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Treatment for adults with Dupuytren’s
contracture with a palpable cord

XIAFLEX® has robust clinical experience across multicenter trials in a range of patients1

MP Joint

Evaluating efficacy in the MP joint

Two randomized, double-blind, placebo-controlled pivotal studies (N=374)1

PRIMARY ENDPOINT1

  • Percentage of patients achieving a reduction in contracture of the MP joint to within 0°–5° of normal 30 days after the last injection of that joint on Days 30, 60, or 90 (after up to 3 injections)

Key Inclusion Criteria1

  • Positive tabletop test
  • Contracture of ≥1 finger (other than thumb) caused by palpable collagen-containing cord
  • MP joint contracture: 20°–100°

Treatment

  • The cord affecting the selected primary joint received up to 3 injections of 0.58 mg of XIAFLEX® or placebo on Days 0, 30, and 601
  • About 24 hours after each injection of study medication, if needed, the investigator manipulated (extended) the treated finger in an attempt to facilitate rupture of the cord1
  • Patients did not receive local anesthesia for the manipulation procedure during the trials2
  • Following manipulation, patients were fitted with a splint, instructed to wear the splint at bedtime for up to 4 months, and instructed to perform a series of finger flexion and extension exercises each day1

MP=metacarpophalangeal; PIP=proximal interphalangeal.

PATIENT CHARACTERISTICS1

  • Approximately 40% of patients with contracture(s) of the MP or PIP joint had been previously treated with surgery
  • Had an average of 3 joints (MP and/or PIP) affected

Proven efficacy in treating MP joints both low and high in severity*

A greater percentage of patients returned to within 0°–5° of normal with XIAFLEX® versus placebo by Day 307,8

CORD I TRIAL MP Joint Response Rates by Severity of Contracture7*

77% of all patients with MP joint contractures returned to within 0°–5° of normal
vs 7% of patients receiving placebo

CORD II TRIAL MP Joint Response Rates by Severity of Contracture8*

65% of all patients with MP joint contractures returned to within 0°–5° of normal
vs 9% of patients receiving placebo

In a combined population from the CORD I and CORD II trials (XIAFLEX® N=153, placebo N=80), XIAFLEX® DEMONSTRATED A REDUCTION IN MP JOINT CONTRACTURES TO VARIOUS LEVELS9

  • 0°–5° XIAFLEX® 75% (n=115) Placebo 8% (n=6)
  • 10°–15° XIAFLEX® 10% (n=16) Placebo 4% (n=3)
  • 20°–25° XIAFLEX® 7% (n=10) Placebo 14% (n=11)
  • 30°–35° XIAFLEX® 4% (n=6) Placebo 20% (n=16)
  • 40°–45° & 50°+ XIAFLEX® 4% (n=6) Placebo 55% (n=44)

MP=metacarpophalangeal.

*Patients may have received up to 3 injections of study medication into the cords associated with contracture of the primary joints on Days 0, 30, and 60. Assessments were made 30 days after the last injection (on Days 30, 60, or 90).1

XIAFLEX®-treated patients received a mean of 1.7 injections in the 90-day controlled period in each clinical trial.1

Nearly a 100% improvement in mean range of motion of the primary MP joint with XIAFLEX®14

Mean increase in range of motion from baseline was observed in MP joints 30 days after up to 3 injections in the CORD I and CORD II trials14*

  • In CORD I, the difference was 41 degrees (N=128) versus 4 degrees with placebo (N=68; range, 46–50)14
  • In CORD II, the difference was 40 degrees (N=20) versus 9 degrees with placebo (N=11; range, 41–50)1

IMPROVEMENT IN
MEAN RANGE OF MOTION

can occur after the first injection15‡

MP=metacarpophalangeal; PIP=proximal interphalangeal.

*Patients may have received up to 3 injections of study medication into the cords associated with contracture of the primary joints on Days 0, 30, and 60. Assessments were made 30 days after the last injection (on Days 30, 60, or 90).1

XIAFLEX®-treated patients received a mean of 1.7 injections in the 90-day controlled period in each clinical trial.1

The mean range of motion increased 30 days after the first injection versus baseline in primary joints, collectively, and in MP and PIP joints, specifically.15

Real-world results from your peers

See what one of our experienced XIAFLEX® injectors achieved for a patient with a single MP joint contracture

Single Joint Procedure

30° MP contracture of the 4th finger

Injection and finger extension procedure performed by Robert Coats II, MD

Actual patient. Images used with permission from physician and patient.

MP=metacarpophalangeal.

*~24–72 hours later.

PIP Joint

Evaluating efficacy in the PIP joint

Two randomized, double-blind, placebo-controlled pivotal studies (N=374)1

PRIMARY ENDPOINT1

  • Percentage of patients achieving a reduction in contracture of the PIP joint to within 0°–5° of normal 30 days after the last injection of that joint on Days 30, 60, or 90 (after up to 3 injections)

Key Inclusion Criteria1

  • Positive tabletop test
  • Contracture of ≥1 finger (other than thumb) caused by palpable collagen-containing cord
  • PIP joint contracture: 20°–80°

Treatment

  • The cord affecting the selected primary joint received up to 3 injections of 0.58 mg of XIAFLEX® or placebo on Days 0, 30, and 601
  • About 24 hours after each injection of study medication, if needed, the investigator manipulated (extended) the treated finger in an attempt to facilitate rupture of the cord1
  • Patients did not receive local anesthesia for the manipulation procedure during the trials2
  • Following manipulation, patients were fitted with a splint, instructed to wear the splint at bedtime for up to 4 months, and instructed to perform a series of finger flexion and extension exercises each day1

MP=metacarpophalangeal; PIP=proximal interphalangeal.

PATIENT CHARACTERISTICS1

  • Approximately 40% of patients with contracture(s) of the MP or PIP joint had been previously treated with surgery
  • Had an average of 3 joints (MP and/or PIP) affected

Proven ability to reduce PIP joint contractures down to 0°–5° of normal*

A greater percentage of patients returned to within 0°–5° of normal with XIAFLEX® versus placebo by Day 307,8

CORD I TRIAL PIP Joint Response Rates by Severity of Contracture7*

40% of all patients with PIP joint contractures returned to within 0°–5° of normal
vs 6% of patients receiving placebo

CORD II TRIAL PIP Joint Response Rates by Severity of Contracture8*

28% of all patients with PIP joint contractures returned to within 0°–5° of normal
vs 0% of patients receiving placebo

In a combined population from the CORD I and CORD II trials (XIAFLEX® N=95, placebo N=44), XIAFLEX® DEMONSTRATED A REDUCTION IN PIP JOINT CONTRACTURES TO VARIOUS LEVELS9

  • 0°–5° XIAFLEX® 37% (n=35) Placebo 5% (n=2)
  • 10°–15° XIAFLEX® 16% (n=15) Placebo 0% (n=0)
  • 20°–25° XIAFLEX® 11% (n=10) Placebo 14% (n=6)
  • 30°–35° XIAFLEX® 14% (n=13) Placebo 14% (n=6)
  • 40°–45° & 50°+ XIAFLEX® 23% (n=22) Placebo 68% (n=30)

PIP=proximal interphalangeal.

*Patients may have received up to 3 injections of study medication into the cords associated with contracture of the primary joints on Days 0, 30, and 60. Assessments were made 30 days after the last injection (on Days 30, 60, or 90).1

XIAFLEX®-treated patients received a mean of 1.7 injections in the 90-day controlled period in each clinical trial.1

An average of 66% improvement in mean range of motion of the primary PIP joint after treatment with XIAFLEX®14

Mean increase in range of motion from baseline seen in PIP joints 30 days after up to 3 injections in the CORD I and CORD II trials1*

  • In CORD I, the difference was 29 degrees (N=65) versus 4 degrees with placebo (N=34; range, 44–49)14
  • In CORD II, the difference was 32 degrees (N=25) versus 7 degrees with placebo (N=10; range, 47–54)1

IMPROVEMENT IN
MEAN RANGE OF MOTION

can occur after the first injection15‡

MP=metacarpophalangeal; PIP=proximal interphalangeal.

*Patients may have received up to 3 injections of study medication into the cords associated with contracture of the primary joints on Days 0, 30, and 60. Assessments were made 30 days after the last injection (on Days 30, 60, or 90).1

XIAFLEX®-treated patients received a mean of 1.7 injections in the 90-day controlled period in each clinical trial.1

The mean range of motion increased 30 days after the first injection versus baseline in primary joints, collectively, and in MP and PIP joints, specifically.15

Real-world results from your peers

See what one of our experienced XIAFLEX® injectors achieved for a patient with a single PIP joint contracture

Single Joint Procedure

45° PIP contracture of the 5th finger

Injection and finger extension procedure performed by F. Thomas Kaplan, MD

Actual patient. Images used with permission from physician and patient.

MP=metacarpophalangeal.

*~24–72 hours later.

Safety

Adverse reactions: CORD I and CORD II

In clinical trials, most adverse reactions were localized to the treatment hand and resolved without medical intervention within 4 weeks1

In ≥5% of patients treated with XIAFLEX® and at a greater incidence than placebo in pivotal trials after up to 3 injections1

  • In clinical trials of 1082 patients treated with 2630 injections, 3 (0.3%) patients had a tendon rupture within 7 days of the injection1

aMost of these events were swelling of the injected hand.

bIncludes the terms: contusion (any body system) and ecchymosis.

cIncludes the terms: injection-site reaction, injection-site erythema, injection-site inflammation, injection-site irritation, injection-site pain, and injection-site warmth.

dIncludes the terms: injection-site swelling and injection-site edema.

eIncludes the terms: pruritus and injection-site pruritus.

fIncludes the terms: lymphadenopathy and axillary mass.

Adverse reactions: Concurrent use in 2 joints trial*

Occurring in ≥5% of patients who received 2 concurrent injections of XIAFLEX®1

  • In the post-approval trial of 715 patients treated with 1450 injections, 1 (0.1%) patient had a tendon rupture within 3 days of the injection1

*In this trial, 2 concurrent injections were performed in the same hand.1

2 Joints

Evaluating safety in 2 joints treated concurrently

An open-label, historically controlled study (N=715)3

PRIMARY OBJECTIVE3

  • Safety of 2 concurrent XIAFLEX® injections into the same hand in subjects with Dupuytren’s contracture with up to 2 palpable cords

SECONDARY OBJECTIVES3

  • Evaluate efficacy of 2 concurrent injections in the same hand
  • Expansion of the finger extension procedure to ~24–72 hours after injection

Key Inclusion Criteria3

  • Positive tabletop test
  • ≥2 fixed flexion contractures on the same hand ≥20° in PIP and/or MP joints in fingers (other than thumbs) caused by palpable cord(s) suitable for treatment

Treatment3

  • The full clinical dose of 0.58 mg of XIAFLEX® was injected into the palpable cord(s) of each affected joint
  • Injection at 2 locations of 2 palpable cords affecting 2 joints or 1 palpable cord affecting 2 joints in the same finger. (Only 2 joints treated concurrently

Extension Procedure

(~24–72 hours after injection):

  • 37% of joint pairs at 24 hours, 41% at 48 hours, and 22% at ≥72 hours3
  • Overall, 85% of joints received local anesthesia prior to the finger extension procedure4

MP=metacarpophalangeal; PIP=proximal interphalangeal.

Palpable cord(s) affecting up to 2 joints on the same hand can be treated during the same office visit1

Safety and clinical success demonstrated in post-approval trial3,4*

PRIMARY OUTCOME: SAFETY1,3

  • Incidence of tendon rupture/ligament injury and anaphylaxis
    • 1 patient experienced tendon rupture and 1 experienced anaphylaxis

SECONDARY OUTCOME: CLINICAL SUCCESS3†

  • Reduction to 0°–5° of normal achieved in 65% of MP joints and 29% of PIP joints treated during the same visit
  • Time of finger extension after injection had no impact on the rate of clinical success for either MP or PIP joints

85% OF JOINTS RECEIVED LOCAL ANESTHESIA

prior to the finger extension procedure4

MP=metacarpophalangeal; PIP=proximal interphalangeal.

*Only 2 cords were treated concurrently in this trial.3

In this trial, clinical success was defined as a reduction of contracture to ≤5° at Day 31 after 2 concurrent injections in the same hand.3

N values are representative of treated joints.

Real-world results from your peers

See what one of our experienced XIAFLEX® injectors achieved for a patient with MP and PIP contractures of the 5th finger

2 Joint Procedure

30º MP and 50º PIP contracture of the 5th finger

Injection and finger extension procedure performed by Damon C. Adamany, MD

MP=metacarpophalangeal; PIP=proximal interphalangeal.

*~24–72 hours later.

Actual patient. Images used with permission from physician and patient.

Recurrence

Evaluating recurrence and safety in patients previously treated successfully with XIAFLEX®

A long-term (5-year), observational study (N=645)1

OBJECTIVE

  • Assess recurrence and safety at years 2 through 5 in successfully treated joints in patients who received up to 8 single injections of XIAFLEX® in previous clinical studies1
    • Successfully treated defined as a reduction in contracture to 5° or less at the Day 30 evaluation after the last injection of XIAFLEX® in a previous study (JOINT I/II, CORD I/II)1,5

Evaluation1

  • Annual assessment for contracture and safety at 2, 3, 4, and 5 years after their first injection. Recurrent patients: defined as an increase in joint contracture by ≥20° in the presence of a palpable cord or joint underwent medical or surgical intervention primarily to correct a new or worsening contracture in that joint
    • Of the 645 patients enrolled, 30% discontinued the study

A long-term, observational follow-up study demonstrated sustained results with XIAFLEX®1

More than 50% of joints successfully treated with XIAFLEX® maintained response for 5 years5*

STUDY 4 Time to recurrence in joints that had been successfully treated with XIAFLEX®1,5†

MP=metacarpophalangeal; PIP=proximal interphalangeal.

*Clinical success was defined as a reduction in contracture to 0°–5° 30 days after last XIAFLEX® injection.1,10

Recurrence was defined as an increase in joint contracture by ≥20° in the presence of a palpable cord, or the joint underwent medical or surgical intervention primarily to correct a new or worsening contracture in that joint.1

GIVEN THE PROGRESSIVE NATURE OF DUPUYTREN’S CONTRACTURE, IT MAY BE HELPFUL TO11-13:

  • Help patients understand the chronic nature of the disease
  • Consider making plans for patients’ long-term follow-up

Retreatment

Evaluating retreatment with XIAFLEX® after recurrence

An open-label phase 4 study where a subset of patients (N=52) from Study 4 (Recurrence) was retreated1

OBJECTIVE1

  • Assess subset of patients with recurrence who were previously successfully treated with up to 3 injections of XIAFLEX®

Treatment1,6

  • Patients were retreated with up to 3 injections of XIAFLEX® followed by a finger extension procedure according to the CORD trials

Proven efficacy in treating recurrent contractures1*

In clinical trials, XIAFLEX® was effective in patients who were retreated where a contracture recurred1

  • A subset of patients (N=52) from the long-term, observational follow-up study (Study 4) was retreated with up to 3 injections of XIAFLEX® 0.58 mg in a recurrent joint that was previously successfully treated (ie, contracture reduction to ≤5° at the Day 30 visit after the last XIAFLEX® injection in the previous study)1
    • No new safety signals were identified among patients who were retreated with XIAFLEX® versus previous clinical studies1

MP=metacarpophalangeal; PIP=proximal interphalangeal.

*Clinical success was defined as a reduction in contracture to 0°–5° 30 days after last XIAFLEX® injection.1,10

Recurrence was defined as an increase in joint contracture by ≥20º in the presence of a palpable cord, or the joint underwent medical or surgical intervention primarily to correct a new or worsening contracture in that joint.1

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Important Safety Information
for XIAFLEX®

  • XIAFLEX® is contraindicated in patients with a history of hypersensitivity to XIAFLEX® or to collagenase used in any other therapeutic application or application method
  • In the controlled and uncontrolled portions of clinical trials in Dupuytren's contracture, flexor tendon ruptures occurred after XIAFLEX® injection. Injection of XIAFLEX® into collagen-containing structures such as tendons or ligaments of the hand may result in damage to those structures and possible permanent injury such as tendon rupture or ligament damage. Therefore, XIAFLEX® should be injected only into the collagen cord with a MP or PIP joint contracture, and care should be taken to avoid injecting into tendons, nerves, blood vessels, or other collagen-containing structures of the hand. When injecting a cord affecting a PIP joint of the fifth finger, the needle insertion should not be more than 2 to 3 mm in depth and avoid injecting more than 4 mm distal to the palmar digital crease
  • Other XIAFLEX®-associated serious local adverse reactions in the controlled and uncontrolled portions of the studies included pulley rupture, ligament injury, complex regional pain syndrome (CRPS), sensory abnormality of the hand, and skin laceration (tear). In a historically controlled post-marketing trial, the incidence of skin laceration (22%) was higher for subjects treated with two concurrent injections of XIAFLEX® compared with subjects treated with up to three single injections in the placebo-controlled premarketing trials (9%). Cases of skin laceration requiring skin graft after finger extension procedures have been reported post-marketing. Signs or symptoms that may reflect serious injury to the injected finger/hand should be promptly evaluated because surgical intervention may be required
  • In the controlled portions of the clinical trials in Dupuytren's contracture, a greater proportion of XIAFLEX®-treated patients (15%) compared to placebo-treated patients (1%) had mild allergic reactions (pruritus) after up to 3 injections. The incidence of XIAFLEX®-associated pruritus increased after more XIAFLEX® injections in patients with Dupuytren's contracture
  • Because XIAFLEX® contains foreign proteins, severe allergic reactions to XIAFLEX® can occur. Anaphylaxis was reported in a post-marketing clinical study in one patient who had previous exposure to XIAFLEX® for the treatment of Dupuytren's contracture. Healthcare providers should be prepared to address severe allergic reactions following XIAFLEX® injections
  • In the XIAFLEX® trials in Dupuytren's contracture, 70% and 38% of XIAFLEX®-treated patients developed an ecchymosis/contusion or an injection site hemorrhage, respectively. Patients with abnormal coagulation (except for patients taking low-dose aspirin, eg, up to 150 mg per day) were excluded from participating in these studies. Therefore, the efficacy and safety of XIAFLEX® in patients receiving anticoagulant medications (other than low-dose aspirin, eg, up to 150 mg per day) within 7 days prior to XIAFLEX® administration is not known. In addition, it is recommended to avoid use of XIAFLEX® in patients with coagulation disorders, including patients receiving concomitant anticoagulants (except for low-dose aspirin)
  • In the XIAFLEX® clinical trials for Dupuytren's contracture, the most common adverse reactions reported in ≥25% of patients treated with XIAFLEX® and at an incidence greater than placebo were edema peripheral (eg, swelling of the injected hand), contusion, injection site hemorrhage, injection site reaction, and pain in the injected extremity

Indication

XIAFLEX® is indicated for the treatment of adult patients with Dupuytren's contracture with a palpable cord.

Please see the full Prescribing Information, including Medication Guide.


  1. References:
  2. 1. XIAFLEX® [package insert]. Malvern, PA: Endo Pharmaceuticals Inc.
  3. 2. Raven RB 3rd, Kushner H, Nguyen D, Naam N, Curtin C. Analysis of efficacy and safety of treatment with collagenase clostridium histolyticum among subgroups of patients with Dupuytren contracture. Ann Plast Surg. 2014;73(3):286-290.
  4. 3. Gaston RG, Larsen SE, Pess GM, et al. The efficacy and safety of concurrent collagenase clostridium histolyticum injections for 2 Dupuytren contractures in the same hand: a prospective, multicenter study. J Hand Surg Am. 2015;40(10):1963-1971.
  5. 4. Data on file. DOF-XDC-03. Endo Pharmaceuticals Inc; August 7, 2015.
  6. 5. Peimer CA, Blazar P, Coleman S, Kaplan FT, Smith T, Lindau T. Dupuytren contracture recurrence following treatment with collagenase clostridium histolyticum (CORDLESS [Collagenase Option for Reduction of Dupuytren Long-Term Evaluation of Safety Study]): 5-year data. J Hand Surg Am. 2015;40(8):1597-1605.
  7. 6. Bear BJ, Peimer CA, Kaplan FTD, et al. Treatment of recurrent Dupuytren contracture in joints previously effectively treated with collagenase clostridium histolyticum. J Hand Surg Am. 2017;42(5):391.e1-391.e8.
  8. 7. Data on file. DOF-XDC-07. Endo Pharmaceuticals Inc; July 29, 2015.
  9. 8. Data on file. DOF-XDC-08. Endo Pharmaceuticals Inc; July 24, 2015.
  10. 9. Data on file. DOF-XDC-27. Endo Pharmaceuticals Inc; January 23, 2018.
  11. 10. Data on file. DOF-XDC-09. Endo Pharmaceuticals Inc; June 10, 2015.
  12. 11. Syed F, Thomas AN, Singh S, Kolluru V, Emeigh Hart SG, Bayat A. In vitro study of novel collagenase (XIAFLEX®) on Dupuytren’s disease fibroblasts displays unique drug related properties. PLoS One. 2012;7(2):e31430.
  13. 12. Hay DC, Louie DL, Earp BE, Kaplan FT, Akelman E, Blazar PE. Surgical findings in the treatment of Dupuytren’s disease after initial treatment with clostridial collagenase (Xiaflex). J Hand Surg Eur Vol. 2014;39(5):463-465.
  14. 13. Townley WA, Baker R, Sheppard N, Grobbelaar AO. Dupuytren’s contracture unfolded. BMJ. 2006;332(7538):397-400.
  15. 14. Data on file. DOF-XDC-23. Endo Pharmaceuticals Inc; January 19, 2017.
  16. 15. Data on file. DOF-XDC-22. Endo Pharmaceuticals Inc; January 9, 2017.