Dosing and uses of Xiaflex (collagenase clostridium histolyticum)
Adult dosage forms and strengths
lyophilized powder for injection plus diluent
- 0.9mg/vial (following reconstitution)
Dupuytren Contracture With Palpable Cord
Inject 0.58 mg into palpable Dupuytren cord with a contracture of metacarpophalangeal (MP) joint or proximal interphalangeal (PIP) joint
If contracture persists 24-72 hr following injection, perform finger extension procedure
May repeat injection and finger extension procedures up to 3 times per cord at 4-week intervals
Inject only 1 cord at a time; if other cords with contractures exist, inject each cord in sequential order
Each vial of drug and sterile diluent should only be used for a single injection; if 2 joints on the same hand are to be treated during a treatment visit, separate vials and syringes should be used for each reconstitution and injection
Approximately 24-72 hr after injection, perform a finger extension procedure if a contracture persists to facilitate cord disruption
May reinject four weeks after the initial injection if MP or PIP contracture still present; may reinject with a single dose of collagenase C. histolyticum
2 injections on same hand per treatment visit
- Perform up to 2 injections in the same hand according to the injection procedure during a treatment visit
- Two palpable cords affecting 2 joints may be injected or 1 palpable cord affecting 2 joints in the same finger may be injected at 2 locations during a treatment visit
- If a patient has other palpable cords with contractures of MP or PIP joints, these cords may be injected at other treatment visits approximately 4 wk apart
Peyronie Disease
Available for treatment of Peyronie disease only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program called the XIAFLEX REMS Program
Indicated in men with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy
Treatment course consists of a maximum of 4 treatment cycles; each treatment cycle consists of 2 injection procedures and 1 penile modeling procedure for a maximum of 8 injection procedures and 4 modeling procedures
The 2nd injection procedure is performed 1-3 days after the 1st; the penile modeling procedure described below is performed 1-3 days after the 2nd injection of the treatment cycle
The interval between treatment cycles is approximately 6 weeks
Induce a penile erection; to achieve it, may use a single intracavernosal injection of 10 or 20 mcg of alprostadiL
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 flaccid state before injecting
Inject 0.58 mg into target plaque once on each of 2 days, 1 to 3 days apart, according to injection procedure
Perform a penile modeling procedure 1 to 3 days after second injection of each treatment cycle
For each plaque causing the curvature deformity, may administer up to four treatment cycles; may repeat each treatment cycle at approximately six-week intervals; if curvature deformity is <15 degrees after 1st, 2nd, or 3rd treatment cycle, or if further treatment not clinically indicated, do not administer subsequent treatment cycles
If curvature deformity is <15 degrees after 1st, 2nd, or 3rd treatment cycle, or if healthcare provider determines that further treatment not clinically indicated, then do not administer subsequent treatment cycles
Administration
Reconstitute lyophilized powder with supplied diluent prior to use
Should only be administered by healthcare providers trained for the various types of injection procedures of the hand or penis
Injection procedure for Dupuytren contracture
- Reconstitute according to instructions in IVand IM Information section
- Use a new 1 mL hubless syringe that contains 0.01 mL graduations with a permanently fixed, 27 gauge 0.5-in needle (not supplied), withdraw the volume of reconstituted solution containing 0.58 mg (0.25 mL for MP joint, 0.2 mL for PIP joint)
- Do not inject reconstituted solution if the solution contains particulates, is cloudy, or is discolored
- With your nondominant hand, secure the patient’s hand to be treated while simultaneously applying tension to the cord; with your dominant hand, place the needle into the cord, using caution to keep the needle within the cord; avoid having the needle tip pass completely through the cord to help minimize the potential for injection into tissues
- After needle placement, if there is any concern that the needle is in the flexor tendon, apply a small amount of passive motion at the distal interphalangeal (DIP) joint; if insertion of the needle into a tendon is suspected or paresthesia is noted by the patient, withdraw the needle and reposition it into the cord. If the needle is in the proper location, there will be some resistance noted during the injection procedure; after confirming that the needle is correctly placed in the cord, inject approximately one-third of the dose
- Next, withdraw the needle tip from the cord and reposition it in a slightly more distal location (approximately 2-3 mm) to the initial injection in the cord and inject another one-third of the dose
- Again withdraw the needle tip from the cord and reposition it a third time proximal to the initial injection (approximately 2-3 mm) and inject the final portion of the dose into the cord
- Wrap the patient’s treated hand with a soft, bulky, gauze dressing
- Instruct the patient to limit motion of the treated finger and to keep the injected hand elevated until bedtime
- Instruct the patient not to attempt to disrupt the injected cord by self-manipulation and to return to the provider’s office within 24-72 hr for follow-up and a finger extension procedure, if needed
- Discard unused portion of the reconstituted solution and diluent after injection; do not store, pool, or use any vials containing unused reconstituted solution or diluent
Finger extension procedure for Dupuytren contracture
- At the follow-up visit 24-72 hr after the injection, if a contracture remains, perform a passive finger extension procedure to facilitate cord disruption
- Local anesthesia may be used; avoid direct pressure on the injection site to avoid pain
- While the patient’s wrist is in the flexed position, apply moderate stretching pressure to the injected cord by extending the finger for approximately 10-20 seconds; for cords affecting the PIP joint, perform the finger extension procedure when the MP joint is in the flexed position
- If the first finger extension procedure does not result in disruption of the cord, a second and third attempt can be performed at 5-10 min intervals; however, no more than 3 attempts are recommended to disrupt a cord
- If the cord has not been disrupted after 3 attempts, a follow-up visit may be scheduled in approximately 4 wk; if, at that subsequent visit, the contracted cord persists, an additional injection with finger extension procedures may be performed
- Following the finger extension procedure(s), fit patient with a splint and provide instructions for use at bedtime for up to 4 months to maintain finger extension; also, instruct the patient to perform finger extension and flexion exercises several times a day for several months
Injection procedure for Peyronie disease
- Apply antiseptic at site of injection and allow skin to dry
- Administer suitable local anesthetic, if desired
- Using a new hubless syringe containing 0.01 mL graduations with a permanently fixed 27-gauge 1/2-inch needle withdraw 0.25 mL of reconstituted solution (containing 0.58 mg)
- Penis should be in flaccid state before injection
- Place needle tip on side of the target plaque in alignment with the point of maximal concavity
- Orient needle to enteredge of plaque and advance needle into plaque itself from the side; do not advance needle beneath plaque nor perpendicularly towards corpora cavernosum
- Insert and advance needle transversely through width of plaque, towards opposite side of plaque without passing completely through it; proper needle position is tested and confirmed by carefully noting resistance to minimal depression of syringe plunger
- With tip of needle placed within plaque, initiate injection, maintaining steady pressure to slowly inject it into plaque
- Withdraw needle slowly so as to deposit the full dose along needle track within plaque or plaques a few millimeters in width, the distance of withdrawal of 9 syringe may be very minimal; always deposit full dose entirely within plaque
- Upon complete withdrawal of needle, apply gentle pressure at injection site; apply dressing as necessary
- Discard unused portion of reconstituted solution and diluent after each injection; do not store, pool, or use any vials containing unused reconstituted solution or diluent
- Make the second injection of each treatment cycle approximately 2 to 3 mm apart from first injection
Penile modeling procedure for Peyronie disease
- Penile modeling helps relieve curvature deformity and straighten penile shaft; at follow-up visit 1 to 3 days after second injection of each treatment cycle, perform penile modeling procedure on flaccid penis to stretch and elongate treated plaque
- Administer suitable local anesthetic, if desired
- Wearing gloves, grasp plaque or indurated portion of flaccid penis about 1 cm proximal and distal to injection site
- Avoid direct pressure on injection site
- Using target plaque as fulcrum point, use both hands to apply firm, steady pressure to elongate and stretch plaque to gradually create bending opposite to patient’s penile curvature, with stretching to point of moderate resistance
- Hold pressure for 30 seconds then release
- After a 30 second rest period, repeat penile modeling technique for total of 3 modeling attempts at 30 seconds for each attempt; in addition to in-office penile modeling procedure, instruct patient to self-perform penile modeling activities at home each day for 6-week period following investigator penile plaque modeling visit of each treatment cycle
- During spontaneous erections, gently attempt to straighten penis without producing pain and hold penis in straightened position for 30 seconds
- The flaccid penis should be gently stretched three times daily; use slow, gentle force without producing pain
Pediatric dosage forms and strengths
Safety and efficacy not established
Xiaflex (collagenase clostridium histolyticum) adverse (side) effects
>10%
Dupuytren contracture
- Peripheral edema (ie, swelling of injected hand) (73%)
- Contusion (70%)
- Injection site hemorrhage (38%)
- Injection site reaction (35%)
- Pain in injected extremity (35%)
- Pruritus (14%)
- Lymphadenopathy (13%)
Peyronie Disease
- Penile hematoma (65.5%)
- Penile swelling (55%)
- Penile pain (45.4%)
- Penile ecchymoses (14.5%)
1-10%
Dupuytren contracture
- Skin laceration (9%)
- Lymph node pain (8%)
- Erythema (6%)
- Axillary pain (6%)
Peyronie Disease
- Blood blister (4.5%)
- Penile blister (3.3%)
- Pruritus genital (3.1%)
- Painful erection (2.9%)
- Erectile dysfunction (1.8%)
- Procedural pain (1.6%)
- Injection site vesicles (1.3%)
- Localized edema (1.3%)
- Dyspareunia (1.1%)
- Injection site pruritus (1.1%)
- Nodule (1.1%)
- Suprapubic pain (1.1%)
<1%
Peyronie Disease
- Corporal rupture
Warnings
Black box warnings
Corporal rupture (penile fracture) was reported as adverse reaction in clinical trials
Promptly evaluate signs or symptoms reflecting serious penile injury to assess for corporal rupture or severe penile hematoma which may require surgical intervention
Because of risks of corporal rupture or other serious penile injury, available for the treatment of Peyronie’s disease only through the XIAFLEX REMS Program
Contraindications
Hypersensitivity
Plaques that involve the penile urethra
Cautions
Pruritus experienced especially after more injections
Use with caution in patients with coagulation disorders, including in patients who have received anticoagulant medications other than low- dose aspirin within 7 days of the injection
Administration in patients with abnormal coagulation may result in ecchymosis/contusion or an injection site hemorrhage
Safety and efficacy when coadministered with anticoagulants (other than low-dose aspirin up to 150 mg/day) within 7 days of administration is unknown
Dupuytren contracture
- Tendon rupture of other serious injury to the injected extremity reported in clinical trials; avoid injecting XIAFLEX into tendons, nerves, blood vessels, or other collagen-containing structure of the hand
- Healthcare providers should be prepared to address hypersensitivity reactions, including anaphylaxis, following XIAFLEX injections
- Incidence of skin laceration (22%) was higher when treating 2 concurrent injections compared with up to 3 single injections in the placebo-controlled premarketing trials (9%)
Peyronie Disease
- The patient should not have sex between first and second injections of treatment cycle; patient should wait two weeks after second injection of treatment cycle before resuming sexual activity, provided pain and swelling have subsided
- May cause corporal rupture (penile fracture) or other serious injury to penis; avoid injecting into urethra, nerves, blood vessels, corpora cavernosa or other collagen-containing structures of the penis since may result in possible permanent injury (eg, corporal rupture)
- If patient experiences severe pain or swelling of the penis, severe purple bruising and swelling of the penis, difficulty urinating or blood in the urine, sudden loss of ability to maintain an erection, should contact health care provider
Pregnancy and lactation
Pregnancy category: B
Lactation: Unknown whether distributed in breast milk, caution advised
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Xiaflex (collagenase clostridium histolyticum)
Mechanism of action
Proteinase that hydrolyzes collagen in its native triple-helical conformation, resulting in lysis of collagen deposits
Injection of into a Dupuytren’s cord, which is comprised mostly of collagen, may result in enzymatic disruption of the cord
Believed to work for Peyronie’s disease by breaking down the buildup of collagen (a structural protein in connective tissue) that causes the curvature deformity
Pharmacokinetics
Absorption: Not absorbed
Administration
Intralesional Injection Preparation
Reconstitution of lyophilized powder
- Must reconstitute lyophilized powder with provided diluent prior to use
- Remove from lyophilized powder and diluent from refrigerator and allow to stand at room temperature for at least 15 min (not to exceed 60 min)
- Remove flip off cap from each vial, utilize aseptic technique and swab rubber stoppers of each vial with sterile alcohol
- Use only the supplied diluent for reconstitution (contains calcium required for activity of collagenase clostridium histolyticum
- Use 1-mL syringe with 0.01 mL gradations and 27-ga 0.5-in needle to withdraw diluent
- Inject diluent slowly into side of lyophilized powder vial, then slowly swirl solution to ensure al powder has gone into solution
- Do not invert vial or shake the solution
Sterile diluent volume for reconstitution
- MP joints: Reconstitute with 0.39 mL diluent (resulting concentration 0.58 mg/0.25 mL)
- PIP joints: Reconstitute with 0.31 mL diluent (resulting concentration
Peyronie Disease
- Using a 1 mL syringe with 0.01 mL graduations with a 27-gauge 1/2-inch needle, withdraw 0.39 mL of diluent supplied
- Inject diluent slowly along sides of vial containing the lyophilized powder; do not invert vial or shake solution; slowly swirl solution to ensure all lyophilized powder has gone into solution
- The reconstituted solution can be kept at room temperature (20-25ºC [68-77ºF]) for up to 1 hr or refrigerated at 2-8 degrees C (36-46ºF) for up to 4 hr prior to administration; if econstituted XIAFLEX solution is refrigerated, allow solution to return to room temperature for approximately 15 min before use
- Discard syringe and needle used for reconstitution and the diluent vial
Storage
Prior to reconstitution, store lyophilized powder for injection and diluent refrigerated
Reconstituted solution stable at room temperature (20-25ºC [68-77ºF]) up to 1 h, or refrigerated (2-8ºC [36-46ºF) up to 4 h before administration
