Collagenase Clostridium Histolyticum

Description

11 DESCRIPTION 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 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 or a Peyronie’s plaque. 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.

What Is Collagenase Clostridium Histolyticum Used For?

1 INDICATIONS AND USAGE XIAFLEX is indicated for the treatment of adult patients with Dupuytren’s contracture with a palpable cord. XIAFLEX is indicated for the treatment of adult men with Peyronie’s disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy. XIAFLEX is a combination of bacterial collagenases indicated for: The treatment of adult patients with Dupuytren’s contracture with a palpable cord ( 1 ) The treatment of adult men with Peyronie’s disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy ( 1 )

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Dupuytren’s Contracture ( 2.1 ) XIAFLEX should be administered by a healthcare provider experienced in injection procedures of the hand and in the treatment of Dupuytren’s contracture. Reconstitute XIAFLEX lyophilized powder with only the supplied diluent prior to use. Inject 0.58 mg of XIAFLEX into each palpable Dupuytren’s cord with a contracture of a metacarpophalangeal (MP) joint or a proximal interphalangeal (PIP) joint according to the injection procedure. Up to two joints in the same hand may be treated during a treatment visit. ( 2.1 ) Approximately 24 to 72 hours following an injection, perform a finger extension procedure if a contracture persists. Injections and finger extension procedures may be administered up to 3 times per cord at approximately 4-week intervals. Inject up to two cords in the same hand at a treatment visit. If a patient has other cords with contractures, inject those cords at another treatment visit. Peyronie’s Disease ( 2.2 ) XIAFLEX should be administered by a healthcare provider experienced in the treatment of male urological diseases. Reconstitute XIAFLEX lyophilized powder with only the supplied diluent prior to use. A treatment cycle consists of two XIAFLEX injection procedures and a penile modeling procedure. Induce a penile erection. A single intracavernosal injection of 10 or 20 mcg of alprostadil may be used for this purpose. With the penis in the erect state, identify and mark the target area in the Peyronie’s plaque to be injected. The penis should be in a flaccid state before injecting XIAFLEX. Inject 0.58 mg XIAFLEX into the target plaque once on each of 2 days, 1 to 3 days apart, according to the injection procedure. Perform a penile modeling procedure 1 to 3 days after the second injection of each treatment cycle. For each plaque causing the curvature deformity, up to 4 treatment cycles may be administered. Each treatment cycle may be repeated at approximately 6-week intervals. If the curvature deformity is less than 15 degrees after the first, second or third treatment cycle, or if further treatment is not clinically indicated, then subsequent treatment cycles should not be administered. 2.1 Dosage and Administration for Dupuytren’s Contracture Dosing Overview for Dupuytren’s Contracture 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 (2.1)] . 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 (2.1)] . Each vial of XIAFLEX and sterile diluent should only be used for a single injection. If two joints on the same hand are to be treated during a treatment visit, separate vials and...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following serious adverse reactions in patients with Dupuytren’s contracture are discussed in greater detail elsewhere in the labeling: Tendon ruptures or other serious injury to the injected extremity [see Warnings and Precautions (5.1)] The following serious adverse reactions in patients with Peyronie’s disease are discussed in greater detail elsewhere in the labeling: Corporal rupture (penile fracture) and severe penile hematoma [see Warnings and Precautions (5.2)] In other XIAFLEX-treated patients, 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 cannot be excluded [see Warnings and Precautions (5.2)] Dupuytren’s Contracture ( 6.1 ) The most common adverse reactions reported in ≥ 25% of patients treated with XIAFLEX and at an incidence greater than placebo were edema peripheral (e.g., swelling of the injected hand), contusion, injection site hemorrhage, injection site reaction, and pain in the injected extremity. Peyronie’s Disease ( 6.2 ) The most frequently reported adverse drug reactions reported with ≥ 25% of patients treated with XIAFLEX and at an incidence greater than placebo were penile hematoma, penile swelling and penile pain. To report SUSPECTED ADVERSE REACTIONS, contact Endo at 1-800-462-3636 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience in Patients with Dupuytren’s Contracture 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 (5.4)]. The most frequently reported adverse drug reactions (≥ 25%) in the XIAFLEX clinical trials in patients with Dupuytren’s contracture included edema peripheral (mostly swelling of the injected hand), contusion, injection site hemorrhage, injection site reaction, and pain in the treated extremity. Table 3 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). Table 3. Adverse Reactions Occurring in ≥ 5% of XIAFLEX-Treated Patients...

Drug Interactions

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 (5.5)] .

Contraindications

4 CONTRAINDICATIONS XIAFLEX is contraindicated in: the treatment of Peyronie’s plaques that involve the penile urethra due to potential risk to this structure. patients with a history of hypersensitivity to XIAFLEX or to collagenase used in any other therapeutic application or application method [see Warnings and Precautions (5.4)] . Peyronie’s plaques that involve the penile urethra ( 4 ) History of hypersensitivity to XIAFLEX or to collagenase used in other therapeutic applications ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy 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. Risk Summary Based on animal data, XIAFLEX is not predicted to increase the risk for major developmental abnormalities in humans. Human Data 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 (12.3)]. 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)]. Animal Data 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/m 2 basis, and have revealed no evidence of impaired fertility or harm to the fetus due to collagenase clostridium histolyticum.

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.

Overdosage

10 OVERDOSAGE 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 than the recommended doses including serious adverse reactions in the injected area (e.g., tendon ruptures or corporal ruptures dependent on the injection site). Supportive care and symptomatic treatment are recommended in these circumstances.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 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. NDC Number Package Size 66887-003-01 Single-use package: 1 carton containing a single-use vial of XIAFLEX and a single-use vial of sterile diluent 66887-003-02 Dual-Pack (2 single-use packages): 1 box containing 2 cartons, each containing a single-use vial of XIAFLEX and a single-use vial of sterile diluent Storage and Stability Prior to reconstitution, the vials of XIAFLEX and diluent should be stored in a refrigerator at 2°C to 8°C (36°F to 46°F). [ see Dosage and Administration (2.1 , 2.2 )] . Do not freeze. The reconstituted XIAFLEX solution can be kept at room temperature (20°C to 25°C/68°F to 77°F) for up to 1 hour or refrigerated at 2°C to 8°C (36°F to 46°F) for up to 4 hours prior to administration [ see Dosage and Administration (2.1 , 2.2 )] .