[1]

For 6 weeks after each cycle, gently straighten the penis once daily during a spontaneous erection that occurs without sexual activity, without causing pain, and hold for 30 seconds; gently stretch the flaccid penis three times daily. Patients should avoid abdominal straining (for example at bowel movements). Do not use a vacuum erection device during Xiaflex treatment under the US label.[1]

Sexual activity and serious injury

No sexual activity between the two injections. Wait at least 4 weeks after the second injection of each cycle, and until pain and swelling have resolved. A popping sensation with sudden detumescence, marked bruising or swelling, severe pain, hematuria or voiding difficulty warrants prompt assessment for corporal rupture or other serious injury.[1]

Safety​

The boxed warning concerns corporal rupture and serious penile injury. In pooled controlled and uncontrolled clinical experience, confirmed rupture occurred in 5/1,044 (0.5%), another 9/1,044 (0.9%) had findings in which rupture could not be excluded, and severe penile hematoma occurred in 39/1,044 (3.7%). Pooled clinical-experience and randomized-trial adverse-event tables use different categories and denominators.[1]

Adverse reactions in the two randomized trials (551 CCH and 281 placebo, up to four cycles) were frequent and mostly local:

ReactionCCHPlacebo
Any adverse reaction92% in label narrative (84.2% in Table 5)61% in label narrative (36.3% in Table 5) [1]
Penile hematoma65.5%19.2% [1]
Penile swelling55.0%3.2% [1]
Penile pain45.4%9.3% [1]
Penile ecchymosis14.5%6.8% [1]
Blood blister4.5%0% [1]
Erectile dysfunction1.8%0.4% [1]

Severe hematoma occurred in 33/551 (6.0%) versus 0/281. A penile popping sound or sensation, sometimes with detumescence, hematoma or pain, was reported by 73/551 (13.2%) versus 1/281 (0.3%). The label reports no meaningful difference in adverse events by baseline ED severity or concomitant PDE5-inhibitor use, and no penile shortening in the trials.[1]

Rupture in routine practice. In a Veterans Affairs cohort of 1,541 men who received at least one CCH injection, 11 (0.7%) had corporal rupture. Among those 11 the median number of injections was 6 and the median initial curvature 35°. Fracture occurred at a median of 8 days after injection, most within 2 weeks, and mostly during spontaneous erections or intercourse. Six were repaired surgically and the rest managed conservatively. This supports explicit counseling about spontaneous erections and the abstinence window.[23]

  • Contraindications: plaque involving the urethra; prior hypersensitivity to Xiaflex or therapeutic collagenase.[1]
  • Bleeding: abnormal-coagulation patients were excluded from trials except low-dose aspirin (up to 150 mg/day).[1] The label recommends avoiding use with coagulation disorders or concomitant anticoagulants other than low-dose aspirin; safety with anticoagulants within the preceding 7 days is unknown. This is not an instruction to stop prescribed anticoagulation without an individualized plan.
  • Other important reactions: anaphylaxis, acute post-injection back pain and syncope or presyncope. Postmarketing penile hematoma has occasionally led to skin or soft-tissue necrosis requiring surgery. Lie down if presyncopal and report serious symptoms promptly.[1]

Pivotal benefit and clinically meaningful outcomes​

IMPRESS I/II randomized 832 men; the label's 612-man efficacy population required curvature and PDQ data plus vaginal intercourse within three months before each PDQ assessment. At 52 weeks, mean curvature improved by 35.0% versus 17.8% in trial 1 and 33.2% versus 21.8% in trial 2.[1] Both groups received modeling. These are changes from baseline; the drug's added benefit is smaller than the treated-group change. In the published pooled analysis the absolute change was -17.0° with CCH versus -9.3° with placebo (both with modeling), a net difference of about 8°.[1][16]

The trials enrolled men in the stable phase with baseline curvature averaging about 49–51° (range 30–90°), randomized 2:1. The percent-change treatment differences were −17.2% (95% CI −26.7 to −7.6) and −11.4% (−19.5 to −3.3), and improvement was numerically similar in the 30–60° and 61–90° strata. The co-primary PDQ bother domain (0–16 scale) fell by 2.8 versus 1.6 points in trial 1 and 2.6 versus 1.5 in trial 2, treatment differences of about 1.1–1.2 points.[1]

The 2023 Cochrane review estimated the longer-term between-group difference at 6.9° (95% CI 4.14–9.64°) favoring CCH, below its prespecified 12° threshold for clinical importance. That judgment depends on the chosen threshold and the patient's goals. Treatment-related adverse events increased (RR 2.32, 95% CI 1.98–2.72). Evidence for intercourse outcomes was absent in this comparison.[5]

Outcomes in routine practice​

StudyFinding and limit
Hellstrom 2019, five-center retrospective series (918 men)Curvature 48.2° to 32.9° (30.1% improvement); 68.7% achieved at least 20% improvement. Among 502 who completed four or more cycles: 49.7° to 32.7° (33%), with 74.4% at least 20%. Complications in 9%. The number of cycles predicted improvement. Retrospective and unblinded.[24]
Ziegelmann 2016, single-practice cohort (69 men, 1–4 series; 31 completed four)Mean objective improvement 23° (38%). Patient-perceived curvature improvement rose with each series (14%, 28%, 30%, 37%). Among completers, 57% said CCH negated the need for surgery, 52% reported restored penetration; overall, 81% considered treatment meaningful, and 88% reported subjective improvement after four series. Hematoma in 10%, no rupture. Small and self-reported.[25]

Later cycles and long-term follow-up​

StudyFinding and limit
Ziegelmann 2023, post hoc IMPRESS analysisAfter cycle 1, 29.9% of CCH recipients had at least a 20% curvature reduction. Of those not responding after cycle 1, 60.8% met it by cycle 4; of cycle 1–2 nonresponders, 42.7%; of cycle 1–3 nonresponders, 23.5%. This supports discussing further cycles in suitable patients; it was not randomization to stopping versus continuing and does not override label stopping rules.[6]
Goldstein 2020, five-year follow-up280 enrolled, 204 completed follow-up; year-5 curvature analysis included 180. An additional mean 4.3° improvement was observed without further CCH.[7]
Goldstein 2020, calcification subgroupsStippled/non-injection-obstructing calcification groups had initial improvements that persisted.[8]

Predictors of response​

Pooled IMPRESS subgroups (Lipshultz 2015). Curvature and bother fell in every subgroup. Versus placebo, curvature reductions were significantly greater with CCH for baseline curvature 30–60° and 61–90°, disease duration over 2 years (2–4 and over 4 years), no plaque calcification, and IIEF at or above 17. Contiguous calcification that did not interfere with injection (n = 62) and IIEF 6–16 (n = 106) were not among the subgroups with a significant difference.[9]

Review of predictors (Masterson 2020). Four characteristics were best studied: baseline curvature, baseline erectile function, disease duration and calcification. The man most likely to improve has curvature of 30–60°, longer disease duration, IIEF above 17, no calcification and completes all four cycles. Calcification appears the strongest factor, plausibly because CCH cannot degrade calcified plaque. Outcome definitions differ widely across studies.[26]

Nomogram (Cocci 2018). In 135 men in a multicenter single-arm study, 57% achieved the success definition of at least a 20° reduction (median change −20°). Greater baseline curvature and basal plaque location predicted success, whereas low and high plaque calcification each carried much lower odds than none. The model's c-index of 0.93 was internal and unvalidated externally.[27]

Cahill 2025 (826 men, single-center prospective series). Greater baseline curvature, hourglass deformity, more CCH series, strong nocturnal erections, higher bother and RestoreX use were associated with larger improvement, RestoreX use most strongly. Reduced patient motivation and pure lateral curvature were associated with less improvement in univariate analysis. Men who had a hematoma, popping sensation or rapid detumescence during treatment also improved more (about 5°), and "suspected controlled penile fracture" remained independently associated with better outcomes; these remain complications to counsel about and manage as described above. The authors stress patient motivation and active participation.[28]

Mechanical adjuncts and surgery comparisons​

Alom's 2019 nonrandomized registry analyzed 113 completers with objective data from 287 men with traction-use information. Mean curvature improvement was 20.3° (31%) with CCH alone, 19.2° (30%) with CCH plus another traction device, and 33.8° (49%) with CCH plus RestoreX; length change was −0.7, −0.4 and +1.9 cm respectively, despite shorter daily use in the RestoreX group (0.9 versus 1.9 hours). The RestoreX group was 6.9 times more likely to reach at least 20° improvement. Adverse events were similar in this single-center registry.[10]

A 2024 meta-analysis of CCH plus varied adjuncts versus CCH alone pooled seven comparative studies (532 men): the length analysis in four studies (346 men) favored combination therapy (mean difference 0.81 cm, 95% CI 0.17–1.45), while the pooled curvature difference across all seven was not significant.[77] In Ziegelmann's 2017 "true-to-life" cohort (51 men who completed CCH and had complete objective data; mean improvement 20.9° from 66.7° baseline), 69% used an Andropenis strap extender about 9.8 hours per week, use declined with later series, and curvature and length outcomes did not differ by traction frequency or duration.[29] In García-Gómez's uncontrolled multicenter series (87 men; IMPRESS protocol plus an extender worn at least 4 hours daily starting 24–48 hours after injection), curvature fell from 57° to 34° (−23.3°, −41%) after a mean of only 2 cycles, which the authors suggest traction may allow.[30] Hatzichristou's "3 Ts" protocol (daily tadalafil, tunneling with intralesional biologics, daily traction) is a proposed multimodal sequence awaiting randomized testing.[31]

CCH versus surgery, nonrandomized (Yafi 2018). In a multi-institutional prospective comparison of 57 men with dorsal, dorsolateral or lateral curvature of 30–90° (ventral curvature, hourglass deformity and prior PD surgery excluded), mean curvature change was 23.3° (34.4%) after CCH (18 men), 72.0° (92.2%) after tunical plication (14) and 71.8° (94.9%) after partial plaque excision and grafting (25), at median follow-up of 12 months. Length change was −0.2, −1.0 and +0.9 cm; IIEF-5 change did not differ significantly. Three CCH patients with bothersome residual curvature underwent uneventful plication. The authors conclude that surgery corrects curvature more and that CCH is an effective, safe option for motivated men who prefer to avoid surgery.[32] See the Peyronie's disease surgical pages for operative options.

A 2023 randomized trial assigned 40 men to CCH or surgery, both with traction and sildenafil; 38 had 3-month data. Surgery achieved greater curvature correction (84% versus 54%); the CCH arm had greater preserved or gained length and fewer reported adverse events.[11]

Cost. A 2019 Markov model (2017 Medicare costs; outcomes from one institution's prospective data) estimated success, defined as at least 20% curvature improvement, at 96% for surgery, 66% for CCH and 48% for RestoreX traction, with 10-year costs per patient of $11,419, $33,628 and $883. At a willingness-to-pay of $100,000/QALY the most cost-effective strategy was traction in 49% of simulations, surgery in 48% and CCH in 3%; CCH would become more cost-effective if its modeled treatment cost was $16,726 or less or a success rate of 76% or more.[33]

Practice pattern. In New York State data (2003–2016), surgery became less common as the primary treatment after CCH approval; patients in the CCH era were 17% more likely to receive injection therapy, and injection was more likely in younger patients, higher socioeconomic status and high-volume surgeons.[34]

For device details see penile traction therapy. CCH remains available in the US through REMS; EAU notes withdrawal from the European market.[1][3]

Interferon α-2b​

The 2015 AUA states that clinicians may administer intralesional interferon α-2b , with counseling about flu-like symptoms, sinusitis and swelling. The 2026 EAU no longer recommends it, citing limited evidence and withdrawal from US/European markets in 2021. Interferon availability is limited; ventral-plaque data come from an uncontrolled single-institution series.[2][3]

Rationale. Interferon α-2b was tried after reports of benefit in keloid, on the hypothesis that it alters myofibroblast behavior; the proposed actions are reduced fibroblast proliferation and collagen synthesis with increased collagenase activity. It is off-label for PD.[36]

Dosing as studied: the single-blind placebo-controlled trial used 5 million units in 10 mL saline injected every 2 weeks for 12 weeks[20]; the practice series used 2 million units every 2 weeks, a median of 12 injections (range 6–24).[21][35] In the largest retrospective series, 54% achieved at least 20% curvature improvement (mean 9.0°), with the best response when baseline curvature was under 30° (86%).[20][21][35]

Evidence​

  • Placebo-controlled trial (Hellstrom 2006). Single-blind, multicenter; 117 men enrolled (55 interferon, 62 saline) and 103 completed. Improvement in curvature, plaque size and density, and pain resolution was significantly greater with interferon; the IIEF change was not different. Penile blood flow improved and vascular pathology decreased with interferon. Adverse effects, mostly flu-like, were mild to moderate and short.[20]
  • Practice series (Trost 2013, 127 men). Mean pretreatment curvature 42.4°; 54% responded, with mean improvement 9.0°. Age, curvature, vascular status, ultrasound findings, curvature site, IIEF and disease duration did not predict response; absolute improvement was independent of pretreatment curvature and duration.[21]
  • Ventral plaques (Stewart 2015, 131 men, single-institution retrospective series). Interferon response rates were 54% for dorsal or lateral plaques and 52% for ventral plaques (p = 0.92), with mean curvature improvements of 8.7° and 9.3°, respectively.[35]
  • Early experience (Wegner 1995, 25 men, 1 million units weekly × 5). One man improved clinically; plaque size fell in 7 (none or mild calcification), was stable in 12 and rose in 6, all with calcified plaques. Myalgia or fever occurred in 4 and two withdrew. The authors concluded any benefit was confined to early, non-calcified plaques and that dose-finding was needed.[36]

Comparative context. In Russo's 2019 network meta-analysis of controlled intralesional trials (8 comparisons, 1,050 men), CCH and interferon α-2b performed best for curvature; hyaluronic acid and verapamil were worse than CCH by 6.66° and 2.30° and worse than interferon by 6.75° and 2.38°. Jordan's 2014 evidence review likewise identified interferon and CCH as the only injectables with level 1–2 evidence for reducing curvature in placebo-controlled studies, and found mixed or negative results for iontophoresis, oral agents, ESWT, verapamil and nicardipine.[38] Both reviews predate the withdrawal of interferon.[37][38]

Older placebo-controlled results suggested curvature improvement; Hellstrom and Kendirci reported the same trial.Cochrane rated the evidence very uncertain. Small series reported no ruptures. Flu-like symptoms were expected, mild to moderate and short-lived in the placebo-controlled trial.[5][20]

Verapamil and nicardipine​

Intralesional verapamil is off-label. The 2015 AUA guideline gives intralesional verapamil a Conditional Recommendation (Grade C) and describes the evidence as weak and conflicting.[2] EAU2026 finds the evidence insufficient to support injected calcium-channel blockers (level 3c, contradictory results, no meaningful curvature benefit over placebo) and gives no recommendation for them.[3] AUA2015 separately recommends against electromotive verapamil (Moderate Recommendation, Grade C; one small RCT with fewer than 25 verapamil-exposed men showed minimal benefit).[2][78] ICSM2024 offers a conditional verapamil option.[4]

Mechanism. Calcium-channel blockers were proposed to alter fibroblast metabolism, decreasing secretion of collagen, glycosaminoglycans and fibronectin, increasing collagenase activity and modulating TGF-β. In a rat Peyronie model, intralesional verapamil reduced collagen, elastin and smooth-muscle α-actin staining more than saline and was associated with better recovery of electrostimulated penile pressure; this is animal data only.[39][41][43]

Study protocols vary widely, which complicates interpretation:

SeriesRegimen
Levine 1994 (14 men, nonrandomized)Dose-escalating, every 2 weeks for 6 months[39]
Levine 199710 mg diluted to 10 mL, multiple-puncture technique throughout the plaque, every 2 weeks for 12 injections[40]
Rehman 1998 (randomized, single-blind)Verapamil or saline weekly for 6 months[41]
Wolff 201515 mg in 6 mL, single-puncture, every 3 weeks, at least 6 injections (mean 12.6)[42]
Favilla 2014 (randomized)10 mg weekly for 12 weeks[45]

The most commonly described regimen is Levine's. Local anesthesia is used as needed.[17][40]

One center's described technique distributes injection passes in rows without withdrawing the needle after every pass; for ventral curvature, the rows are placed lateral to the urethra, with urethral bleeding listed as a possible complication, using 10 mg verapamil in 5 mL saline, a concentration distinct from the Levine regimen above.[73]

Key studies​

  • Levine 1994 pilot. 14 men: subjective improvement in plaque-associated narrowing in all and in curvature in 42%; plaque volume decreased by more than 50% in 30%; plaque softened in all; 83% reported that changes in erectile function had arrested or improved; no toxicity.[39]
  • Levine 1997. 46 men began and 38 completed. Pain resolved in 97% of those with pain after a mean of 2.5 injections; 76% reported decreased curvature; objective curvature decreased in 54%, increased in 11% and was unchanged in 34%; 72% reported improved coital ability. Response did not differ by disease duration or Kelami class. Only transient ecchymosis was noted. Nonrandomized.[40]
  • Rehman 1998, randomized single-blind (14 completers, 7 per arm). Plaque volume decreased in 57% of verapamil-treated men versus 28% with saline (p < 0.04); the curvature trend (37.7° to 29.6°) did not reach significance (p < 0.07). Quality of erections improved in 43% versus none. The authors judged intralesional verapamil reasonable for selected men with non-calcified plaque and angulation under 30°, and suggested that men whose plaque did not respond within 3 months, or whose angulation exceeded 30°, were more likely to benefit from surgery.[41]
  • Levine 2002. Of 156 treated men, 140 completed treatment and 121 had repeat duplex measurements; objective curvature decreased in 73 of 121 (60%) with repeat measurements.[17]
  • Wolff 2015 (60 men, prospective). Curvature 37.3° to 21.0°, Lue severity score 9.4 to 4.5, 78% globally improved, no serious side effects. Younger age was the only predictor of response (multivariate OR 0.87); most men needed at least 12 injections.[42]
  • Randomized and cohort data with less favorable results. The randomized single-blind trial of 80 men (verapamil versus saline, 24 weeks) found no difference in curvature, plaque size or pain. A cohort of 131 men with disease under 1 year found greater improvement with younger age and larger baseline curvature, and only 26% improved at least 10° after 3 months.[18][19]
  • Verapamil plus oral antioxidants (Favilla 2014, 105 men). Both arms improved plaque size and curvature with no between-group difference; the antioxidant arm had greater improvement in IIEF-15 and pain (VAS).[45]

Pooled and comparative evidence. The Cochrane 2023 review's verapamil comparison rested on one trial of 14 men: curvature difference −1.86° (95% CI −10.39 to 6.67) and intercourse ability RR 7.00 (95% CI 0.43–114.70), both very low certainty, with no long-term data.[5] Sadagopan's exploratory meta-analysis of seven study groups, mixing populations and protocols, found significant improvement in sexual function and curvature but not plaque size, with pain effect questionable. In the network meta-analysis verapamil was worse than CCH (by 2.30°) and interferon α-2b (by 2.38°) for curvature, and slightly better than interferon for IIEF.[5][44][37]

Practical positioning. Verapamil's advantages are low cost, no REMS requirement and use at any plaque location. It is a reasonable option to discuss when CCH is unavailable, unaffordable or contraindicated, particularly for non-calcified plaque and modest curvature in younger men, with clear counseling that benefit is uncertain and guidelines diverge.[41][42]

Neither verapamil nor nicardipine has robust evidence of a clinically important advantage over placebo. Local bruising and pain, dizziness and nausea require counseling; “no systemic effects” or “no rupture risk” is too absolute.[2][3][5]

Nicardipine​

Nicardipine is a dihydropyridine calcium-channel blocker studied as an alternative to verapamil, with a reportedly greater in vitro potency. In Soh's 2010 randomized single-blind trial (74 men randomized in the transition between acute and chronic phase; 37 nicardipine, 37 saline; six biweekly injections), curvature improved significantly in both arms without a between-group difference, suggesting that the injection procedure itself contributes. Pain fell in both arms with a greater reduction with nicardipine (p = 0.019); IIEF-5 and plaque size improved significantly only with nicardipine at 48 weeks; no hypotension or cardiovascular events occurred. Jordan's evidence review placed it with agents showing mixed or negative results.[65][38]

Oral agents​

Pain and concomitant erectile dysfunction​

Oral NSAIDs can treat active-phase pain when otherwise appropriate (AUA Expert Opinion: clinicians may offer oral NSAIDs for active disease with pain).[2] PDE5 inhibitors can treat coexisting ED or difficulty with penetration; see the PDE5 hub for doses and contraindications. A retrospective tadalafil study (191 men) reported less short-term curvature progression among men choosing treatment. ICSM concludes oral drugs have little established effect on significant deformity reduction.[3][4][12]

Agents without a supported routine role​

AgentEvidence and practical interpretation
Vitamin E, tamoxifen, procarbazine, omega-3, vitamin E plus L-carnitineAUA recommends against offering these for PD and notes that oral therapy is not appropriate for stable disease.[2]
Pentoxifylline, colchicine, CoQ10AUA lists these as “Other Treatments” because evidence is insufficient even for a conditional recommendation.[2] Cochrane excluded specified studies for data-integrity concerns.[5]
POTABAAUA 2015 places it, with pentoxifylline, colchicine and CoQ10, under "Other Treatments" (one RCT at high risk of bias, fewer than 100 men treated). Dosed at 3 g four times daily (12 g/day) for 12 months. One trial randomized 103 men with early noncalcified disease, but emphasized 75 completers. The trial reported a plaque/composite response.[13]

Reliability of some oral-agent trials. A single investigator produced several placebo-controlled oral PD trials. The omega-3 trial has been retracted, the pentoxifylline trial carries a retraction statement from BJU International, and Journal of Urology has published an Expression of Concern for the vitamin E and propionyl-L-carnitine trial. Cochrane excluded studies for data-integrity concerns. The retracted or flagged oral-agent trials provide unreliable results; these concerns apply only to those reports.[46][47][59][60]

Vitamin E and propionyl-L-carnitine​

The vitamin E, propionyl-L-carnitine and combination trial (236 men, 6 months; vitamin E 300 mg twice daily, propionyl-L-carnitine 1 g twice daily, both, or placebo) found no significant difference from placebo in the proportion of men with decreased pain (60.4%, 63.0%, 62.3% versus 59.2%), reduced penile curvature (18.9%, 20.4%, 22.6% versus 18.4%) or decreased plaque size (11.3%, 12.9%, 13.2% versus 11.1%); see the reliability caveat above.[46] Jordan's review found mixed or negative results for oral therapies as a group.[46][38]

A meta-analysis of 19 trials (135,967 participants) found that high-dose supplementation (400 IU/day or more) was associated with higher all-cause mortality (pooled risk difference 39 per 10,000, 95% CI 3–74; P = 0.035), with increased risk above 150 IU/day, although the high-dose trials were often small and in patients with chronic disease.[48]

Tamoxifen​

A placebo-controlled trial of 25 men with non-calcified plaque (tamoxifen 20 mg twice daily for 3 months) found no significant benefit: pain subsided in 66.6% versus 75%, deformity reduced in 46.1% versus 41.7%, plaque size decreased in 30.7% versus 25%, and objective plaque area and curvature angle did not differ.[49]

The laboratory rationale is real but early-phase only.[50] Vardenafil plus tamoxifen synergistically inhibited myofibroblast transformation, collagen-gel contraction and extracellular-matrix production in vitro, and in a rat model the combination was more antifibrotic than either drug alone.[50] In human tunica-derived fibroblasts, tamoxifen prevented myofibroblast transformation only up to 36 hours after TGF-β1 exposure (vardenafil 24 hours) and could not reverse established transformation.[51]

Tamoxifen has clinically important harms despite attractive laboratory mechanisms. In a 64-patient male breast-cancer cohort, sexual dysfunction occurred in 14 and 13 stopped treatment for toxicity, including four thromboembolic events.[14] In an earlier series of 24 men, 62.5% reported a side effect (decreased libido 29.2%, weight gain 25%, hot flashes and mood change 20.8% each, one deep venous thrombosis) and 20.8% stopped within a year.[52]

Potassium para-aminobenzoate (POTABA)​

POTABA has a long history in fibrotic disease. In a randomized trial in scleroderma (146 entered, 76 completed), aminobenzoate potassium 12 g/day for 48 weeks did not change skin outcomes; 18 patients in the drug arm and 6 on placebo withdrew for adverse reactions, most often gastrointestinal intolerance and headache.[53]

In Weidner's PD trial, 103 men with a history under 12 months and non-calcified plaques were randomized (51 POTABA, 52 placebo) to 3 g four times daily for 12 months; no severe adverse events occurred and analysis focused on the 75 who completed the study.[13]

EndpointPOTABAPlacebo
Response (plaque regression and/or curvature reduction of at least 30%)74.3%50.0% (p = 0.016)
Mean plaque size259 to 142 mm²259 to 303 mm² at 6 months, 233 mm² at 12 months (p = 0.042)
Pre-existing curvatureNo significant improvement (p = 0.066)—
Curvature deteriorationRemained stableDeteriorated in 32.5%
Pain decrease82.6%77.3% (not significant)

In Weidner’s randomized trial, among the 75 completers across both arms, curvature remained stable with POTABA while 32.5% of placebo recipients had worsening; pre-existing curvature did not significantly improve.[13] Cochrane found no objective curvature-degree outcome and rated the patient-reported curvature evidence very low certainty, and AUA 2015 considered POTABA unproven.[2][5][13] About 27% of enrolled men did not complete the study.[13] Acute liver injury has been linked to POTABA in six reported individuals, including a case with full biochemical recovery 4 months after stopping, so liver symptoms warrant attention and the drug should be stopped if hepatitis is suspected.[13][54]

Pentoxifylline​

Pentoxifylline is a non-specific phosphodiesterase inhibitor. In tunica albuginea-derived fibroblasts it attenuated TGF-β1-stimulated collagen deposition and elastogenesis, with interference in Smad-dependent signaling; it also lowered collagen production in Peyronie's-derived cells to control levels but not in normal tunica cells. These are cell-culture findings.[55][56]

Clinical data are limited to observational reports. Its main supporting data are a single-practice retrospective cohort of 71 men with calcified plaques, 62 treated with pentoxifylline for a mean of about 1 year, in which calcium burden was stable or improved in 57/62 (91.9%) versus 4/9 (44.4%) comparison men (untreated or on vitamin E); among questionnaire respondents, subjective condition was unchanged or improved in 47/60 (78.3%) versus 2/8 (25.0%). The authors called for a randomized trial.[22] In Abern's series of 74 men who completed 12 verapamil injections together with L-arginine 1 g twice daily and pentoxifylline 400 mg three times daily, 39 elected to add traction (advised 2–8 hours daily).[57] Response, defined as at least 10° curvature reduction, was 54% with traction versus 46% without (p = 0.75), with mean improvement among responders of 26.9° versus 20.9°.[57] Each additional hour of daily traction predicted 0.38 cm of length gain (p = 0.007).[57] Pentoxifylline is inexpensive and generic, which explains its use as an adjunct, but efficacy is unproven.

Coenzyme Q10​

CoQ10 is a lipid-soluble antioxidant with a plausible antifibrotic rationale. The only dedicated placebo-controlled trial (186 men with early chronic PD randomized to 300 mg daily or placebo for 24 weeks) reported reduced plaque size and curvature, IIEF-5 of 17.8 versus 8.8, and disease progression among patients with outcome data in 11 (13.6%) versus 46 (56.1%).[58] Routine treatment lacks support from this unreplicated trial by an investigator with retracted or flagged PD trials. CoQ10 is available over the counter and generally well tolerated; use, if any, is as a low-risk adjunct with explicit counseling that evidence is unproven.

Shock wave therapy and traction​

Randomized trials did not show curvature improvement with ESWT: EAU2026 gives a strong recommendation against ESWT to improve curvature and a weak recommendation to use it for pain in the acute phase, and AUA2015 likewise advises against ESWT for curvature or plaque size , while allowing it for pain .[2][3] Cochrane found little to no curvature effect (three trials, 166 men, low certainty).[2][3][5]

Traction and vacuum devices are offered by EAU2026 to reduce deformity or within multimodal care, with limited outcome data.[3] Cochrane found a 7.4° curvature difference for traction in one trial (very low certainty). See penile traction therapy.[3][5]

Emerging injections​

Hyaluronic acid​

EAU 2026 weakly recommends intralesional HA for acute-phase pain and/or curvature while acknowledging limited outcome data and a lack of placebo-controlled data; the Fifth ICSM review does not support HA injections because robust evidence is lacking.[3][4] This does not establish FDA approval for PD, nor superiority for erectile function.[3]

Hyaluronic acid is a glycosaminoglycan proposed to disrupt plaque architecture and modulate extracellular matrix and inflammation; some formulations are designed for intraplaque use. Older network rankings rely on sparse, heterogeneous direct and indirect comparisons. In Russo's 2019 network meta-analysis, HA was worse than CCH (by 6.66°) and interferon α-2b (by 6.75°) for curvature but showed the largest IIEF gain (+2.39 points versus CCH, +0.62 versus verapamil and +1.74 versus interferon α-2b).[37]

A 2024 non-placebo randomized trial in 42 men with acute PD compared 12 weekly HA injections with verapamil; 12 weeks after therapy, final mean curvature was 24.7° versus 30.8° (p = 0.038).[74]

Uncontrolled clinical data:

  • Cilio 2024 (62 men with stable-phase PD, retrospective). Three injections two weeks apart plus vacuum therapy, stretching and modeling. Mean curvature 52.7°; 54 men (87.1%) improved, to a mean 40.3° (p < 0.001), 8 (12.9%) had no improvement, all PDQ domains improved, and 80.6% reported subjective curvature improvement.[63]
  • Falcone 2025 (16 acute-phase men, Perovial, preliminary perspective). Ten weekly sessions plus daily vacuum therapy and modeling; median baseline curvature 43°, median reduction 15° (IQR 7.5-19), significant pain relief, no complications. The authors themselves describe the results as preliminary.[64]

Platelet-rich plasma​

Ledesma's 2024 trial update reported 41 randomized, with a preliminary analysis of 28. A within-sequence curvature improvement after crossover does not establish comparative efficacy or prove a delayed mechanism. The small interim sample reported no adverse events. The Fifth ICSM consensus finds no convincing evidence supporting PRP or cell-based therapy; EAU emphasizes its limited evidence.[3][4][15]

Uncontrolled series report short-term improvement. Dachille's prospective cohort (72 men; three 6 mL intraplaque injections two weeks apart; assessment 4 weeks after the third) found median curvature 50° to 40° (p < 0.001), median plaque size 11.1 to 8.2 mm, improvement in all three PDQ domains, no change in IIEF-5 and no adverse events.[61] Zugail's pilot combined percutaneous needle tunneling with PRP (54 men, six sessions under local anesthesia, then vacuum therapy): median curvature 45° to 30° (median correction −44.4%, p = 0.001); 50% had a minor hematoma, 75.9% ecchymosis and one had a skin infection.[62] Neither series had a control group, and needle tunneling itself may contribute to the effect.

See platelet-rich plasma for the broader evidence and formulation limitations.

Botulinum toxin and corticosteroids​

EAU2026 excludes them from detailed treatment discussion because of poor evidence. AUA2015 lists intralesional dexamethasone and betamethasone combinations among Other Treatments with insufficient evidence to support even a Conditional Recommendation.[2] Neither limited historical responses nor proposed scar biology justifies an established treatment protocol.[2][3]

Botulinum toxin. The hypothesis, borrowed from dermatologic scar literature, is that paralyzing musculature next to a scar reduces repetitive tension on the wound edges and the fibroblastic response. It has not been shown to work in PD, and it remains investigational.

Corticosteroids. Steroids were among the earliest intralesional agents, on an anti-inflammatory rationale for active-phase disease.

  • Cipollone 1998 (randomized betamethasone vs placebo, 30 men). No significant differences: pain at erection disappeared in 66.6% versus 53.3%, curvature diminished in 20% versus 26.6%, and plaque volume and consistency decreased by 50% in 40% of each group. The authors attributed clinical results to the mechanical effect of the injected volume rather than the drug.[66]
  • Ure 2021 (48 men with active-phase symptoms, nonrandomized). Methylprednisolone 40 mg weekly for 8 weeks: plaque size 13.6 to 10.8 mm (p = 0.025) and all PDQ domains improved, with no adverse events. Symptom duration averaged 3.4 months, so the natural history of active-phase disease confounds an uncontrolled result.[67]
  • Di Stasi 2004 (electromotive delivery). 96 men were randomized to intraplaque electromotive verapamil 5 mg plus dexamethasone 8 mg or electromotive lidocaine, 4 sessions weekly for 6 weeks; 73 completed. The active group's median plaque volume fell from 824 to 348 mm³ and curvature from 43° to 21°, with permanent pain relief, while controls were unchanged. The combination and delivery route make it impossible to isolate a steroid effect.[68]

Agent summary​

AgentRegulatory and guideline positionBest evidence
CCH (Xiaflex)FDA-approved with REMS; AUA 2015 moderate recommendation (Grade B) with clinician/patient modeling for stable disease, curvature >30° and <90° and intact erectile function; EAU 2026 strong recommendation for dorsal or lateral curvature above 30° when non-surgical treatment is requestedIMPRESS I/II (832 men); Cochrane 6.9° between-group difference; routine-practice series[1][2][3][5]
Interferon α-2bOff-label; AUA 2015 moderate recommendation (may administer; Grade C); EAU 2026 does not recommend (evidence limited; withdrawn from the European and US markets in 2021); level 2bOne single-blind placebo-controlled trial; retrospective series including ventral plaques[2][3][20][35]
Verapamil / nicardipineOff-label; AUA 2015 conditional option for intralesional verapamil (Grade C) and a recommendation against electromotive verapamil; ICSM conditional verapamil; EAU 2026 finds evidence insufficient and makes no recommendationUncontrolled series; small randomized trials with mixed results; Cochrane very low certainty[2][3][4][5]
Hyaluronic acidEAU 2026 weak recommendation for acute-phase pain and/or curvatureUncontrolled series; sparse network data[3][37]
PRPEAU: counsel that data are limited; ICSM: no convincing evidenceSmall trial update and uncontrolled cohorts[3][4][15]
Oral agents (vitamin E, tamoxifen, others)AUA recommends against vitamin E, tamoxifen, procarbazine, omega-3 and vitamin E plus L-carnitine; pentoxifylline, colchicine, CoQ10 and POTABA are unprovenNegative or unreliable trials; POTABA early-disease trial[2][13]
PDE5 inhibitors and NSAIDsEAU: PDE5 inhibitors for coexisting ED ; NSAIDs for acute-phase pain Symptom treatment, not curvature correction[3]
ESWTEAU: do not use for curvature ; may be used for acute-phase pain Cochrane low-certainty, little to no curvature effect[3][5]
Traction / vacuum devicesEAU weak recommendation to offerNonrandomized CCH combination series; Cochrane very low certainty[3][5][10]

Sequencing by disease phase​

Active phase (pain, evolving curvature). Counsel about natural history. Treat pain with NSAIDs and coexisting ED with a PDE5 inhibitor .[3] For selected men with active-phase PD, a palpable plaque, and dorsal or lateral curvature above 30° who request nonsurgical treatment, CCH can be discussed with counseling that active-phase efficacy data remain observational; the US label has no stability criterion, EAU 2026 gives a Strong recommendation without specifying phase but calls acute-phase evidence preliminary, and AUA 2015's Moderate Recommendation specifies stable disease.[1][2][3][70] Other options with limited evidence include intralesional hyaluronic acid, ESWT for pain only, and traction or vacuum devices; daily low-dose tadalafil is supported only by a retrospective comparison. Avoid vitamin E, tamoxifen, procarbazine, omega-3 and vitamin E plus L-carnitine.[2][3][12]

Stable phase. Discuss CCH after counseling on its modest mean incremental curvature benefit and corporal rupture risk. The US label indicates treatment for adult men with a palpable plaque and curvature of at least 30° and contraindicates plaques involving the urethra.[1] AUA 2015 says clinicians may administer CCH with clinician and patient modeling in stable disease with curvature >30° and <90° and intact erectile function ; EAU 2026 recommends it for dorsal or lateral curvature >30° when nonsurgical care is requested .[2][3] Calcification that interfered with injection was excluded from the pivotal trials.[1][2][3] Verapamil is an off-label option only after discussion of its uncertain benefit. Traction may accompany injection therapy. Surgery is indicated when the disease is stable and intercourse is compromised by the deformity, and corrects curvature more completely than CCH in nonrandomized comparison; men with severe or complex deformity, calcified or hourglass plaques, or ED needing a prosthesis are generally directed to the surgical pathways.[1][3][32]

Use the surgical pages for Peyronie's disease operations.

See Also​

References​

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3. EAU. Guidelines on Sexual and Reproductive Health, Limited Update March 2026, sections 8.1 and 8.2 (penile curvature and Peyronie's disease). Current chapter.

4. Chung E, Ziegelmann M, Lin HC, et al. Management of Peyronie's disease: recommendations from the Fifth International Consultation on Sexual Medicine (ICSM 2024). Sex Med Rev. 2026;14:qeaf068. doi:10.1093/sxmrev/qeaf068.

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