These highlights do not include all the information needed to use XIAFLEX safely and effectively. See full prescribing information for XIAFLEX. XIAFLEX (collagenase clostridium histolyticum) for injection, for intralesional use Initial | XIAFLEX
1 INDICATIONS AND USAGE
XIAFLEX is indicated for the treatment of adult patients with Dupuytren’s contracture with a palpable cord.
2 DOSAGE AND ADMINISTRATION
2.1 Dosing Overview
XIAFLEX should be administered by a healthcare provider experienced in injection procedures of the hand and in the treatment of patients with Dupuytren’s contracture.
XIAFLEX, supplied as a lyophilized powder, must be reconstituted with the provided diluent prior to use [see Dosage and Administration (2.2)]. The dose of XIAFLEX is 0.58 mg per injection into a palpable cord with a contracture of a metacarpophalangeal (MP) joint or a proximal interphalangeal (PIP) joint [see Dosage and Administration (2.4)]. Table 1 displays an overview of the volumes of sterile diluent for reconstitution and the reconstituted XIAFLEX solution to be used in the intralesional injection [see Dosage and Administration (2.2, 2.4)]. Approximately 24 hours after injection, perform a finger extension procedure if a contracture persists to facilitate cord disruption [see Dosage and Administration (2.5)].
Four weeks after the XIAFLEX injection and finger extension procedure, if a MP or PIP contracture remains, the cord may be re-injected with a single dose of 0.58 mg of XIAFLEX and the finger extension procedure may be repeated (approximately 24 hours after injection). Injections and finger extension procedures may be administered up to 3 times per cord at approximately 4-week intervals.
Inject only one cord at a time. If a patient has other palpable cords with contractures of MP or PIP joints, these cords may be injected with XIAFLEX in a sequential order.
1 The reconstituted XIAFLEX solution to be used in the intralesional injection contains 0.58 mg of XIAFLEX.
Note: The entire reconstituted XIAFLEX solution contains 0.9 mg of XIAFLEX. Reconstituted XIAFLEX solution remaining in the vial after the injection should be discarded.
|For cords affecting MP joints||For cords affecting PIP joints|
|Sterile Diluent for Reconstitution|
|Volume||0.39 mL||0.31 mL|
|Reconstituted XIAFLEX Solution to be Injected1|
|Volume||0.25 mL||0.20 mL|
2.2 Reconstitution of the Lyophilized Powder
2.3 Preparation Prior to Injection
2.4 Injection Procedure
2.5 Finger Extension Procedure
3 DOSAGE FORMS AND STRENGTHS
XIAFLEX is supplied in single-use glass vials containing 0.9 mg of collagenase clostridium histolyticum as a sterile, lyophilized powder for reconstitution. Sterile diluent for reconstitution is provided in the package in a single-use glass vial containing 3 mL of 0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride.
5 WARNINGS AND PRECAUTIONS
5.1 Tendon Rupture or Other Serious Injury to the Injected Extremity
In the controlled and uncontrolled portions of the clinical trials, flexor tendon ruptures occurred after XIAFLEX injection [see Adverse Reactions (6.1)]. 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 (2.3, 2.4)].
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), and sensory abnormality of the hand.
5.2 Allergic Reactions
In the controlled portions of the clinical trials (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 XIAFLEX-associated pruritus increased after more XIAFLEX injections.
Although there were no severe allergic reactions observed in the XIAFLEX studies (e.g., those associated with respiratory compromise, hypotension, or end-organ dysfunction), severe reactions including anaphylaxis could occur following XIAFLEX injections. XIAFLEX contains foreign proteins and patients 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.
5.3 Patients with Abnormal Coagulation
In the XIAFLEX trials (Studies 1 and 2), 70% and 38% of XIAFLEX-treated patients developed an ecchymosis/contusion or an injection site hemorrhage, respectively. 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. Therefore, XIAFLEX should be used with caution in patients with coagulation disorders including patients receiving concomitant anticoagulants (except for low-dose aspirin).
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail elsewhere in the labeling:
The most frequently reported adverse drug reactions (≥ 25%) in the XIAFLEX clinical trials included edema peripheral (mostly swelling of the injected hand), contusion, injection site reaction, injection site hemorrhage, and pain in the treated extremity.
6.1 Clinical Studies Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
Out of 1082 patients who received 0.58 mg of XIAFLEX in the controlled and uncontrolled portions of the XIAFLEX studies (2630 XIAFLEX injections), 3 (0.3%) patients had a flexor tendon rupture of the treated finger within 7 days of the injection.
The data described below are based on two pooled randomized, double-blind, placebo-controlled trials through Day 90 in patients with Dupuytren’s contracture (Studies 1 and 2). In these trials, patients were treated with up to 3 injections of 0.58 mg of XIAFLEX or placebo with approximately 4-week intervals between injections and the patients had finger extension procedures the day after injection, if needed, to facilitate disruption of the cord [see Clinical Studies (14)]. These trials were comprised of 374 patients of whom 249 and 125 received 0.58 mg of XIAFLEX and placebo, respectively. The mean age was 63 years, 80% were male and 20% were female, and 100% were white.
In the placebo-controlled portions of Studies 1 and 2 through Day 90, 98% and 51% of XIAFLEX-treated and placebo-treated patients had an adverse reaction after up to 3 injections, respectively. Over 95% of XIAFLEX-treated patients had an adverse reaction of the injected extremity after up to 3 injections. Approximately 81% of these local reactions resolved without intervention within 4 weeks of XIAFLEX injections. The adverse reaction profile was similar for each injection, regardless of the number of injections administered. However, the incidence of pruritus increased with more injections [see Warnings and Precautions (5.2)].
Table 2 shows the incidence of adverse reactions that were reported in greater than or equal to 5% of XIAFLEX-treated patients and at a frequency greater than placebo-treated patients after up to 3 injections in the pooled placebo-controlled trials through Day 90 (Studies 1 and 2).
Some patients developed vasovagal syncope after finger extension procedures.
Immunogenicity During clinical studies, patients with Dupuytren’s contracture were tested at multiple time points for antibodies to the protein components of XIAFLEX (AUX-I and AUX-II). At 30 days post the first injection of XIAFLEX 0.58 mg, 92% of patients had antibodies detected against AUX-I and 86% of patients had antibodies detected against AUX-II. After the fourth injection of XIAFLEX, every XIAFLEX-treated patient developed high titers of antibodies to both AUX-I and AUX-II. Neutralizing antibodies to AUX-I or AUX-II, were detected in 10% and 21%, respectively, of patients treated with XIAFLEX. However, there was no apparent correlation of antibody frequency, antibody titers, or neutralizing status to clinical response or adverse reactions.
Since the protein components in XIAFLEX (AUX-I and AUX-II) have some sequence homology with human matrix metalloproteinases (MMPs), anti-product antibodies could theoretically interfere with human MMPs.
Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay used in detection and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to collagenase clostridium histolyticum with the incidence of antibodies to other products may be misleading.
|a Most of these events were swelling of the injected hand.|
|b Includes the terms: contusion (any body system) and ecchymosis|
|c Includes the terms: injection site reaction, injection site erythema, injection site inflammation, injection site irritation, injection site pain, and injection site warmth|
|d Includes the terms: injection site swelling and injection site edema|
|e Includes the terms: pruritus and injection site pruritus|
|f Includes the terms: lymphadenopathy and axillary mass|
|All Adverse Reactions||98%||51%|
|Injection Site Hemorrhage||38%||3%|
|Injection Site Reactionc||35%||6%|
|Pain in Extremity||35%||4%|
|Injection Site Swellingd||24%||6%|
|Lymph Node Pain||8%||0%|
7 DRUG INTERACTIONS
Anticoagulant drugs: XIAFLEX should be used with caution in patients receiving concomitant anticoagulants (except for low-dose aspirin) [see Warnings and Precautions (5.3)].
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category B There are no adequate and well-controlled studies of XIAFLEX in pregnant women. Human pharmacokinetic studies showed that XIAFLEX levels were not quantifiable in the systemic circulation following injection into a Dupuytren’s cord [see Clinical Pharmacology (12.3)]. Reproduction studies have been performed in rats with intravenous doses up to 0.13 mg (approximately 45 times the human dose of XIAFLEX on a mg/kg basis, if administered intravenously) and have revealed no evidence of impaired fertility or harm to the fetus due to collagenase clostridium histolyticum. 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 (6.1)]. Because animal reproduction studies are not always predictive of human response, XIAFLEX should be used during pregnancy only if clearly needed.
8.3 Nursing Mothers
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.
8.4 Pediatric Use
The safety and effectiveness of XIAFLEX in pediatric patients less than 18 years old have not been established.
8.5 Geriatric Use
Of the 249 XIAFLEX-treated patients in the double-blind, placebo-controlled, clinical trials (Studies 1 and 2), 104 (42%) were 65 years of age or older and 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.
The effects of overdose of XIAFLEX are unknown. It is possible that multiple simultaneous or excessive doses of XIAFLEX may cause more severe local effects including serious adverse reactions (e.g., tendon ruptures) than the recommended doses. Supportive care and symptomatic treatment are recommended in these circumstances.
XIAFLEX contains purified collagenase clostridium histolyticum, consisting of two microbial collagenases in a defined mass ratio, Collagenase AUX-I and Collagenase AUX-II, which are isolated and purified from the fermentation of Clostridium histolyticum bacteria.
Collagenase AUX-I is a single polypeptide chain consisting of approximately 1000 amino acids of known sequence. It has an observed molecular weight of 114 kiloDaltons (kDa). It belongs to the class I Clostridium histolyticum collagenases.
Collagenase AUX-II is a single polypeptide chain consisting of approximately 1000 amino acids of deduced sequence. It has an observed molecular weight of 113 kDa. It belongs to the class II Clostridium histolyticum collagenases.
XIAFLEX is supplied as a sterile lyophilized powder (white cake) intended for reconstitution with 0.39 mL (for a MP joint) or 0.31 mL (for a PIP joint) of the supplied sterile diluent (0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride) prior to intralesional injection into a Dupuytren’s cord.
XIAFLEX is available in single-use, glass vials containing 0.9 mg of collagenase clostridium histolyticum. Each vial also contains 0.5 mg of hydrochloric acid, 18.5 mg of sucrose, and 1.1 mg of tromethamine.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Collagenases are proteinases that hydrolyze collagen in its native triple helical conformation under physiological conditions, resulting in lysis of collagen deposits. Injection of XIAFLEX into a Dupuytren’s cord, which is comprised mostly of collagen, may result in enzymatic disruption of the cord.
Results of in vitro studies suggest that the collagenases (AUX-I and AUX-II) worked synergistically to provide hydrolyzing activity towards collagen. However, there are no clinical data regarding the relative contributions of the individual collagenases (AUX-I or AUX-II) to the efficacy of XIAFLEX in the treatment of Dupuytren’s contracture.
Following administration of a single XIAFLEX dose of 0.58 mg into a Dupuytren’s cord in 20 patients, no quantifiable levels of XIAFLEX (AUX-I or AUX-II) were detected in plasma up to 30 days post injection.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long term animal studies to evaluate the carcinogenic potential of collagenase clostridium histolyticum have not been conducted.
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.
Collagenase clostridium histolyticum did not impair fertility and early embryonic development when administered intravenously in rats at doses up to 0.13 mg/dose (approximately 45 times the human dose on a mg/kg basis).
14 CLINICAL STUDIES
The efficacy of 0.58 mg of XIAFLEX was evaluated in two randomized, double-blind, placebo-controlled, multi-centered trials in 374 adult patients with Dupuytren’s contracture (Studies 1 and 2). At study entry, patients must have had: (1) a finger flexion contracture with a palpable cord of at least one finger (other than the thumb) of 20° to 100° in a metacarpophalangeal (MP) joint or 20° to 80° in a proximal interphalangeal (PIP) joint and (2) a positive “table top test” defined as the inability to simultaneously place the affected finger(s) and palm flat against a table top. Patients could not have received a surgical treatment (e.g., fasciectomy, fasciotomy) on the selected primary joint within 90 days before the first injection of study medication and patients could not have received anticoagulation medication (except for up to 150 mg of aspirin per day) within 7 days before the first injection of study medication.
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 60. 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 cord (finger extension procedure). 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 day.
See Table 3 for the baseline disease characteristics of patients with Dupuytren’s contracture in Studies 1 and 2.
In Studies 1 and 2, the primary endpoint was to evaluate the proportion of patients who achieved a reduction in contracture of the selected primary joint (MP or PIP) to within 0° to 5° of normal, 30 days after the last injection of that joint on Days 30, 60, or 90 (after up to 3 injections). A greater proportion of XIAFLEX-treated patients compared to placebo-treated patients achieved the primary endpoint (see Table 4).
The proportion of patients who achieved a contracture reduction of the primary joint to 0° to 5° after the first injection was 39% and 1% in Study 1 and 27% and 5% in Study 2 in the XIAFLEX and placebo groups respectively.
XIAFLEX-treated patients, compared to placebo-treated patients, showed a greater increase from baseline in the range of motion of MP and PIP joints (see Table 5).
|1 Prior surgery for Dupuytren’s contracture included fasciotomy and fasciectomy|
|Study 1||Study 2|
|Proportion of patients with prior surgery for Dupuytren’s contracture1||38%||53%|
|Proportion of patients with prior surgery for Dupuytren’s contracture on the same finger as the primary joint1||8%||18%|
|Mean number of affected joints||3.0||3.3|
|a 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).|
|b For XIAFLEX-treated patients, the mean (±SD) number of injections given to the cord associated with the contracture was 1.7 (±0.8) in the 90-day controlled period in each trial.|
|c MP joints are metacarpophalangeal joints|
|d PIP joints are proximal interphalangeal joints|
|e 95% confidence interval|
|Treated Joint||Study 1||Study 2|
|All Joints (MP and PIP)c,d
57% (47%, 67%)
40% (14%, 62%)
69% (57%, 79%)
56% (19%, 83%)
34% (14%, 52%)
28% (-10%, 61%)
|a 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). Baseline and final range of motion degree values are expressed in mean (SD).|
|b MP = Metacarpophalangeal joint|
|c PIP = Proximal interphalangeal joint|
|Range of Motion = Degrees of Full Flexion minus Degrees of Fixed Extension|
|Not all patients had range of motion values at both time points.|
|Treated Joint||Study 1||Study 2|
|All Joints b,c||N=196||N=102||N=45||N=21|
|Baseline||44 (20)||45 (19)||40 (15)||44 (16)|
|Final||80 (20)||50 (22)||76 (18)||52 (20)|
|Increase||36 (21)||4 (15)||35 (18)||8 (15)|
|MP Joints b||N=129||N=68||N=20||N=11|
|Baseline||43 (20)||46 (19)||40 (12)||41 (21)|
|Final||83 (16)||50 (21)||80 (11)||50 (22)|
|Increase||41 (20)||4 (13)||40 (13)||9 (15)|
|PIP Joints c||N=67||N=34||N=25||N=10|
|Baseline||46 (20)||44 (18)||41 (18)||47 (10)|
|Final||75 (24)||49 (24)||73 (21)||54 (18)|
|Increase||28 (22)||5 (19)||32 (20)||7 (16)|
16 HOW SUPPLIED/STORAGE AND HANDLING
Each single-use vial of XIAFLEX is packaged with a single-use vial of sterile diluent in an outer carton. The National Drug Code is:
XIAFLEX is available in single-use, glass vials containing 0.9 mg of collagenase clostridium histolyticum as a sterile, lyophilized powder.
Sterile diluent for reconstitution is available in single-use, glass vials containing 3 mL of 0.3 mg/mL calcium chloride dihydrate in 0.9% sodium chloride.
Storage and Stability Prior to reconstitution, the vials of XIAFLEX and diluent should be stored in a refrigerator at 2° to 8°C (36° to 46°F) [see Dosage and Administration (2.2)]. Do not freeze.
The reconstituted XIAFLEX solution can be kept at room temperature (20° to 25°C/68° to 77°F) for up to one hour or refrigerated at 2° to 8°C (36° to 46°F) for up to 4 hours prior to administration [see Dosage and Administration (2.2)].
17 PATIENT COUNSELING INFORMATION
See Medication Guide
Advise patients of the following:
After the XIAFLEX injections, instruct patients:
Following the finger extension procedure(s) and fitting patient with a splint, instruct patients:
Manufactured and distributed by: Auxilium Pharmaceuticals, Inc. Malvern, PA 19355 USA US License No. 1816 US Patent No. 7,811,560
MEDICATION GUIDE XIAFLEX (Zī a flex) (collagenase clostridium histolyticum)
Read this Medication Guide before you receive XIAFLEX and each time you get an injection. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or treatment.
What is the most important information I should know about XIAFLEX?
XIAFLEX can cause serious side effects, including:
Call your healthcare provider right away if you have any of these symptoms of an allergic reaction after an injection of XIAFLEX:
What is XIAFLEX?
XIAFLEX is a prescription medicine used to treat adults with Dupuytren’s contracture when a “cord” can be felt.
In people with Dupuytren’s contracture, there is thickening of the skin and tissue in the palm of your hand that is not normal. Over time, this thickened tissue can form a cord in your palm. This causes one or more of your fingers to bend toward the palm, so you can not straighten them.
XIAFLEX should be injected into a cord by a healthcare provider who is skilled in injection procedures of the hand and treating people with Dupuytren’s contracture. The proteins in XIAFLEX help to “break” the cord of tissue that is causing the finger to be bent.
It is not known if XIAFLEX is safe and effective in children under the age of 18.
What should I tell my healthcare provider before starting treatment with XIAFLEX?
XIAFLEX may not be right for you. Before receiving XIAFLEX, tell your healthcare provider if you:
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.
Especially tell your healthcare provider if you use:
How will I receive XIAFLEX?
What are the possible side effects of XIAFLEX?
XIAFLEX can cause serious side effects. See “What is the most important information I should know about XIAFLEX?”.
Common side effects with XIAFLEX include:
These are not all of the possible side effects with XIAFLEX. Tell your healthcare provider about any side effect that bothers you or does not go away.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
General information about XIAFLEX
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
This Medication Guide summarizes the most important information about XIAFLEX. If you would like more information, talk to your healthcare provider. You can ask your healthcare provider for information about XIAFLEX that is written for health professionals. For more information visit www.XIAFLEX.com or call 1-877-663-0412.
What are the ingredients in XIAFLEX?
Active ingredient: collagenase clostridium histolyticum.
Ingredients: hydrochloric acid, sucrose, and tromethamine. The diluent contains:calcium chloride dihydrate in 0.9% sodium chloride.
Manufactured and distributed by:Auxilium Pharmaceuticals, Inc.Malvern, PA 19355USA
Revised October 2010
This Medication Guide has been approved by the U.S. Food and Drug Administration.
US License No. 1816
US Patent No. 7,811,560
Package Label - Principal Display Panel – 3 mL Vial, Sterile Diluent
Package Label - Principal Display Panel – 0.9 mg Vial, XIAFLEX Injection
Package Label - Principal Display Panel – 1 Count Carton, XIAFLEX Injection
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