Collagenase clostridium histolyticum (DB00048): A Comprehensive Monograph on its Pharmacology, Clinical Efficacy, and Therapeutic Applications

1.0 Executive Summary

Collagenase clostridium histolyticum (CCH) represents a landmark therapeutic innovation, establishing a new class of injectable enzymatic agents for the treatment of localized fibroproliferative disorders. Derived from the bacterium Clostridium histolyticum, CCH is a highly purified biologic drug designed to enzymatically lyse pathological collagen deposits that are the hallmark of specific debilitating conditions.[1] Its primary mechanism of action involves the targeted disruption of the collagen triple helix, a process that effectively performs a non-surgical, biochemical fasciotomy at the site of injection.[3]

Under the brand name Xiaflex, CCH has secured U.S. Food and Drug Administration (FDA) approval for two distinct indications: the treatment of Dupuytren's contracture in adults with a palpable cord and the treatment of Peyronie's disease in adult men with a palpable plaque and significant penile curvature.[5] A third formulation, formerly marketed as Qwo, was approved for the aesthetic treatment of cellulite in adult women but has since been discontinued.[1]

Clinical efficacy for its approved medical indications has been robustly demonstrated in large-scale, pivotal Phase III trials. For Dupuytren's contracture, Xiaflex produced statistically and clinically significant reductions in finger contracture compared to placebo.[9] For Peyronie's disease, it achieved co-primary endpoints of significantly reducing penile curvature and alleviating the psychological "bother" associated with the condition.[10] However, this efficacy is intrinsically linked to a significant safety profile. The drug's mechanism of action—localized tissue digestion—gives rise to a predictable set of local adverse events, including swelling, bruising, and pain. More critically, in the treatment of Peyronie's disease, it carries a risk of severe penile injury, including corporal rupture (penile fracture). This risk necessitated the implementation of a stringent FDA Boxed Warning and a restricted Risk Evaluation and Mitigation Strategy (REMS) program to ensure safe use by trained professionals.[9]

The commercial trajectory of CCH provides a compelling study in the context-dependent nature of a drug's risk-benefit profile. While the adverse events associated with Xiaflex are considered acceptable trade-offs for treating functionally and psychologically debilitating medical conditions, the same fundamental side effect profile, particularly extensive bruising, proved to be a commercial barrier in the elective aesthetics market, leading to the withdrawal of Qwo.[8]

In conclusion, Collagenase clostridium histolyticum stands as a paradigm of targeted enzymatic therapy. Its clinical success is predicated on a combination of potent biochemical action and requisite procedural expertise, while its commercial viability has been sharply defined by the specific risk tolerance of its target patient populations. This monograph provides a comprehensive examination of CCH, detailing its biochemical properties, pharmacological principles, clinical trial evidence, safety profile, and the divergent market histories of its branded formulations.

2.0 Biochemical Profile and Pharmacological Principles

2.1 Identification and Physicochemical Properties

Collagenase clostridium histolyticum is a biotech therapeutic agent classified as a collagen-specific enzyme.[1] As a complex biological product, it is identified and cataloged through a variety of international and regulatory systems to ensure precise tracking and classification. Its primary DrugBank Accession Number is DB00048, and its Chemical Abstracts Service (CAS) Registry Number is 9001-12-1.[1] The FDA's Unique Ingredient Identifier (UNII) code assigned to the substance is 9X7O8V25IT.[1]

The drug is known by numerous synonyms and brand names depending on its formulation and indication. These include the injectable forms Xiaflex and the discontinued Qwo, as well as the topical ointment Santyl. Other historical or chemical synonyms include Euphaulysin and Morikraz.[1] Its therapeutic and chemical properties are further categorized by standardized codes. The Anatomical Therapeutic Chemical (ATC) Classification System assigns it the codes M09AB02 (Other drugs for disorders of the musculo-skeletal system), D03BA02, and D03BA52 (Proteolytic enzymes).[1] The Enzyme Commission (EC) number, which classifies enzymes based on the chemical reactions they catalyze, is 3.4.24.3.[16]

In its therapeutic form, CCH is supplied as a sterile, white, lyophilized (freeze-dried) powder intended for reconstitution before injection.[17] The active components are proteins whose molecular weights range from 68 to 130 kilodaltons (kDa).[14] The solubility of the enzyme complex is dependent on specific buffer conditions; for instance, it is soluble at concentrations of 0.05-0.1 mg/mL in TESCA buffer (50 mM TES, 0.36 mM Calcium chloride, pH 7.4) at 37 °C.[16]

Table 2.1: Drug Identification and Key Properties

Property	Value/Identifier	Source(s)
Generic Name	Collagenase clostridium histolyticum	2
DrugBank ID	DB00048	1
Type	Biotech	User Query
CAS Number	9001-12-1	1
UNII Code	9X7O8V25IT	1
ATC Codes	M09AB02, D03BA02, D03BA52	1
EC Number	3.4.24.3	16
Brand Names	Xiaflex, Qwo (discontinued), Santyl	1
Molecular Weight Range	68-130 kDa	16
Physical Form	Sterile, white, lyophilized powder	18

2.2 Source, Composition, and Enzymatic Characteristics

The biological source of this therapeutic enzyme complex is a specific strain of the bacterium Clostridium histolyticum, which has been known since 1950. The drug product is prepared through a controlled process of anaerobic fermentation.[1] This process yields a crude filtrate containing at least seven different proteases, from which the therapeutic components are purified.[16]

A defining feature of the injectable therapeutic product (Xiaflex, Qwo) is its precise and constant composition. It is a mixture of two distinct, co-purified bacterial collagenases, designated AUX-I and AUX-II.[21] These belong to Class I and Class II clostridial collagenases, respectively.[1] Both are large proteinases, with AUX-I consisting of 1,008 amino acid residues and AUX-II consisting of 991 residues.[1] Their amino acid sequences are known, allowing for a highly characterized and consistent drug product.[21] This dual-enzyme composition is not an incidental feature of its bacterial origin but rather a fundamental aspect of its therapeutic design. The two enzymes act synergistically to achieve a more efficient and comprehensive degradation of the target collagen than either enzyme could accomplish alone, functioning in concert as a "biochemical scalpel" to dismantle pathological tissue structures.[21]

The enzymatic activity of CCH is highly regulated by its biochemical environment. The enzymes are metalloproteinases and require specific divalent metal ions as cofactors for their catalytic function. Notably, Calcium (Ca2+) and Zinc (Zn2+) ions are essential activators.[14] The clinical significance of this requirement is profound; the sterile diluent provided for reconstitution of the lyophilized powder explicitly contains calcium chloride dihydrate to ensure the enzymes are fully active upon injection.[19] Conversely, the activity of CCH is strongly inhibited by metal-chelating agents such as ethylenediaminetetraacetic acid (EDTA) and ethylene glycol tetraacetic acid (EGTA), which sequester these essential cofactors.[14] Other inhibitors include certain metal ions like mercury (

Hg2+) and lead (Pb2+), as well as reducing agents such as cysteine and dithiothreitol (DTT).[14] The optimal pH for CCH stability and activity is in the neutral to slightly alkaline range, approximately 6.3 to 8.8.[14]

2.3 Mechanism of Action: Targeted Enzymatic Fasciotomy

The therapeutic effect of Collagenase clostridium histolyticum is achieved through a direct and targeted enzymatic process that degrades pathological collagen deposits.[3] The primary substrates for CCH are collagen types I and III, which are the principal structural components of the fibrotic cords in Dupuytren's contracture and the dense plaques in Peyronie's disease.[2] These collagen types form a highly stable, triple-helical protein structure that provides tensile strength to connective tissues but becomes pathological when overproduced and disorganized.[24]

The mechanism of collagen lysis by CCH is a sophisticated, multi-step molecular process [24]:

1. Binding and Recognition: The CCH enzymes possess domains that specifically recognize and bind to the triple-helical conformation of native collagen fibrils. This specificity ensures that the enzymatic activity is directed primarily at the target collagen structures.[24]
2. Helix Unwinding: Upon binding, the enzymes initiate a localized unwinding or "melting" of the collagen triple helix. This is a critical step, as it disrupts the stabilizing hydrogen bonds and exposes the individual polypeptide chains that are otherwise protected within the helical core.[24]
3. Peptide Bond Cleavage: With the collagen chains exposed, the catalytic domains of the enzymes can access and cleave the peptide bonds. The two enzymes, AUX-I and AUX-II, work in a complementary fashion to dismantle the collagen molecule. AUX-I, a Class I collagenase, primarily attacks the C- and N-termini of the tropocollagen molecule. In contrast, AUX-II, a Class II collagenase, cleaves internal peptide bonds within the molecule.[21] This synergistic action leads to the rapid and efficient fragmentation of the collagen protein.
4. Solubilization and Lysis: The cleavage of the collagen molecules into smaller fragments disrupts the integrity of the fibril, leading to its solubilization and the overall lysis of the collagen deposit.[1]

The physiological outcome of this molecular process is the weakening and breakdown of the targeted pathological structure. In the context of its clinical applications, this process is effectively a non-surgical, targeted "enzymatic fasciotomy".[4] By dissolving the collagenous cord or plaque, CCH reduces tissue stiffness and allows for the subsequent mechanical disruption and correction of the deformity.[1]

2.4 Pharmacokinetic Profile: Localized Action and Minimal Systemic Exposure

The pharmacokinetic profile of Collagenase clostridium histolyticum is a cornerstone of its therapeutic strategy and safety profile. The drug is designed for localized action with minimal systemic exposure, a property that has been consistently demonstrated in clinical studies.[9]

• Absorption and Distribution: Following intralesional injection of the standard 0.58 mg dose into a Dupuytren's cord or a Peyronie's plaque, systemic absorption of the active enzymes (AUX-I and AUX-II) is negligible and transient. In pharmacokinetic studies involving patients with Dupuytren's contracture, no quantifiable plasma levels of either enzyme were detected for up to 30 days post-injection.[9] In studies of patients with Peyronie's disease, where quantifiable levels were detected in some subjects, the plasma concentrations were minimal (maximal concentrations <29 ng/mL for AUX-I and <71 ng/mL for AUX-II) and extremely short-lived, falling below the limits of quantification within 30 minutes of dosing.[9] Crucially, there is no evidence of systemic accumulation of the enzymes following repeated injections.[9] The drug is presumed to remain largely at the site of injection, where it exerts its therapeutic effect.[21]
• Metabolism and Excretion: Due to the lack of significant systemic exposure, the enzymes are not expected to reach major metabolic organs like the liver in meaningful concentrations. It is presumed that the protein-based enzymes are locally catabolized at the injection site by endogenous proteases into smaller peptides and amino acids, which then enter the body's general amino acid pool.[21] Consequently, formal systemic metabolism and excretion studies, which are standard for systemically acting drugs, have not been conducted and are not considered necessary.[21]

This pharmacokinetic profile, characterized by highly localized action, is the key enabler of the entire therapeutic concept. It allows for the safe administration of a potent proteolytic enzyme directly into target tissues. This profile dictates that the drug's safety is almost entirely a function of its local effects and the precision of its administration. It explains why systemic side effects are rare and why systemic drug-drug interaction studies are not required. This understanding underpins the entire risk management strategy for the drug, which focuses on mitigating local, mechanism-based adverse events through procedural training and careful patient selection, rather than managing systemic toxicity.

3.0 Clinical Efficacy and Therapeutic Applications

3.1 Indication: Dupuytren's Contracture

3.1.1 Pathophysiology and Rationale for Collagenase Therapy

Dupuytren's contracture is a progressive, benign fibroproliferative disorder affecting the palmar fascia of the hand.[2] The pathophysiology involves the abnormal thickening and shortening of this connective tissue, leading to the formation of discrete nodules and, subsequently, dense, rope-like cords rich in type I and type III collagen.[2] As these cords mature and contract, they pull the fingers—most commonly the ring and small fingers—into a state of permanent flexion at the metacarpophalangeal (MP) and/or proximal interphalangeal (PIP) joints. This results in a debilitating loss of hand function, making it difficult or impossible to perform activities of daily living such as grasping objects, shaking hands, or placing a hand flat on a surface.[25]

The therapeutic rationale for using Collagenase clostridium histolyticum is to directly address the underlying pathology. By injecting the enzyme complex directly into the palpable collagen cord, the treatment aims to achieve an "enzymatic fasciotomy," lysing the collagen fibers that are responsible for the contracture.[23] This offers a minimally invasive, non-surgical alternative to traditional treatments like open fasciectomy (surgical removal of the cord) or percutaneous needle fasciotomy (mechanical disruption with a needle), which have been the mainstays of treatment for nearly two centuries.[4]

3.1.2 Critical Analysis of Pivotal Phase III Clinical Trials (Studies 1 & 2)

The efficacy of Xiaflex for Dupuytren's contracture was established in two pivotal, multicenter, randomized, double-blind, placebo-controlled Phase III trials, referred to as Study 1 and Study 2.[9] These trials enrolled a total of 374 adult patients who presented with at least one finger flexion contracture of 20° to 100° at an MP joint or 20° to 80° at a PIP joint, a palpable cord, and a positive "tabletop test" (the inability to place the affected finger and palm flat on a table).[9]

The treatment protocol involved up to three injections of 0.58 mg of Xiaflex or placebo administered into the cord affecting the primary joint at approximately 30-day intervals. A critical component of the therapy occurred approximately 24 hours after each injection, when the investigator performed a passive finger extension procedure designed to mechanically rupture the enzymatically weakened cord. This two-step process—enzymatic weakening followed by mechanical disruption—is fundamental to the treatment's success. Following the procedure, patients were fitted with a splint for nighttime use and instructed to perform daily finger exercises.[9]

The primary efficacy endpoint was the proportion of patients who achieved a reduction in contracture of the primary joint to within 0° to 5° of normal (full extension), measured 30 days after the last injection.[9] The results demonstrated a profound and statistically significant superiority of Xiaflex over placebo.

• In Study 1, 64% of patients in the Xiaflex group achieved the primary endpoint, compared to only 7% in the placebo group.
• In Study 2, the success rates were 44% for the Xiaflex group versus 5% for the placebo group.[9]

The data also revealed a notable difference in efficacy based on the affected joint, a finding that reflects the underlying anatomical challenges of the condition. Treatment of contractures at the MP joint was more successful than at the PIP joint. In a pooled analysis, success rates for MP joints were significantly higher than for the more complex and difficult-to-treat PIP joints.[9] This differential efficacy is not a failure of the drug but an important clinical nuance, highlighting that the drug's effectiveness is modulated by the anatomical and pathological realities of the target tissue. The more complex ligamentous and capsular structures surrounding the PIP joint can contribute to contractures that are not solely caused by the palpable cord, thus limiting the potential for complete correction by cord lysis alone.[26]

Secondary outcomes, such as the mean improvement in range of motion, further supported the primary findings, with Xiaflex-treated patients showing significantly greater increases in joint mobility compared to placebo-treated patients.[9]

Table 3.1: Summary of Pivotal Trial Results for Dupuytren's Contracture

Endpoint	Study 1 (Xiaflex)	Study 1 (Placebo)	Study 2 (Xiaflex)	Study 2 (Placebo)	Source(s)
Primary Endpoint Success (0-5° Contracture)
All Joints	64%	7%	44%	5%	9
MP Joints	77%	7%	65%	9%	9
PIP Joints	40%	6%	28%	0%	9
Secondary Endpoint (Mean Improvement in Range of Motion)
All Joints	36°	4°	35°	8°	9
MP Joints	41°	4°	40°	9°	9
PIP Joints	28°	5°	32°	7°	9

3.1.3 Long-Term Efficacy, Recurrence Rates, and Retreatment Outcomes

Recurrence is a well-known characteristic of Dupuytren's disease, regardless of the treatment modality employed.[27] Long-term observational follow-up of patients from the pivotal trials (Study 4) was conducted to assess the durability of the treatment effect.[9] While specific data from this study is not fully detailed in the provided materials, other sources suggest a 5-year recurrence rate of approximately 47% following CCH treatment, a figure that is within the range reported for surgical interventions.[28]

The potential for retreatment is a key consideration for a chronic, recurrent condition. A subsequent open-label study (Study 5) specifically evaluated the efficacy of retreating patients from Study 4 who had experienced a recurrence in a previously successfully treated joint. The results were promising, demonstrating that retreatment with Xiaflex was effective. In this cohort, 65% of recurrent MP joints and 45% of recurrent PIP joints once again achieved clinical success (reduction of contracture to 0-5°) after a new course of treatment.[9] This indicates that CCH remains a viable option for managing recurrent disease over the long term.

3.2 Indication: Peyronie's Disease

3.2.1 Pathophysiology and the Role of Collagen Plaque

Peyronie's disease (PD) is an acquired connective tissue disorder of the penis, widely considered to be a result of abnormal wound healing following acute or repetitive microtrauma to the tunica albuginea.[29] This process triggers an excessive inflammatory response and the subsequent deposition of fibrin, which in turn stimulates profibrotic cytokines like transforming growth factor-

β1 (TGF-β1).[29] The result is the formation of a dense, inelastic, and sometimes calcified fibrotic plaque, composed primarily of type I and III collagen, within the normally elastic tunica albuginea.[2] This plaque restricts tissue expansion during erection, leading to the characteristic symptoms of PD: penile curvature or deformity, pain during erection, and often, significant psychological distress and erectile dysfunction.[22]

The rationale for using CCH in PD is analogous to its use in Dupuytren's contracture: to enzymatically target and degrade the pathological collagen that constitutes the plaque.[29] By breaking down the plaque's collagenous scaffold, the treatment aims to reduce the penile curvature and improve the physical and psychological burdens of the disease, offering the first and only FDA-approved non-surgical treatment option for this condition.[6]

3.2.2 Critical Analysis of the IMPRESS I & II Pivotal Trials

The approval of Xiaflex for PD was based on the robust evidence from two identical, large-scale, randomized, double-blind, placebo-controlled Phase III trials known as IMPRESS I and IMPRESS II (The Investigation for Maximal Peyronie's Reduction Efficacy and Safety Studies).[6] These landmark studies enrolled a combined total of 832 men with stable PD, a palpable plaque, and a penile curvature deformity between 30° and 90°.[11]

The treatment protocol was intensive. Patients were randomized in a 2:1 ratio to receive either Xiaflex or placebo for up to four treatment cycles, spaced approximately six weeks apart. Each cycle consisted of two injections of 0.58 mg of the study drug administered directly into the plaque 24 to 72 hours apart. Following the second injection of each cycle, a crucial "penile modeling" procedure was performed by the investigator to mechanically stretch and disrupt the enzymatically weakened plaque. Patients were also instructed to perform gentle, at-home penile modeling exercises daily between cycles.[11] The inclusion of this mechanical modeling component underscores that, as with Dupuytren's contracture, the treatment is a combination of enzymatic and physical intervention.

The trials were designed with two co-primary endpoints to capture both the physical and psychological impact of the disease:

1. The percentage improvement in penile curvature deformity from baseline to week 52.
2. The change from baseline to week 52 in the "Bother" domain score of the validated Peyronie's Disease Questionnaire (PDQ), which measures the degree to which a patient is troubled by their symptoms.[6]

A post-hoc meta-analysis of the combined data from both trials demonstrated that Xiaflex was statistically superior to placebo on both co-primary endpoints. CCH-treated men experienced a mean 34.0% improvement in penile curvature, which corresponded to a mean absolute reduction of 17.0°. In contrast, the placebo group, which also underwent the modeling procedures, showed a mean improvement of 18.2%, or a 9.3° absolute reduction. The difference between the groups was highly statistically significant (p < 0.0001).[10] Equally important was the impact on patient-reported outcomes. The mean change in the PDQ Bother score was significantly greater in the Xiaflex group (-2.8) compared to the placebo group (-1.8), with a p-value of 0.0037.[10] This dual success confirmed that the treatment not only physically straightened the penis but also meaningfully reduced the psychological burden of the disease.

Table 3.2: Summary of IMPRESS I & II Trial Results for Peyronie's Disease (Meta-Analysis)

Endpoint	Xiaflex Group	Placebo Group	P-value	Source(s)
Co-Primary Endpoint 1: Penile Curvature Improvement
Mean Percent Change from Baseline	34.0%	18.2%	< 0.0001	10
Mean Absolute Change from Baseline	-17.0° (± 14.8°)	-9.3° (± 13.6°)	< 0.0001	10
Co-Primary Endpoint 2: PDQ Bother Score
Mean Change from Baseline	-2.8 (± 3.8)	-1.8 (± 3.5)	0.0037	10

3.2.3 Post-Approval Studies and Impact on Patient-Reported Outcomes

Post-approval studies and meta-analyses have generally corroborated the findings of the IMPRESS trials, confirming the clinical efficacy and safety profile of CCH for PD.[22] An open-label Phase III study published in 2015 reproduced the results, showing a similar mean improvement in penile curvature (34.4%) and change in PDQ bother score (-3.3).[11]

However, it is also important to note that real-world experience may differ from the highly controlled environment of a clinical trial. One retrospective study from a high-volume institution reported a less robust response to CCH than seen in the pivotal trials and noted a high degree of patient dissatisfaction, primarily related to a perceived lack of change in curvature.[32] This highlights a critical aspect of treatment: the necessity for thorough and realistic patient counseling prior to initiating therapy. The significant improvement in the PDQ "Bother" score remains a key outcome, as it demonstrates that even if complete straightening is not achieved, the reduction in deformity can have a profound positive impact on a patient's quality of life and psychological well-being.[10]

3.3 Indication: Edematous Fibrosclerotic Panniculopathy (Cellulite)

3.3.1 Pathophysiology and the Targeting of Fibrotic Septae

Cellulite, clinically known as edematous fibrosclerotic panniculopathy or gynoid lipodystrophy, is a multifactorial condition that results in a dimpled or "orange-peel" appearance of the skin, most commonly on the buttocks and thighs of women.[2] The underlying pathophysiology involves the interplay of several factors, but a key structural component is the network of fibrous septae—collagen-rich connective tissue bands—that run vertically from the deep dermis through the subcutaneous fat layer to the underlying fascia.[2] In individuals with cellulite, these septae become tense and shortened, tethering the skin down. Simultaneously, subcutaneous fat lobules herniate upwards between these tethers, creating the characteristic dimpled surface topography.[2]

The therapeutic rationale for using CCH to treat cellulite was to directly target and lyse these collagen-rich fibrous septae.[1] By injecting the enzyme into the areas of cellulite dimpling, the goal was to enzymatically release the septal tethers, allowing the skin to smooth out and reducing the visible signs of cellulite.[1]

3.3.2 Clinical Development and Regulatory Approval of Qwo

Following this rationale, Endo International, through its Endo Aesthetics division, developed an injectable formulation of CCH specifically for this indication under the brand name Qwo.[1] After successful completion of Phase 2 and Phase 3 clinical trials that demonstrated its efficacy in reducing the severity of cellulite, Qwo received approval from the U.S. FDA on July 6, 2020. This marked a significant milestone, as Qwo became the first-ever FDA-approved injectable treatment for moderate to severe cellulite in the buttocks of adult women.[1]

3.4 Ancillary Therapeutic and Research Applications

Beyond its use as a targeted injectable therapy, collagenase derived from Clostridium histolyticum has long-standing applications in other areas of medicine and biomedical research.

• Enzymatic Debridement: A topical ointment formulation of collagenase, marketed under the brand name Santyl, is widely used for the enzymatic debridement of chronic dermal ulcers (such as pressure sores or diabetic ulcers) and severely burned tissues.[1] In this application, the enzyme selectively digests the necrotic, denatured collagen that comprises the eschar and slough in a wound bed. By removing this non-viable tissue, the treatment promotes a healthier wound environment conducive to healing.[1]
• Research Tool for Tissue Dissociation: In laboratory settings, purified collagenase from C. histolyticum is an indispensable tool for biomedical research.[14] It is used to digest the extracellular matrix of tissue samples to liberate individual cells for primary cell culture. This technique is essential for isolating a wide variety of cell types, including pancreatic islets for diabetes research, hepatocytes from liver tissue, epithelial cells, and adrenal cells, among others.[16] Different preparations of collagenase (e.g., Type I, II, IV) with varying levels of other proteolytic activities are available to optimize cell isolation from different tissue types.[20]

4.0 Safety, Tolerability, and Risk Management

4.1 Comprehensive Adverse Event Profile

The adverse event (AE) profile of Collagenase clostridium histolyticum is overwhelmingly characterized by local, injection-site reactions that are a direct and predictable consequence of its enzymatic mechanism of action.[28] The digestion of collagen and disruption of the local tissue architecture, including small blood vessels, inevitably leads to a consistent constellation of AEs across all its injectable indications.

• Dupuytren's Contracture AEs: In the pivotal clinical trials for Dupuytren's contracture, the most common AEs (reported in ≥ 25% of patients treated with Xiaflex and at a higher incidence than placebo) were edema peripheral (swelling of the injected hand), contusion (bruising), injection site hemorrhage, injection site reaction, and pain in the injected extremity.[9] Other common local reactions included tenderness, pruritus (itching), lymphadenopathy (swollen lymph nodes), and skin lacerations, which can occur during the finger extension procedure.[9]
• Peyronie's Disease AEs: Similarly, for the Peyronie's disease indication, the most frequently reported AEs (≥ 25%) were penile hematoma (a collection of blood under the skin, or severe bruising), penile swelling, and penile pain.[9] These events are expected sequelae of injecting a proteolytic enzyme into the vascular penile tissue.
• Cellulite (Qwo) AEs: For the aesthetic treatment of cellulite, the primary AE of concern was bruising at the injection sites. While bruising is an expected outcome, the extent, variability, and potential for prolonged skin discoloration in patients treated with Qwo raised significant market concerns. This patient and provider perception of the AE profile ultimately led to the product's commercial discontinuation, illustrating how the acceptability of an AE is highly dependent on the clinical context and indication.[8]

Table 4.1: Comparative Common and Serious Adverse Events by Indication

Adverse Event	Dupuytren's Contracture (% Incidence)	Peyronie's Disease (% Incidence)	Source(s)
Most Common AEs (≥25%)
Edema / Swelling	73% (peripheral edema)	55.0% (penile swelling)	9
Hematoma / Contusion / Bruising	70% (contusion)	65.5% (penile hematoma)	9
Injection Site Hemorrhage	38%	N/A (covered by hematoma)	9
Pain	35% (in injected extremity)	45.4% (penile pain)	9
Injection Site Reaction	35%	N/A	9
Serious AEs
Tendon Rupture / Ligament Damage	0.3% (flexor tendon rupture)	N/A	9
Corporal Rupture / Penile Fracture	N/A	0.5%	9
Severe Hematoma	N/A	3.7%	9

4.2 In-Depth Analysis of the Boxed Warning

The most significant risk associated with Xiaflex is detailed in an FDA Boxed Warning, the agency's most stringent safety alert. This warning applies specifically to its use in the treatment of Peyronie's disease and highlights the risk of corporal rupture (penile fracture) or other serious penile injury.[9]

This severe adverse event is a direct extension of the drug's potent, localized mechanism of action. The corpora cavernosa, the two erectile chambers of the penis, are encased by the collagen-rich tunica albuginea, the very structure targeted by the therapy. An errant or overly deep injection can inadvertently introduce the enzyme into the corpora cavernosa itself or excessively weaken the tunica, making it susceptible to rupture during a subsequent erection.[9]

In the extensive clinical trial program for PD, which included 1,044 patients treated with Xiaflex, corporal rupture was confirmed as an adverse reaction in 5 patients (0.5%). An additional 9 patients (0.9%) reported a combination of symptoms highly suggestive of corporal rupture—such as a penile "popping" sound or sensation, sudden penile detumescence, and severe ecchymosis or hematoma—where a definitive diagnosis of rupture could not be excluded. Furthermore, severe penile hematoma, which may require surgical drainage, was reported in 39 patients (3.7%).[9] Signs and symptoms that may indicate a serious penile injury, such as a popping sound, sudden loss of erection, severe pain, swelling and bruising, or difficulty urinating, require prompt medical evaluation, as surgical intervention may be necessary.[9]

4.3 The XIAFLEX REMS Program

Given the severity of the potential for corporal rupture, the FDA mandated that Xiaflex for the Peyronie's disease indication be available only through a restricted distribution program known as a Risk Evaluation and Mitigation Strategy (REMS).[6] The existence of this REMS program is a formal regulatory acknowledgment that the drug's safety is inextricably linked to the procedural skill of the person administering it.

The REMS program includes Elements to Assure Safe Use (ETASU), which are specific, required interventions beyond standard professional labeling to mitigate a known serious risk.[6] For Xiaflex, the REMS program requires that:

1. Prescribers must be certified: Healthcare providers who prescribe Xiaflex for PD must be specially trained on the condition, the proper injection technique to avoid injuring underlying structures, and the potential risks. They must enroll in the program to become certified.[6]
2. Healthcare settings must be certified: The facilities where the drug is administered must also be certified, ensuring they have the necessary resources to manage potential adverse events.[6]

This program effectively codifies the "procedural imperative" of the treatment, making the skill of the user a formal component of the drug's official safety apparatus. It ensures that the therapy is delivered only by clinicians who understand the precise anatomical targets and the techniques required to minimize the risk of severe, mechanism-based injury.

4.4 Contraindications, Warnings, and Precautions

Beyond the Boxed Warning, the prescribing information for CCH includes several other important safety limitations.

• Contraindications: CCH is contraindicated in patients with a known history of hypersensitivity to collagenase or any of the excipients in the formulation.[8] For the Peyronie's disease indication, it is specifically contraindicated for the treatment of plaques that involve the penile urethra, due to the risk of causing permanent damage to this structure.[39]
• Warnings for Dupuytren's Contracture: The primary warning for this indication is the risk of tendon rupture or other serious injury to the injected hand. The prescribing information emphasizes that injections must be carefully placed to avoid direct administration into tendons, nerves, blood vessels, or other critical collagen-containing structures, as this could result in permanent injury such as tendon rupture, ligament damage, or complex regional pain syndrome.[9]
• Precautions: CCH should be used with caution in patients with coagulation disorders or those receiving anticoagulant medications (with the exception of low-dose aspirin up to 150 mg per day).[9] Patients with abnormal coagulation were excluded from the pivotal clinical trials, so the safety and efficacy in this population are unknown. The potential for increased bleeding and hematoma formation at the injection site is the primary concern.[2]

4.5 Immunogenicity and Drug Interaction Profile

As a foreign protein administered to humans, CCH is expectedly immunogenic.

• Antibody Formation: Clinical studies have shown that the vast majority of patients develop neutralizing antibodies to both active enzyme components, AUX-I and AUX-II, after treatment. In the Dupuytren's contracture studies, 92% of patients developed antibodies to AUX-I and 86% to AUX-II after just the first injection; after four injections, virtually all patients had high antibody titers.[9] Similarly, in the Peyronie's disease studies, after the full course of eight injections, over 99% of patients developed high titers of antibodies to both enzymes.[9]
• Clinical Significance of Antibodies: The development of high-titer, neutralizing antibodies against a biologic therapeutic would typically raise significant concerns about potential loss of efficacy over time (due to neutralization) or an increased risk of hypersensitivity reactions. However, in the case of CCH, this robust immune response appears to be clinically benign. Extensive analyses found no apparent correlation between antibody frequency, titers, or neutralizing status and either the clinical response or the incidence of adverse reactions, including systemic allergic reactions, which are rare (<1% of patients).[9] This suggests that for a locally acting, rapidly degraded enzyme, the systemic immune response may be largely decoupled from the clinical outcomes at the target site. This finding is significant for the development of other localized biologic therapies, as it suggests that immunogenicity may serve more as a biomarker of exposure rather than a predictor of adverse outcomes.
• Drug Interactions: Due to its localized action and minimal systemic exposure, no formal drug interaction studies have been conducted.[21] It is theorized that concomitant use of drugs that interfere with matrix metalloproteinases, such as tetracycline antibiotics, could potentially reduce the efficacy of CCH, but this has not been observed clinically.[21] The primary interaction of concern is with anticoagulant and antiplatelet drugs, which can increase the risk or severity of bleeding and bruising at the injection site.[2]

5.0 Regulatory and Commercial Landscape

5.1 Regulatory History and Key Milestones

The regulatory journey of Collagenase clostridium histolyticum has been marked by a series of landmark approvals that established it as a first-in-class therapy for multiple conditions. The development was initially driven by BioSpecifics Technologies Corp. and brought to market by Auxilium Pharmaceuticals, which was later acquired by Endo International.[5]

• Xiaflex for Dupuytren's Contracture: On February 3, 2010, the U.S. FDA approved Xiaflex for the treatment of adult patients with Dupuytren's contracture with a palpable cord. This was a significant event, introducing the first non-surgical, drug-based treatment for a condition that had historically been managed primarily by invasive surgical procedures.[4]
• Xiaflex for Peyronie's Disease: On December 6, 2013, Xiaflex received its second major FDA approval, for the treatment of adult men with Peyronie's disease with a palpable plaque and curvature deformity of at least 30 degrees. This approval was another milestone, as Xiaflex became the first and only FDA-approved drug treatment for this physically and psychologically distressing disorder.[5]
• Qwo for Cellulite: On July 6, 2020, a formulation of CCH developed by Endo Aesthetics under the brand name Qwo was approved by the FDA for the treatment of moderate to severe cellulite in the buttocks of adult women. This marked the entry of CCH into the lucrative aesthetics market and was the first injectable treatment ever approved for cellulite.[7]

5.2 The Case of Qwo: A Commercial Post-Mortem

The story of Qwo provides a powerful case study on the critical importance of product-market fit and the context-dependent nature of a drug's risk-benefit profile.

• Launch and Market Position: Qwo was launched with significant anticipation into the medical aesthetics market. Cellulite is a widespread concern with a large, motivated patient base and a significant unmet need for effective, non-invasive treatments. Qwo, as the first FDA-approved injectable, was positioned to be a disruptive and highly successful product.[1]
• The Bruising Problem: Despite demonstrating clinical efficacy in releasing the fibrous septae that cause cellulite, the treatment was plagued by a significant side effect: bruising. While bruising is an expected and well-documented AE for Xiaflex, its manifestation in the context of an elective aesthetic procedure proved problematic. Patients and providers reported concerns about the extent, variability, and in some cases, the prolonged duration of bruising and skin discoloration following Qwo injections.[8]
• Market Rejection and Discontinuation: Endo Aesthetics actively worked to address these concerns. In June 2022, the company initiated the APHRODITE study, an open-label trial designed to test various interventions aimed at mitigating the bruising. While some modest reductions were observed, none of the strategies achieved a consistent level of improvement sufficient to alleviate the market's concerns.[8] Consequently, on December 6, 2022, Endo International announced that it was ceasing all production and sale of Qwo, concluding that it did not represent a viable commercial opportunity.[8]
• Analysis: The failure of Qwo was not a failure of its biochemical mechanism but a failure of its product-market fit. The same active pharmaceutical ingredient, with the same mechanism of action and the same primary local side effect (bruising/hematoma), was a successful therapeutic for serious medical needs but a commercial failure for an aesthetic one. The risk-benefit calculus is entirely indication-specific. For a patient with Dupuytren's contracture, significant bruising is an acceptable trade-off for restoring hand function. For a patient with Peyronie's disease, penile hematoma is a tolerated risk in exchange for reduced deformity and psychological distress. However, for a consumer seeking cosmetic improvement for cellulite, extensive and unpredictable bruising was not an acceptable "cost" for the aesthetic benefit. This history serves as a crucial reminder that a drug's ultimate value is defined not in a vacuum, but by the specific problem it solves and the subjective risk tolerance of its target population.

5.3 Brand and Manufacturer Overview

Several corporate entities have been involved in the development and commercialization of CCH-based products.

• Key Entities: The foundational technology was developed by BioSpecifics Technologies Corp..[5] Auxilium Pharmaceuticals was responsible for obtaining the initial FDA approvals for Xiaflex.[5] Endo International plc subsequently acquired Auxilium and now markets Xiaflex through its Endo Pharmaceuticals division. The discontinued Qwo was marketed through its Endo Aesthetics affiliate.[8]
• Brand Names: The primary brand names associated with CCH are:
• Xiaflex: The injectable formulation for Dupuytren's contracture and Peyronie's disease.[15]
• Qwo: The discontinued injectable formulation for cellulite.[15]
• Santyl: A topical ointment formulation for enzymatic wound debridement.[1]

6.0 Prescribing and Administration Guidelines

The administration of Xiaflex is a precise medical procedure that requires adherence to specific protocols for reconstitution, dosing, and post-injection management. These protocols differ between its two approved indications.

6.1 Formulation, Reconstitution, and Handling Protocols

• Contents and Storage: Each Xiaflex kit contains one single-use vial with 0.9 mg of lyophilized CCH powder and one single-use vial of sterile diluent. The vials must be stored upright in a refrigerator at 2°C to 8°C (36°F to 46°F) and must not be frozen.[19]
• Reconstitution: Proper reconstitution is critical for ensuring the drug's activity and correct dosage.

1. The vials should be removed from the refrigerator and allowed to stand at room temperature for at least 15 minutes but no more than 60 minutes before use.[19]
2. Only the supplied sterile diluent must be used for reconstitution. This is a critical step because the diluent contains calcium chloride, a necessary cofactor for the collagenase enzymes' activity.[19]
3. Using aseptic technique, the appropriate volume of diluent is withdrawn and slowly injected down the side of the vial containing the lyophilized powder. The volume of diluent is indication-specific:

• For cords affecting an MP joint in Dupuytren's contracture: 0.39 mL.[19]
• For cords affecting a PIP joint in Dupuytren's contracture: 0.31 mL.[19]
• For Peyronie's disease: The prescribing information specifies reconstitution to deliver a 0.58 mg dose, with specific volumes detailed in the full instructions.

4. The vial should be gently swirled until the powder is completely dissolved. Shaking or inverting the vial should be avoided to prevent denaturation of the enzymes.[19]
5. The reconstituted solution should be used within 1 hour if kept at room temperature, or within 4 hours if refrigerated and then brought back to room temperature before use.[19]

6.2 Dosing and Administration for Dupuytren's Contracture

• Dosage: The recommended dose of Xiaflex is 0.58 mg administered via a single injection into a palpable Dupuytren's cord.[9]
• Injection Procedure: The injection must be performed by a healthcare provider experienced in injection procedures of the hand. The needle is inserted into the cord, and the dose is distributed. Care must be taken to avoid injecting into tendons, nerves, or blood vessels.[39] Up to two cords or two joints on the same hand may be treated during a single treatment visit.[9]
• Post-Injection Care: Immediately following the injection, the patient's hand is wrapped in a soft, bulky dressing. The patient is instructed to keep the hand elevated until bedtime and to limit movement of the treated finger to minimize diffusion of the enzyme away from the cord.[19]
• Finger Extension Procedure: Approximately 24 to 72 hours after the injection, the patient returns to the provider's office. If the contracture persists, the provider performs a passive finger extension procedure. This is a firm, steady extension of the treated finger for 10-20 seconds to facilitate the rupture of the enzymatically weakened cord. Local anesthesia may be used.[9]
• Follow-Up and Retreatment: This entire cycle of injection and finger extension may be repeated up to three times for a single cord, with procedures spaced approximately four weeks apart.[9] Following the final extension procedure, patients are fitted with a splint to be worn at bedtime for up to four months and are instructed to perform a series of finger flexion and extension exercises several times a day for several months to maintain mobility.[9]

6.3 Dosing and Administration for Peyronie's Disease

• Dosage: The dose is 0.58 mg per injection, administered directly into the Peyronie's plaque that is causing the curvature deformity.[6]
• Treatment Cycle: A full treatment course for Peyronie's disease consists of a maximum of four treatment cycles. Each cycle involves two 0.58 mg injections, administered 24 to 72 hours apart. The interval between treatment cycles is approximately six weeks. Therefore, a complete course of therapy involves a maximum of eight injections.[11]
• Penile Modeling Procedure: A critical component of the therapy is penile modeling. One to three days after the second injection of each cycle, the healthcare provider performs an in-office modeling procedure, gently stretching the penis to elongate the treated plaque. In addition, the patient is instructed on how to perform gentle at-home penile modeling activities for six weeks following each treatment cycle.[6]
• Post-Treatment Restrictions: Due to the risk of corporal rupture, patients are given strict instructions to avoid sexual activity (intercourse or other activities) between the first and second injections of a cycle, and for at least four weeks after the second injection of each cycle, and until any pain and swelling have completely resolved.[30]

Table 6.1: Dosing and Administration Summary for Xiaflex

Parameter	Indication: Dupuytren's Contracture	Indication: Peyronie's Disease
Reconstitution Diluent Volume	0.39 mL (MP joint) or 0.31 mL (PIP joint)	Per prescribing information to yield 0.58 mg
Dose per Injection	0.58 mg	0.58 mg
Injections per Cycle	1	2 (administered 24-72 hours apart)
Max Cycles/Injections	Up to 3 injections per cord	Up to 4 cycles (8 injections) per plaque
Interval Between Cycles	Approx. 4 weeks	Approx. 6 weeks
Required Follow-up Procedure	Finger Extension Procedure (24-72 hours post-injection)	Penile Modeling Procedure (1-3 days after 2nd injection)
Post-Procedure Care	Nighttime splinting (up to 4 months), daily exercises	At-home penile modeling (6 weeks), sexual activity restrictions

7.0 Synthesis and Expert Insights

7.1 Comparative Analysis of Risk-Benefit Across Indications

The clinical and commercial history of Collagenase clostridium histolyticum provides a masterclass in the principle that a drug's value and acceptability are not absolute but are defined by the specific clinical context in which it is used. The divergent fates of Xiaflex and Qwo, two brands based on the identical active pharmaceutical ingredient, serve as a stark illustration of this indication-specific risk-benefit calculus.

For Dupuytren's contracture and Peyronie's disease, Xiaflex is used to treat conditions that cause significant functional impairment and deep psychological distress. A patient with Dupuytren's contracture faces the progressive loss of hand function, impacting their livelihood and daily activities. A patient with Peyronie's disease contends with penile deformity, pain, and often devastating effects on sexual function and self-esteem. In these contexts, the adverse event profile of Xiaflex—including significant local swelling, bruising, pain, and even the rare but serious risks of tendon rupture or corporal fracture—is generally considered an acceptable trade-off for the potential to restore function and alleviate suffering. The "benefit" of treatment is substantial and directly addresses a pressing medical need.

In stark contrast, Qwo was developed for cellulite, a condition that is cosmetically undesirable but medically benign. The "unmet need" was purely aesthetic. For this consumer base, the very same mechanism-based side effects, particularly the high incidence and unpredictable nature of extensive bruising and potential for long-term discoloration, were not perceived as an acceptable trade-off. The "risk" of a significant and visible recovery period outweighed the "benefit" of cosmetic improvement. This demonstrates that the commercial viability of a therapeutic is determined not just by its FDA-approved efficacy but by the subjective risk tolerance of its target market, which is scaled to the severity of the problem being solved.

7.2 The Procedural Imperative: A Drug-Procedure Symbiosis

A central theme that emerges from a thorough analysis of CCH is that its success is not solely a pharmacological phenomenon. The treatment paradigm for both Dupuytren's contracture and Peyronie's disease represents a true symbiosis between the biochemical action of the drug and the mechanical force of a subsequent physical procedure. The enzyme's role is to act as a "biochemical tool" that selectively weakens the pathological collagen structure. However, the definitive therapeutic outcome—the rupture of the cord or the remodeling of the plaque—is achieved only through the application of external force via the finger extension or penile modeling procedures.

This drug-procedure symbiosis has profound implications. First, it places a heavy emphasis on the skill and training of the administering healthcare provider. The precision of the injection and the correct performance of the follow-up manipulation are critical variables that directly influence both efficacy and safety. The FDA's mandate for a REMS program for the Peyronie's disease indication is the ultimate regulatory codification of this principle, acknowledging that the drug's safety cannot be assured by its label alone but requires active control over the procedural competency of the user. Second, it introduces patient adherence as a key factor in the treatment's success, particularly in Peyronie's disease, where at-home modeling is required. Finally, it complicates the attribution of outcomes, as success or failure is a product of both the drug's effect and the quality of the associated procedure.

7.3 Future Perspectives

The story of Collagenase clostridium histolyticum offers valuable lessons and points toward future avenues of research and development.

• Future Research: The established efficacy and safety profile of CCH invites exploration into other localized fibrotic conditions. Pathologies characterized by accessible, focal collagen deposits, such as adhesive capsulitis ("frozen shoulder") or postsurgical adhesions and scar tissue, could be potential future targets. Further research could also focus on optimizing existing protocols to minimize adverse events, such as the bruising that led to Qwo's demise, or exploring the efficacy of treatment courses beyond the initially studied eight injections for Peyronie's disease. The development of next-generation, bioengineered collagenases with enhanced specificity for pathological collagen or improved safety profiles represents another promising frontier.
• Lessons for Enzymatic Therapies: The development of CCH provides a powerful template for future locally administered, enzyme-based therapeutics. Key lessons include the critical importance of a deep understanding of the target anatomy to ensure precise delivery and avoid off-target effects. It highlights the need to anticipate and proactively manage mechanism-based adverse events, which are often predictable extensions of the enzyme's desired activity. Most importantly, the contrasting stories of Xiaflex and Qwo underscore the necessity of aligning a product's entire profile—including its side effects and recovery timeline—with the specific needs and risk tolerance of the intended market.
• Concluding Statement: Collagenase clostridium histolyticum represents a triumph of targeted biochemical engineering, providing a potent and effective tool for non-surgical tissue remodeling. Its clinical and commercial history, however, serves as a crucial and enduring reminder that in the complex ecosystem of medicine and healthcare, a drug's ultimate success is measured not only by the elegance of its mechanism but by its thoughtful and judicious application within a specific clinical, procedural, and human context.

Works cited

1. Collagenase Clostridium Histolyticum - PubChem, accessed August 19, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Collagenase-Clostridium-Histolyticum
2. Collagenase clostridium histolyticum: Uses, Interactions, Mechanism ..., accessed August 19, 2025, https://go.drugbank.com/drugs/DB00048
3. go.drugbank.com, accessed August 19, 2025, https://go.drugbank.com/drugs/DB00048#:~:text=The%20collagen%20deposition%20in%20the,target%20of%20collagenase%20enzyme%20therapy.&text=These%20enzymes%20are%20proteinases%20acting,plaques%20associated%20with%20several%20conditions.
4. FDA approves Collagenase for Dupuytren's, accessed August 19, 2025, https://dupuytrens.org/fda-approves-collagenase-for-dupuytrens/
5. Xiaflex (collagenase clostridium histolyticum) FDA Approval History ..., accessed August 19, 2025, https://www.drugs.com/history/xiaflex.html
6. FDA approves drug treatment for Peyronie's disease - Urology Times, accessed August 19, 2025, https://www.urologytimes.com/view/fda-approves-drug-treatment-peyronies-disease
7. Qwo (collagenase clostridium histolyticum-aaes) FDA Approval History - Drugs.com, accessed August 19, 2025, https://www.drugs.com/history/qwo.html
8. Endo to Cease Production and Sale of Qwo® (collagenase clostridium histolyticum-aaes), accessed August 19, 2025, https://investor.endo.com/2022-12-06-Endo-to-Cease-Production-and-Sale-of-Qwo-R-collagenase-clostridium-histolyticum-aaes
9. This label may not be the latest approved by FDA. For current ..., accessed August 19, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125338s109lbl.pdf
10. Clinical Efficacy, Safety and Tolerability of Collagenase Clostridium Histolyticum for the Treatment of Peyronie Disease in 2 La, accessed August 19, 2025, https://med-fom-urlgsci.sites.olt.ubc.ca/files/2007/06/Collagenase_Phase_3_RCTs_-_JUrol_20131.pdf
11. Collagenase Clostridium histolyticum in the treatment of Peyronie's disease: patient selection and perspectives - Dove Medical Press, accessed August 19, 2025, https://www.dovepress.com/collagenase-clostridium-histolyticum-in-the-treatment-of-peyroniersquo-peer-reviewed-fulltext-article-PPA
12. Clinical Criteria, accessed August 19, 2025, https://ldh.la.gov/assets/medicaid/MCPP/2.23.21/Xiaflex10.26.20ING-CC-0017_TC.pdf
13. Endo Aesthetics Stops Sale and Production of Qwo - Dr. J. J. Wendel Plastic Surgery, accessed August 19, 2025, https://www.drjjwendel.com/plastic-surgery-news/endo-asethetics-stops-production-of-qwo/
14. Collagenase | 9001-12-1 - ChemicalBook, accessed August 19, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB2112176.htm
15. Collagenase clostridium histolyticum - brand name list from Drugs.com, accessed August 19, 2025, https://www.drugs.com/ingredient/collagenase-clostridium-histolyticum.html
16. Collagenase from Clostridium histolyticum CAS No.9001-12-1 Sigma, accessed August 19, 2025, https://www.sigmaaldrich.com/US/en/product/sigma/c7657
17. Collagenase, Type I, Clostridium histolyticum CAS 9001-12-1 | 234153 - Merck Millipore, accessed August 19, 2025, https://www.merckmillipore.com/INTL/en/product/Collagenase-Type-I-Clostridium-histolyticum,EMD_BIO-234153
18. Collagenase, Type I from Clostridium histolyticum 100 mg - Thermo Fisher Scientific, accessed August 19, 2025, https://www.thermofisher.com/order/catalog/product/J13820.MC
19. Preparation and Procedure | XIAFLEX® (collagenase clostridium ..., accessed August 19, 2025, https://dupuytrens-contracture.xiaflex.com/hcp/about-xiaflex/
20. Collagenase Type I Source : Clostridium histolyticum Suggested for epithelial, liver, lung and adrenal primary cell isolations Cell Culture Tested - CDH Fine Chemical, accessed August 19, 2025, https://www.cdhfinechemical.com/collagenase-type-i-source-clostridium-histolyticum-suggested-for-epithelial-liver
21. Collagenase clostridium histolyticum - Wikipedia, accessed August 19, 2025, https://en.wikipedia.org/wiki/Collagenase_clostridium_histolyticum
22. The efficacy and safety of intralesional injection of collagenase Clostridium histolyticum for Peyronie's disease: A meta-analysis of published prospective studies - Frontiers, accessed August 19, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.973394/full
23. Collagenase Clostridium Histolyticum (Xiaflex) - Medical Clinical ..., accessed August 19, 2025, https://www.aetna.com/cpb/medical/data/1000_1099/1061.html
24. What is the mechanism of Collagenase ABC? - Patsnap Synapse, accessed August 19, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-collagenase-abc
25. Xiaflex (collagenase, clostridium histolyticum)_Dupuytren's Contracture MCP-259 - Molina Healthcare, accessed August 19, 2025, https://www.molinahealthcare.com/-/media/Molina/PublicWebsite/PDF/Providers/common/pa-criteria/Xiaflex-collagenase-clostridium-histolyticum_Dupuytrens-Contracture.pdf
26. Collagenase Clostridium histolyticum : emerging practice patterns and treatment advances, accessed August 19, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5044771/
27. About XIAFLEX® for Dupuytren's Contracture, accessed August 19, 2025, https://dupuytrens-contracture.xiaflex.com/patient/about-xiaflex/
28. Mechanism of action of collagenase clostridium histolyticum for clinical application, accessed August 19, 2025, https://www.researchgate.net/publication/309211658_Mechanism_of_action_of_collagenase_clostridium_histolyticum_for_clinical_application
29. Role of collagenase clostridium histolyticum in Peyronie's disease - PMC, accessed August 19, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4598203/
30. "Prime Time," a Branded Peyronie's Disease Commercial for XIAFLEX® (collagenase clostridium histolyticum) - Aug 12, 2025 - Investors | Endo, accessed August 19, 2025, https://investor.endo.com/2025-08-12-Prime-Time,-a-Branded-Peyronies-Disease-Commercial-for-XIAFLEX-R-collagenase-clostridium-histolyticum
31. 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 | Journal of Urology, accessed August 19, 2025, https://www.auajournals.org/doi/10.1016/j.juro.2013.01.087
32. Limited success with clostridium collagenase histolyticum following FDA approval for the treatment of Peyronie's disease - PubMed, accessed August 19, 2025, https://pubmed.ncbi.nlm.nih.gov/30120383/
33. Collagenase clostridium histolyticum Completed Phase 2 Trials for Cutis Laxa / Edematous Fibrosclerotic Panniculopathy (Cellulite) Treatment - DrugBank, accessed August 19, 2025, https://go.drugbank.com/drugs/DB00048/clinical_trials?conditions=DBCOND0002768%2CDBCOND0106680&phase=2&purpose=treatment&status=completed
34. QWO Cellulite Treatment - Benefits, Costs, Results & Procedure Steps - Skinly Aesthetics, accessed August 19, 2025, https://skinlyaesthetics.com/qwo-cellulite-treatment/
35. U.S. FDA Approves Qwo™ (collagenase clostridium histolyticum-aaes), the First Injectable Treatment for Cellulite - PR Newswire, accessed August 19, 2025, https://www.prnewswire.com/news-releases/us-fda-approves-qwo-collagenase-clostridium-histolyticum-aaes-the-first-injectable-treatment-for-cellulite-301088803.html
36. Collagenase from Clostridium histolyticum CAS No.9001-12-1 Sigma POWDER, accessed August 19, 2025, https://www.sigmaaldrich.com/MM/en/product/sigma/c9407
37. Xiaflex: Mild to serious side effects and how to manage them - Medical News Today, accessed August 19, 2025, https://www.medicalnewstoday.com/articles/drugs-xiaflex-side-effects
38. Possible Side Effects - XIAFLEX for Peyronie's disease, accessed August 19, 2025, https://peyronies-disease.xiaflex.com/patient/xiaflex/side-effects/
39. Xiaflex - FepBlue, accessed August 19, 2025, https://www.fepblue.org/-/media/PDFs/Medical-Policies/2024/January/Pharmacy-Policies-Dec-2023/Remove-and-Replace/599006-Xiaflex-collagenase-clostridium-histolyticum.pdf
40. Clinical Studies | XIAFLEX® (collagenase clostridium histolyticum), accessed August 19, 2025, https://peyronies-disease.xiaflex.com/hcp/efficacy-safety/study-design/
41. XIAFLEX® (collagenase clostridium histolyticum), accessed August 19, 2025, https://dupuytrens-contracture.xiaflex.com/hcp/
42. Nonsurgical Peyronie's Disease Treatment | XIAFLEX®, accessed August 19, 2025, https://peyronies-disease.xiaflex.com/patient/
43. QWO! – The Latest FDA-Approved Treatment for Cellulite | LM Medical NYC, accessed August 19, 2025, https://lmmedicalnyc.com/qwo-the-latest-fda-approved-treatment-for-cellulite/
44. Xiaflex - Pharmacy Management Drug Policy, accessed August 19, 2025, https://provider.excellusbcbs.com/documents/d/global/xiaflex-collagenase-clostridium-histolyticum-policy-pdf
45. Physician Information for XIAFLEX® (collagenase clostridium histolyticum), accessed August 19, 2025, https://dupuytrens-contracture.xiaflex.com/hcp/not-xiaflex-trained/
46. XIAFLEX® (collagenase clostridium histolyticum) | Peyronie's Disease | Sexual Health, accessed August 19, 2025, https://www.shupanmd.com/sexual-health-peyronies-disease-xiaflex-collagenase-clostridium-histolyticum