Tendon Rupture Or Other Serious Injury To The Injected Finger/Hand In The Treatment Of Dupuytren's Contracture
In the controlled and uncontrolled portions of clinical trials in Dupuytren's contracture, flexor tendon ruptures occurred after XIAFLEX injection [see ADVERSE REACTIONS]. 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 [see DOSAGE AND ADMINISTRATION].
Other XIAFLEX-associated serious local adverse reactions 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.
Corporal Rupture (Penile Fracture) Or Other Serious Injury To The Penis In The Treatment Of Peyronie's Disease
Corporal rupture was reported as an adverse reaction after XIAFLEX injections in 5 of 1044 (0.5%) XIAFLEX treated patients in the controlled and uncontrolled clinical trials in Peyronie's disease.
In other XIAFLEX-treated patients (9 of 1044; 0.9%), a combination of penile ecchymoses or hematoma, sudden penile detumescence, and/or a penile “popping” sound or sensation was reported, and in these cases, a diagnosis of corporal rupture can not be excluded. These patients were managed without surgical intervention, but the long-term consequences are unknown.
Severe penile hematoma was also reported as an adverse reaction in 39 of 1044 patients (3.7%) in the controlled and uncontrolled clinical trials in Peyronie's disease [see ADVERSE REACTIONS].
Signs or symptoms that may reflect serious injury to the penis should be promptly evaluated in order to assess for corporal rupture or severe penile hematoma, which may require surgical intervention.
Injection of XIAFLEX into collagen-containing structures such as the corpora cavernosa of the penis may result in damage to those structures and possible injury such as corporal rupture (penile fracture). Therefore, XIAFLEX should be injected only into the Peyronie's plaque and care should be taken to avoid injecting into the urethra, nerves, blood vessels, corpora cavernosa or other collagen-containing structures of the penis.
XIAFLEX REMS Program
Because of the risks of corporal rupture (penile
fracture) or other serious penile injury in the treatment of Peyronie's
disease, XIAFLEX is available only through the XIAFLEX REMS Program [see
Corporal Rupture (Penile Fracture) or Other Serious Injury to the Penis in the
Treatment of Peyronie’s Disease].
Required components of the XIAFLEX REMS Program include the following:
- Prescribers must be certified with the program by enrolling and completing training in the administration of XIAFLEX treatment for Peyronie's disease.
- Healthcare sites must be certified with the program and ensure that XIAFLEX is only dispensed for use by certified prescribers.
Further information is available at www.XIAFLEXREMS.com or 1-877-313-1235.
Hypersensitivity Reactions, Including Anaphylaxis
In the controlled portions of the clinical trials in Dupuytren's contracture (Studies 1 and 2), 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 XIAFLEXassociated pruritus increased after more XIAFLEX injections in patients with Dupuytren's contracture.
In the double-blind, placebo-controlled portions of the clinical trials in Peyronie's disease (Studies 1 and 2), a greater proportion of XIAFLEX-treated patients (4%) compared to placebotreated patients (1%) had localized pruritus after up to 4 treatment cycles (involving up to 8 XIAFLEX injection procedures). The incidence of XIAFLEX-associated pruritus was similar after each injection regardless of the number of injections administered.
Because XIAFLEX contains foreign proteins, severe allergic reactions to XIAFLEX can occur. Anaphylaxis was reported in a post-marketing clinical trial (Study 3) in one patient who had previous exposure to XIAFLEX for the treatment of Dupuytren's contracture. Some patients with Dupuytren's contracture developed IgE-anti-drug antibodies in greater proportions and higher titers with successive XIAFLEX injections. Healthcare providers should be prepared to address severe allergic reactions following XIAFLEX injections.
Risk Of Bleeding In Patients With Abnormal Coagulation
In the XIAFLEX trials in Dupuytren's contracture (Studies 1 and 2), 70% and 38% of XIAFLEX-treated patients developed an ecchymosis/contusion or an injection site hemorrhage, respectively (see Table 3). In the XIAFLEX controlled trials in Peyronie's disease (Studies 1 and 2), 65.5% of XIAFLEX-treated patients developed penile hematoma, and 14.5% developed penile ecchymosis (see Table 4). Patients with abnormal coagulation (except for patients taking low-dose aspirin, e.g., 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, e.g., 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).
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide).
Patient Counseling For Dupuytren's Contracture
Advise patients of the following:
- Serious complications of XIAFLEX injection include tendon rupture, serious ligament damage, or skin laceration that may result in the inability to fully bend the finger and may require surgery to correct the complication.
- XIAFLEX injection is likely to result in swelling, bruising, bleeding, and/or pain of the injected site and surrounding tissue.
After the XIAFLEX injections, instruct patients:
- Not to flex or extend the fingers of the injected hand to reduce extravasation of XIAFLEX out of the cord(s).
- Not to attempt to disrupt the injected cord(s) by self-manipulation.
- To elevate the injected hand until bedtime.
- To promptly contact their physician if there is evidence of infection (e.g., fever, chills, increasing redness or edema), sensory changes in the treated finger(s), trouble bending the finger(s) after the swelling goes down (symptoms of tendon rupture), or skin laceration.
- To return to their healthcare provider's office one to three days after the injection visit for an examination of the injected hand and for possible finger extension procedure(s) to disrupt the cord.
Following the finger extension procedure(s) and fitting patient with a splint, instruct patients:
- Not to perform strenuous activity with the injected hand until advised to do so.
- To wear the splint at bedtime for up to 4 months.
- To perform a series of finger flexion and extension exercises each day.
Patient Counseling For Peyronie's Disease
Advise patients of the following:
- Serious complications of XIAFLEX injection include corporal rupture and penile hematoma and may require surgery to correct the complication.
After the XIAFLEX injections, instruct the patient:
- That their penis may appear bruised and/or swollen
- That they may have mild-to-moderate penile pain that can be relieved by taking over-thecounter pain medications
- To promptly contact their physician if, at any time, they have severe pain or severe swelling of the penis, severe purple bruising and swelling of the penis, difficulty urinating or blood in the urine, or sudden loss of the ability to maintain an erection. These symptoms may be accompanied by a popping or cracking sound from the penis
- To return to their healthcare provider's office when directed for further injection(s) and/or penile modeling procedure(s)
- To wait two weeks after the second injection of a treatment cycle before resuming sexual activity, provided pain and swelling have subsided
Provide the patient instructions on the appropriate technique to perform penile modeling activities at home, as described in “What You Need to Know About XIAFLEX Treatment for Peyronie's Disease: A Patient Guide”, and give the patient a copy.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Purified collagenase Clostridium histolyticum was not mutagenic in Salmonella typhimurium (AMES test) and was not clastogenic in both an in vivo mouse micronucleus assay and an in vitro chromosomal aberration assay in human lymphocytes.
Impairment Of Fertility
Collagenase Clostridium histolyticum did not impair fertility and early embryonic development when administered intravenously in rats at exposures up to approximately 11 times the maximum recommended human dose (MRHD) on a mg/m² basis.
Use In Specific Populations
Pregnancy Category B
There are no adequate and well-controlled studies of XIAFLEX in pregnant women.
Because animal reproduction studies are not always predictive of human response, XIAFLEX should be used during pregnancy only if clearly needed.
Based on animal data, XIAFLEX is not predicted to increase the risk for major developmental abnormalities in humans.
Human pharmacokinetic studies showed that XIAFLEX levels were not quantifiable in the systemic circulation following injection into a Dupuytren's cord.
Low levels of XIAFLEX were quantifiable in the plasma of evaluable male subjects for up to 30 minutes following administration of XIAFLEX into the penile plaque of subjects with Peyronie's disease [see CLINICAL PHARMACOLOGY].
Almost all patients develop anti-product antibodies (anti-AUX-I and anti-AUX-II) after treatment with XIAFLEX, and the clinical significance of anti-product antibody formation on a developing fetus is not known [see ADVERSE REACTIONS].
Reproduction studies have been performed in rats with intravenous exposures up to approximately 11 times the maximum recommended human dose (MRHD) of XIAFLEX on a mg/m² basis, and have revealed no evidence of impaired fertility or harm to the fetus due to collagenase clostridium histolyticum.
It is not known whether collagenase Clostridium histolyticum is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when XIAFLEX is administered to a nursing woman.
The safety and effectiveness of XIAFLEX in pediatric patients less than 18 years old have not been established.
Of the 249 XIAFLEX-treated patients in the double-blind, placebo-controlled, clinical trials in Dupuytren's contracture (Studies 1 and 2), 104 (42%) were 65 years of age or older and 9% were 75 years of age or older. Of the 551 XIAFLEX-treated patients in the double-blind, placebocontrolled, clinical trials in Peyronie's disease (Studies 1 and 2), 100 (18%) were 65 years of age or older and 5 (0.9 %) were 75 years of age or older. No overall differences in safety or effectiveness of XIAFLEX were observed between these patients and younger patients.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 7/6/2016
Additional Xiaflex Information
Report Problems to the Food and Drug Administration
Find out what women really need.