ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Xiapex 0.9 mg powder and solvent for solution for injection.
2.
Each vial of powder contains 0.9 mg of collagenase
clostridium histolyticum
*.
*A formulation of two collagenase enzymes co-expressed and harvested from anaerobic fermentation
of a phenotypically selected strain of C
lostridium histolyticum
bacterium.
Excipients:
Sodium injected per joint:
Metacarpophalangeal (MP) joints: 0.9 mg.
Proximal interphalangeal (PIP) joints: 0.7 mg.
For a full list of excipients, see section 6.1.
3.
Powder and solvent for solution for injection.
(Powder for injection).
The powder is a white lyophilised powder.
The solvent is a clear colourless solution.
4.
Xiapex is indicated for the treatment of Dupuytren’s contracture in adult patients with a palpable cord.
Xiapex must be administered by a physician appropriately trained in the correct administration of the
product and experienced in the diagnosis and management of Dupuytren’s disease.
Posology
The recommended dose of Xiapex is 0.58 mg per injection into a palpable Dupuytren’s cord. The
volume of reconstituted Xiapex to be administered into the Dupuytren’s cord differs depending on the
type of joint being treated (see Table 1).
Approximately 24 hours after injection, a finger extension procedure may be performed, as necessary,
to facilitate cord disruption. If a satisfactory response has not been achieved, the injection and finger
extension procedures may be repeated after approximately 4 weeks. Injections and finger extension
procedures may be administered up to 3 times per cord at approximately 4-week intervals. Only one
cord must be treated at a time. If the disease has resulted in multiple contractures, treatment of each
cord must be undertaken in a sequential order, as determined by the physician. Clinical study
experience with Xiapex is currently limited to up to 3 injections per cord and up to 8 injections in
total.
2
Patients should be instructed to return to see their physician the next day for an examination of the
injected hand and a finger extension procedure to disrupt the cord.
Special population
Elderly
Due to the lack of quantifiable systemic exposure of Xiapex no dose adjustment is necessary. No
overall differences in safety or effectiveness were observed between elderly and younger patients.
Hepatic Impairment
Due to the lack of quantifiable systemic exposure, no dose adjustment is necessary.
Renal Impairment
Due to the lack of quantifiable systemic exposure, no dose adjustment is necessary.
Paediatric population
There is no relevant use of Xiapex in the paediatric population aged 0-18 years for the treatment of
Dupuytren’s contracture.
Method of administration
Intralesional use.
For single use only
Volume for reconstitution
Xiapex must only be reconstituted with the solvent provided and to the appropriate volume prior to
use:
-For metacarpophalangeal (MP) joints use 0.39 ml of solvent.
-For proximal interphalangeal (PIP) joints use 0.31 ml of solvent (see Table 1).
Volume for injection
-For cords affecting MP joints each dose is administered in an injection volume of 0.25 ml.
-For cords affecting PIP joints, each dose is administered in an injection volume of 0.20 ml.
Table 1. Volumes needed for reconstitution and administration
Joint to be treated
Solvent
required for
reconstitution
Injection volume
to deliver
Xiapex 0.58 mg
dose†
MP joints
0.39 ml
0.25 ml
PIP joints
0.31 ml
0.20 ml
†Note that injection volume for delivery of a 0.58 mg dose is less
than the total volume of solvent used for reconstitution.
Patients should be instructed:
Not to flex or extend the fingers of the injected hand to reduce extravasation of Xiapex out
of the cord until the finger extension procedure is completed.
Not to attempt to disrupt the injected cord by self manipulation at any time.
3
To elevate the injected hand as much as possible until the day after the finger extension
procedure.
Detailed instructions for the physician in the preparation of the medicinal product for injection
(reconstitution procedure) are provided in section 6.6.
Hypersensitivity to the active substance or to any of the excipients.
Allergic reactions
In the double blind portion of the three phase 3 placebo-controlled clinical studies, 17% of Xiapex-
treated patients had mild allergic reactions (i.e. pruritus). Although there were no severe allergic
reactions observed in the Xiapex studies (e.g., those associated with respiratory impairment,
hypotension, or end-organ dysfunction) physicians must be prepared to address any severe local or
systemic allergic reactions including the potential for anaphylaxis that may occur following injection
.
Whilst there is no evidence from the clinical data of an increased risk of serious allergic reactions
upon repeated injections, the potential for such reactions following repeated use cannot be excluded.
Tendon rupture or other serious injury to the injected extremity
Xiapex must only be injected into the Dupuytren’s cord. Because Xiapex lyses collagen, care must be
taken to avoid injecting into tendons, nerves, blood vessels, or other collagen-containing structures of
the hand. Injection of Xiapex into collagen containing structures may result in damage to those
structures, and possible permanent injury such as tendon rupture or ligament damage. When injecting
a cord affecting a PIP joint of the fifth finger, the needle insertion must not be more than 2 to 3 mm in
depth and not more than 4 mm distal to the palmar digital crease. Patients should be instructed to
promptly contact the physician if there is trouble bending the finger after the swelling goes down
(symptoms of tendon rupture).
Patients with Dupuytren’s contractures that adhere to the skin may be at higher risk of skin lesions as
a result of the pharmacological effect of Xiapex and the finger extension procedure on the skin
overlying the targeted cord.
Use in patients with coagulation disorders
Xiapex must be used with caution in patients with coagulation disorders or those taking
anticoagulants. In the three double-blind, placebo-controlled phase 3 studies, 73% of Xiapex-treated
patients reported an ecchymosis or a contusion and 38% reported a haemorrhage at the injection site.
The efficacy and safety of Xiapex in patients receiving anticoagulant medicinal products other than up
to 150 mg acetylsalicylic acid per day prior to Xiapex administration is not known. Use of Xiapex in
patients who have received anticoagulants (with the exception of up to 150 mg acetylsalicylic acid
daily) within 7 days prior to receiving an injection of Xiapex is not recommended.
Immunogenicity
As with any non-human protein medicinal product, patients may develop antibodies to the therapeutic
protein. During clinical studies, blood samples from patients with Dupuytren’s contracture were tested
at multiple time points for antibodies to the protein components of the medicinal product (AUX-I and
AUX-II). At 30 days post the first injection, 92% of patients had circulating antibodies detected
against AUX-I and 86% of patients against AUX-II. After a third or fourth injection, all subjects
developed positive antibodies to both AUX-I and AUX-II. No apparent correlation of antibody
development to clinical response or adverse reactions was observed. Since the enzymes in XIAPEX
have some sequence homology with human matrix metalloproteinases (MMPs), anti-drug antibodies
(ADA) could theoretically interfere with human MMPs. No safety concerns related to the inhibition of
endogenous MMPs have been observed, in particular no adverse events indicating the development or
exacerbation of autoimmune diseases or the development of a musculoskeletal syndrome (MSS).
Whilst there is no clinical evidence from the current safety data of a musculoskeletal syndrome
4
developing following the administration of XIAPEX, the potential for it to occur cannot be excluded.
If this syndrome were to develop, it would occur progressively and is characterized by one or more of
the following signs and symptoms: arthralgia, myalgia, joint stiffness, stiffness of the shoulders, hand
oedema, palmar fibrosis and thickening or nodules forming in the tendons.
Long-term safety
Long-term safety of Xiapex is not fully characterised. The impact of treatment with Xiapex on
subsequent surgery, if needed, is not known.
Excipients
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-
free’.
Due to the lack of quantifiable systemic exposure, no formal medicinal product interaction studies
with Xiapex have been performed.
Whilst there is no clinical evidence of an interaction between tetracycline and
anthracycline/anthraquinolone antibiotics and anthraquinone derivatives and Xiapex, such
derivatives have been shown to inhibit matrix metalloproteinase-mediated collagen degradation at
pharmacologically relevant concentrations
in vitro
. Therefore, use of Xiapex in patients who have
received tetracycline antibiotics (e.g. doxycycline) within 14 days prior to receiving an injection of
Xiapex is not recommended.
Pregnancy and fertility
For Xiapex no clinical data on exposed pregnancies are available. Animal studies do not indicate
direct or indirect harmful effects with respect to fertility, pregnancy, or embryonal/ foetal
development, (see section 5.3). Parturition or postnatal development studies in animals were not
conducted since human pharmacokinetic studies show that Xiapex levels are not quantifiable in the
systemic circulation following injection into a Dupuytren’s cord (see section 5.1). Patients develop
ADAs after repeated administration, the cross-reactivity of which versus endogenous MMPs involved
in pregnancy and labour cannot be excluded. The potential risk for humans on parturition and
postnatal development is unknown. Therefore the use of Xiapex is not recommended in pregnancy
and treatment should be postponed until after pregnancy.
Breast-feeding
No effect on the breastfed newborn/infant is anticipated since the systemic exposure of the breast-
feeding woman to Xiapex is negligible. Xiapex can be used during breast-feeding.
Xiapex may have a major influence on the ability to drive and use machines due to the swelling and
pain which may impair the use of the treated hand. Other minor influences on the ability to drive and
use machines include dizziness, paresthesia, hypoesthesia, and headache that have also been reported
following injection of Xiapex. Patients must be instructed to avoid potentially hazardous tasks such as
driving or using machines until it is safe to do so or as advised by the physician.
Xiapex 0.58 mg was studied in patients with Dupuytren’s contracture in three randomised, double-
blind, placebo-controlled studies. The double-blind study population comprised 409 patients of whom
5
272 received Xiapex 0.58 mg and 137 received placebo. The mean age was 63 years (range 33 to
89 years) and 80% of patients were male.
The most frequently reported adverse reactions during the Xiapex clinical studies were local injection
site reactions such as oedema peripheral (local to the injection site), contusion (including
ecchymosis), injection site haemorrhage and injection site pain. Injection site reactions were very
common, occurring in the vast majority of patients, were mostly mild to moderate in severity and
generally subsided within 1-2 weeks post injection. Serious adverse reactions of tendon rupture
(3 cases), tendonitis (1 case), other ligament injury (1 case) and complex regional pain syndrome
(1 case) related to the medicinal product were reported.
Table 2 presents adverse reactions listed by system organ class and frequency categories, using the
following convention: very common (≥1/10), common (≥1/100 to <1/10), and uncommon (≥1/1,000 to
<1/100).Within each frequency group, adverse reactions are presented in order of decreasing
seriousness. Adverse reactions reported from the clinical programme are those that occurred in the
Phase 3 double blind placebo controlled studies.
Table 2: Tabulated list of adverse reactions.
System organ class
Very common
Common
Uncommon
Infections and infestations
injection site cellulitis
Blood and lymphatic
system disorders
lymphadenopathy
lymph node pain
thrombocytopenia
Immune system disorders
hypersensitivity
Psychiatric disorders
disorientation
agitation
insomnia
irritability
restlessness
Nervous system disorders
paresthesia
hypoesthesia
burning sensation
dizziness
headache
complex regional pain syndrome
monoplegia
syncope vasovagal
tremor
Eye disorders
eyelid oedema
Vascular disorders
haematoma
hypotension
Respiratory, thoracic and
mediastinal disorders
dyspnoea
hyperventilation
Gastrointestinal disorders
nausea
diarrhoea
vomiting
abdominal pain upper
Skin and subcutaneous
tissue disorders
pruritus
ecchymosis
blood blister
blister
rash
erythema
hyperhidrosis
rash erythematous
rash macular
eczema
swelling face
pain of skin
skin exfoliation
skin lesion
skin disorder
scab
skin discoloration
skin tightness
6
Musculoskeletal and
connective tissue disorders
pain in extremity
arthralgia
joint swelling
myalgia
axillary mass
chest wall pain
groin pain
joint crepitation
joint stiffness
limb discomfort
muscle spasms
muscular weakness
musculoskeletal discomfort
musculoskeletal stiffness
neck pain
shoulder pain
Reproductive system and
breast disorders
breast tenderness
hypertrophy breast
General disorders and
administration site
conditions
oedema peripheral*
injection site
haemorrhage
injection site pain
injection site
swelling
tenderness
axillary pain
inflammation
injection site
inflammation
swelling
injection site
erythema
injection site
pruritus
injection site
warmth
injection site
vesicles
local swelling
pyrexia
pain
discomfort
fatigue
feeling hot
influenza like illness
injection site anaesthesia
injection site desquamation
injection site discoloration
injection site irritation
injection site nodule
injection site reaction
malaise
Investigations
lymph node palpable
alanine aminotransferase
increased
aspartate aminotransferase
increased
body temperature increased
Injury, poisoning and
procedural complications
contusion
skin laceration
tendon rupture
ligament injury
limb injury
open wound
wound dehiscence
* “oedema peripheral” includes “injection site oedema” and “oedema”
Administration of Xiapex at greater than recommended doses is expected to be associated with
increased local reactions at the site of injection. Routine supportive care and symptomatic treatment
must be provided in the case of overdose.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other Drugs For Disorders of the Musculo-Skeletal System – Enzymes,
ATC code: M09AB02
7
Xiapex is a lyophilized product for parenteral administration containing collagenase
clostridium
histolyticum
which is comprised of two collagenases in a defined mass ratio. These collagenases,
referred to as AUX-I and AUX-II, are representative of the two major collagenase classes (Class I and
Class II) produced by
Clostridium histolyticum.
AUX-I and AUX-II are single polypeptide chains
consisting of approximately 1000 amino acids of known sequence with a molecular weight of 114 kDa
and 113 kDa respectively as determined by mass spectrometry. The two polypeptides are purified by
chromatographic steps customary for the separation and isolation of biotherapeutic proteins to yield a
consistent, well characterized and controlled mixture of two collagenase enzymes.
Because the collagen lysis process following Xiapex administration is localized and does not require
or result in quantifiable systemic levels of AUX-I and AUX-II, the primary pharmacodynamic activity
of Xiapex cannot be evaluated in subjects and therefore, such studies have not been undertaken.
Mechanism of action
Collagenases are proteinases that hydrolyze collagen under physiological conditions. Injection of
Xiapex into a Dupuytren’s cord, which is comprised mostly of interstitial collagen types I and III,
results in enzymatic disruption of the cord. Xiapex is comprised of a mixture of Class I (AUX-I) and
Class II (AUX-II) clostridial collagenases in a defined mass ratio. The two classes of collagenases
have similar but complementary substrate specificity. Both collagenases effectively cleave interstitial
collagen but at different sites on the molecule; additionally, they prefer different conformations (triple
helical versus denatured or cleaved). These differences account for the ability of the two classes of
enzymes to digest collagen in a complementary manner. Class I collagenases (α, β, γ, and η) are the
products of the
colG
gene, they initiate collagen hydrolysis near the amino and carboxy termini of
triple helical domains, and generate large proteolytic fragments. In contrast, the Class II collagenases
(δ, ε, and ζ,) are products of
colH
gene, their initial cleavage sites are located within the interior of the
collagen molecule, and generate smaller collagen fragments. Both classes of collagenases readily
hydrolyze gelatin (denatured collagen) and small collagen peptides, whereas Class II has higher
affinity for small collagen fragments. Class I cleaves insoluble triple helical collagen with higher
affinity than Class II collagenase. Together, these collagenases work to provide broad hydrolytic
activity towards collagen.
Clinical results
The efficacy of Xiapex 0.58 mg was evaluated in two pivotal randomized, double-blind, placebo-
controlled studies, CORD I (AUX-CC-857) and CORD II (AUX-CC-859), in adult patients with
Dupuytren’s contracture. At study entry, patients in the clinical studies 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 MP
joint or 20
°
to 80
°
in 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. The cord affecting a
selected primary joint received up to 3 injections of 0.58 mg of Xiapex or placebo. A finger extension
procedure was performed if needed, approximately 24 hours after injection to facilitate disruption of
the cord. Each injection was separated by approximately 4 weeks.
The primary endpoint of each study was to evaluate the proportion of patients who achieved a
reduction in contracture of the selected primary joint (MP or PIP) to 5° or less of normal,
approximately 4 weeks after the last injection of that joint. Other endpoints included ≥50% reduction
from baseline in degree of contracture, percent change from baseline in degree of contracture, change
from baseline in range of motion, subject global assessment of treatment satisfaction and physician
global assessment of severity.
Xiapex demonstrated a clinically significant benefit compared to placebo in the proportion of patients
achieving the primary endpoint of a reduction in the contracture of all joints treated to 5° or less,
approximately 4 weeks after the last injection (MP plus PIP, MP only, PIP only). For patients who
achieved a contracture of the selected joint to 5° or less, the mean number of injections required to
achieve this was 1.5 in the 2 studies. Xiapex also demonstrated a clinically significant benefit
8
compared to placebo in decreasing the degree of contracture and increasing both the range of motion
from baseline for all joints treated (MP plus PIP, MP only, PIP only) and the subject global
assessment of treatment satisfaction.
Table 3 provides demographic and baseline characteristics for the study population and Tables 4-5
provide the results of the major efficacy endpoints measured in the 2 double-blind placebo controlled
studies CORD I (AUX-CC-857) and CORD II (AUX-CC-859).
Table 3.
Demographic and baseline characteristics
Phase 3 Double-Blind, Placebo controlled studies (CORD I, CORD II)
VARIABLE
Xiapex
(N=249)
Placebo
(N=125)
Age (years)
Mean
62.7
64.2
Age category (years), n (%)
< 45
9 (3.6)
5 (4.0)
45 – 54
33 (13.2)
17 (13.6)
55 – 64
103 (41.4)
44 (35.2)
65 – 74
82 (33.0)
40 (32.0)
≥ 75
22 (8.8)
19 (15.2)
Gender, n (%)
Male
210 (84.3)
91 (72.8)
Female
39 (15.7)
34 (27.2)
Family history of Dupuytren’s disease, n
(%)
Yes
107 (43.0)
62 (49.6)
No
142 (57.0)
63 (50.4)
Physician Rating of Severity at Baseline
Mild
38 (15.4 %)
21 (16.8 %)
Moderate 148 (59.9 %) 71 (56.8 %)
Severe 61 (24.7 %) 33 (26.4 %)
Missing
1
2 (0.8 %) -
Note: Includes all patients who received at least 1 injection of double-blind study
medicinal product (Xiapex 0.58 mg or placebo).
1
Not used to calculate physician rating of severity at baseline percentage – actual
denominator of N=247 used.
9
Table 4.
Percentage of patients who achieved reduction in contracture to 5° or less
(Last injection)
CORD I
CORD II
Xiapex
Placebo
Xiapex
Placebo
N=203
c
N=103
c
N=45
N=21
All Joints
p-value
64.0 %
<0.001
6.8 %
-
44.4 %
<0.001
4.8 %
-
MP Joints
a
N=133
N=69
N=20
N=11
p-value
76.7 %
<0.001
7.2 %
-
65.0 %
0.003
9.1 %
-
PIP Joints
b
N=70
N=34
N=25
N=10
0.0 %
-
a
Metacarpophalangeal joint;
b
Proximal interphalangeal joint;
c
2 primary
joints were excluded from the efficacy analysis (1 joint from the placebo
group was not evaluated and 1 joint from the Xiapex treated group had
a baseline contracture of 0 degrees before treatment).
40.0 %
<0.001
5.9 %
-
28.0 %
0.069
TREATED
PRIMARY JOINTS
Table 5.
Mean increase in range of motion from baseline
(Last injection)
CORD I
CORD II
Xiapex
Placebo
Xiapex
Placebo
All Joints
N=203
c
N=103
c
N=45
N=21
Mean Baseline (SD)
Mean Final (SD)
Mean increase (SD)
43.9 (20.1)
80.7 (19.0)
36.7 (21.0)
45.3 (18.7)
49.5 (22.1)
4.0 (14.8)
40.3 (15.2)
75.8 (17.7)
35.4 (17.8)
44.0 (16.5)
51.7 (19.6)
7.6 (14.9)
MP Joints
a
N=133
N=69
N=20
N=11
Mean Baseline (SD)
Mean Final (SD)
Mean increase (SD)
42.6 (20.0)
83.7 (15.7)
40.6 (20.0)
45.7 (19.2)
49.7 (21.1)
3.7 (12.6)
39.5 (11.8)
79.5 (11.1)
40.0 (13.5)
41.4 (20.8)
50.0 (21.5)
8.6 (14.7)
PIP Joints
b
N=70
N=34
N=25
N=10
47.0 (10.3)
53.5 (18.3)
6.5 (15.8)
a
Metacarpophalangeal joint;
b
Proximal interphalangeal joint;
c
2 primary joints
were excluded from the efficacy analysis (1 joint from the placebo group was
not evaluated and 1 joint from the Xiapex treated group had a baseline
contracture of 0 degrees before treatment).
All p-values < 0.001 for all comparisons between Xiapex and placebo, except
for PIP joints in Study CORD II which was not eligible for statistical testing due
to a hierarchical testing procedure.
46.4 (20.4)
74.9 (23.1)
29.0 (20.9)
44.4 (17.9)
49.1 (24.4)
4.7 (18.5)
41.0 (17.7)
72.8 (21.3)
31.8 (20.1)
10
TREATED
PRIMARY JOINTS
p-value
Mean Baseline (SD)
Mean Final (SD)
Mean increase (SD)
Physician-rated change in contracture severity was reported as very much improved or much improved
in 86% and 80% of the subjects in the Xiapex group compared to 3% and 5% of subjects in the
placebo group for the CORD I and CORD II studies, respectively (p<0.001). Based on the Patient
Global Assessment of Treatment Satisfaction, more than 85% of subjects in the CORD I and CORD II
studies reported either being quite satisfied or very satisfied with their treatment with Xiapex versus
approximately 30% treated with placebo (p<0.001). Greater patient satisfaction was correlated with
improved range of motion (r=0.51, p<0.001).
Recurrence of contracture was evaluated in joints that achieved the primary endpoint, a reduction in
contracture to 5° or less. Recurrence was defined as an increase in joint contracture to at least 20° in
the presence of a palpable cord, at any time during the double-blind phase or open-label extension
phase that persisted at the last available measurement. In a pooled analysis, across the pivotal Phase 3
double-blind placebo controlled and open label studies, there were a total of 838 successfully treated
joints. Of these, 28 joints (7 MP and 21 PIP joints) had a recurrent contracture, giving a recurrence
rate of 3.3% at 12 months after subjects had achieved clinical success following treatment with
Xiapex.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with
Xiapex in all subsets of the paediatric population in the treatment of Dupuytren’s contracture (see
section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Absorption and Distribution
Following administration of a single dose of 0.58 mg of Xiapex to 16 patients with Dupuytren’s
contracture, no quantifiable levels of Xiapex were detected in plasma from 5 minutes to 30 days post
injection. There has been no evidence of systemic toxicity to date in the clinical studies conducted
with Xiapex administered through localized injection into the Dupuytren’s cord.
Biotransformation and Elimination
Because Xiapex is not a substrate for cytochrome P450 or other medicinal product metabolizing
enzyme pathways, and because no active metabolites are expected, no metabolism studies have been
performed.
Because there is no quantifiable systemic exposure following a single injection of Xiapex, no formal
studies on elimination have been performed.
Special subject groups
Paediatric population
Xiapex has not been studied in children aged 0-18 years and hence no pharmacokinetic data are
available.
Due to the lack of quantifiable systemic exposure of Xiapex no dose adjustment is necessary
in any
special subject groups e.g., Elderly, Renally or Hepatically Impaired, by Gender or Race.
11
5.3 Preclinical safety data
Carcinogenesis, Mutagenesis, Impairment of Fertility
Standard two-year rodent bioassays have not been performed with Xiapex. Thus, the carcinogenic risk
is unknown.
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.
When Xiapex was given intravenously every other day to male and female rats before cohabitation
and through mating and implantation, no effects on the oestrus cycle, tubal transport, implantation and
pre-implantation development and/or on libido or epididymal sperm maturation were noted with
intravenous doses up to 0.13 mg/dose (approximately 11 times the human dose on a mg/m
2
basis).
There were no adverse reactions on early embryonic development (indicating no evidence of
teratogenicity) in rats. No systemic toxicity was observed in this study at any dose level.
6.
6.1 List of excipients
Powder
Sucrose
Trometamol
Hydrochloric acid 2.4% w/w (for pH adjustment)
Solvent
Calcium chloride dihydrate
Sodium chloride
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products or solvents for reconstitution.
6.3 Shelf life
2 years.
After reconstitution, immediate use is recommended. Reconstituted Xiapex can be kept at ambient
room temperature (20ºC-25ºC) for up to one hour or refrigerated 2ºC-8˚C for up to 4 hours prior to
administration. If refrigerated, the reconstituted solution must be allowed to return to ambient room
temperature (20ºC-25ºC) for approximately 15 minutes before use.
6.4 Special precautions for storage
Store in a refrigerator (2ºC-8ºC).
Do not freeze.
For storage condition of the reconstituted medicinal product, see section 6.3.
12
6.5
Nature and contents of container
Xiapex powder is supplied in a clear glass vial (3 ml, type I glass) with rubber stopper, aluminium
seal and flip-off cap (polypropylene).
Solvent
: 3 ml solution supplied in a clear glass vial (5 ml, type I glass) with rubber stopper, aluminium
seal and flip-off cap (polypropylene).
Pack of 1 vial of powder and 1 vial of solvent
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material must be disposed of in accordance with local
requirements.
Detailed information on the injection procedure and finger extension procedure are provided in the
package leaflet.
Instructions for use and handling
Preparation - Reconstitution procedure
The single dose vial containing Xiapex and the single dose vial containing the solvent for solution for
injection for reconstitution must be refrigerated. Prior to use, the vial containing Xiapex and the vial
containing the solvent for solution for reconstitution must be removed from the refrigerator and
allowed to stand at room temperature for at least 15 minutes and no longer than 60 minutes
.
Using an aseptic technique, the following procedure for reconstitution must be followed:
1. Confirm the joint to be treated (MP or PIP) as the volume of solvent required for reconstitution is
determined by the type of joint (PIP joint requires a smaller volume for injection).
2. Remove the flip-off plastic caps from both vials and swab the rubber stopper and surrounding
surface of the vial containing Xiapex and the vial containing the solvent for reconstitution with sterile
alcohol (no other antiseptics must be used).
3. Use only the supplied solvent for reconstitution; it contains calcium which is required for the
activity of Xiapex. Using a sterile syringe calibrated with 0.01 ml graduations, withdraw the
appropriate amount of solvent supplied in order to deliver as follows:
0.39 ml for cords affecting a MP joint or
0.31 ml for cords affecting a PIP joint
4. Inject the solvent slowly into the sides of the vial containing the lyophilised powder of Xiapex. Do
not invert the vial or shake the solution. Slowly swirl the solution to ensure that all of the lyophilised
powder has gone into solution. Remove and discard the syringe and needle used for reconstitution.
5. Inspect the solution visually for particulate matter and discoloration prior to administration. The
reconstituted solution of Xiapex must be clear. If the solution contains particles, is cloudy or
discoloured, do not inject it.
Pfizer Limited
Ramsgate Road
Sandwich, Kent
CT13 9NJ
United Kingdom
13
8.
9.
Detailed information on this product is available on the website of the European Medicines
Agency http://www.ema.europa.eu
14
ANNEX II
A.
MANUFACTURER OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER(S) RESPONSIBLE FOR BATCH RELEASE
B
.
CONDITIONS OF THE MARKETING AUTHORISATION
15
A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND>
MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers of the biological active substance
Auxilium Pharmaceuticals Inc
102 Witmer Road, Horsham, PA 19044.
USA
Name and address of the manufacturer responsible for batch release
Pfizer Manufacturing Belgium NV
Rijksweg 12, 2870 Puurs
Belgium
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
The MAH shall ensure that all physicians who are expected to prescribe/use Xiapex are appropriately
trained in the correct administration of the product and experienced in the diagnosis and management
of Dupuytren’s disease.
The MAH, in agreement with the competent authorities in the Member States, shall implement, prior
to the launch, an educational programme for physicians aiming to ensure proper injection placement
to minimize occurrence of injection-related adverse events and to inform on expected and potential
risks associated with the treatment.
The physician educational programme should contain the following key elements:
Injection technique and dosing interval.
Proper amount of volumes for both reconstitution and injection differences in the
metocarpophalangeal (MP)
and
proximal interphalangeal (PIP)
joints.
Recognition and treatment of severe immune-mediated reaction, including anaphylaxis.
Information on bleeding risk in patients with coagulation disorders including those on concurrent
anti-coagulation therapy.
Information on the potential risk of
matrix metalloproteinases
(MMP) cross reactivity including
the development of musculoskeletal syndrome and exacerbation/initiation of autoimmune
disorders.
Reminder of the need to report adverse events, including medication errors.
The need to inform the patient about the signs and symptoms associated with the treatment and
when to seek attention from the health care provider.
The summary of product characteristics and the patient information leaflet
OTHER CONDITIONS
Pharmacovigilance system
16
The MAH must ensure that the system of pharmacovigilance presented in Module 1.8.1. of the
Marketing Authorisation Application, is in place and functioning before and whilst the product
is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities
detailed in the Pharmacovigilance Plan, as agreed in version 6.0 of the Risk Management Plan
(RMP) presented in Module 1.8.2. of the Marketing Authorisation Application and any
subsequent updates of the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted:
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
At the request of the European Medicines Agency
17
ANNEX III
LABELLING AND PACKAGE LEAFLET
18
A. LABELLING
19
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton containing 1 vial of powder and 1 vial of solvent
1.
XIAPEX 0.9 mg powder and solvent for solution for injection.
collagenase
clostridium histolyticum
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each powder vial contains 0.9 mg collagenase
clostridium histolyticum
3.
LIST OF EXCIPIENTS
Powder: Contains sucrose, trometamol, hydrochloric acid
Solvent: Contains calcium chloride dihydrate, sodium chloride, water for injection
4.
Powder and solvent for solution for injection
1 vial of powder
1 vial of solvent
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Reconstitute with appropriate volume before use.
Intralesional use only
Read the package leaflet before use.
For single use only
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SITE OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
20
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator. Do not freeze.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Pfizer Ltd.
Ramsgate Road
Sandwich, Kent
CT13 9NJ
United Kingdom
13. BATCH NUMBER, DONATION AND PRODUCT CODES
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
21
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
XIAPEX powder vial label
1.
XIAPEX 0.9 mg powder for injection
collagenase
clostridium histolyticum
Intralesional use
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER, DONATION AND PRODUCT CODES
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
6.
OTHER
22
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Solvent vial for use with XIAPEX label
1.
Solvent for XIAPEX
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER, DONATION AND PRODUCT CODES
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
3 ml
6.
OTHER
23
B. PACKAGE LEAFLET
24
PACKAGE LEAFLET: INFORMATION FOR THE USER
Xiapex 0.9 mg powder and solvent for solution for injection
collagenase
clostridium histolyticum
Read all of this leaflet carefully before you are given this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor.
-
This medicine has been prescribed for you and must only be administered by your doctor.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1. What Xiapex is and what it is used for
2. Before you are given Xiapex
3. How Xiapex is administered
4. Possible side effects
5.
How to store Xiapex
6.
Further information
1.
WHAT XIAPEX IS AND WHAT IT IS USED FOR
Xiapex is used for the treatment of Dupuytren’s contracture in adult patients with a palpable cord.
Dupuytren’s contracture is a disease that causes your finger(s) to bend inward. This bending is called
a contracture and is caused by the abnormal formation of a cord containing collagen under your skin.
For many people, a contracture causes significant difficulties with performing everyday tasks like
driving, shaking hands, playing sports, opening jars, typing or holding objects.
The active substance is collagenase
clostridium histolyticum
, and is naturally produced by a bacterium
named
Clostridium histolyticum
. Xiapex is injected into this cord by your doctor and works by
breaking down the collagen in the cord and thereby helps to remove the cause of your contracture so
that your finger(s) can straighten.
2.
BEFORE YOU ARE GIVEN XIAPEX
You must not be given Xiapex
If you are allergic (hypersensitive) to collagenase
clostridium histolyticum
or any of the other
ingredients of Xiapex (see section 6 ‘further information’ for a full list of ingredients).
Take special care with Xiapex
This medicine must only be injected into the collagen cord in your hand by your doctor. Your doctor
will take care to avoid injecting into tendons, nerves or blood vessels. Incorrect injection into tendons,
nerves or blood vessels may result in bleeding or damage and possible permanent injury to these
structures. If your cord to be treated is attached to the skin, you are at higher risk of the skin splitting
or tearing during the finger extension procedure following the injection of Xiapex.
No evidence of an increased risk of serious allergic reactions or the development of a musculoskeletal
syndrome upon repeated use of Xiapex has been demonstrated. However the potential for such
adverse reactions to occur cannot be excluded. The symptoms of musculoskeletal syndrome could be
joint or muscle pain, shoulder stiffness, hand swelling, fibrosis of the palms, and thickening or nodule
forming of tendons. If you notice such symptoms you should inform your doctor.
25
Before you are given this medicine, make sure your doctor knows:
if you have a history of problems with the normal clotting of your blood or if you are taking
any medicines to help control the normal clotting of your blood (known as anticoagulation
medicines).
if you are currently taking any anticoagulation medicines, you must not receive Xiapex within
7 days of last dose of your anticoagulation medicine. One exception is the use of up to 150 mg
daily dose of acetylsalicylic acid (a substance present in many medicines used to prevent
blood clotting) which can be taken.
Children
Xiapex has not been tested in children, therefore the use in children aged 0-18 years is not
recommended.
Taking other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines to help control the normal clotting of your blood (known as anticoagulation medicines),
anthraquinone derivatives, some antibiotics (tetracyclines and anthracyclines/anthraquinolones) used
to treat infections and those medicines obtained without a prescription.
Pregnancy and breast-feeding
Please tell your doctor if you are pregnant or if you are planning to become pregnant. There is no
experience in the use of Xiapex in pregnant women therefore the use of Xiapex is not recommended
in pregnancy, and treatment should be postponed until after pregnancy.
Xiapex can be used during breast-feeding.
Driving and using machines
Swelling and pain which may impair the use of the treated hand and dizziness, numbness or altered
sensation, and headache have been reported as side effects immediately after injection of Xiapex. You
must avoid potentially hazardous tasks such as driving or using machines until it is safe to do so or as
advised by your doctor.
Important information about some of the ingredients of Xiapex
This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially ‘sodium- free’.
3.
HOW XIAPEX IS ADMINISTERED
Your doctor will perform all injections of Xiapex.
The recommended dose of your prescribed medicine is 0.58 mg.
The total volume of the injection depends on the joint being treated. Your doctor will carefully select
an area where the collagen cord is best accessible and will proceed with the injection into the cord.
After the injection, your doctor will place a dressing on your hand. You must limit motion of the
treated finger for a day and it is not uncommon for the finger to straighten on its own for some
patients. Until advised by your doctor, do not flex or extend the fingers of the injected hand. Do not
attempt to disrupt the injected cord by self manipulation at any time. Elevate the injected hand as
much as possible until the day after the finger extension procedure.
Your doctor will ask you to return the day after your injection to attempt to extend your finger to
straighten it. Following extension of your finger, your doctor will fit you with a splint to wear at
bedtime for up to 4 months.
26
If your finger is still not able to straighten during a follow-up visit with your doctor, you may need
additional treatments with Xiapex which may be administered approximately 4 weeks after the first
treatment. Injections and finger extension procedures may be administered up to 3 times per cord at
approximately 4-week intervals. Only one cord must be treated at a time. If the disease has resulted in
multiple contractures, treatment of each cord must be undertaken in a sequential order, as determined
by your doctor.
Be sure to ask your doctor when you can resume normal activities after treatment with Xiapex. It is
recommended to avoid strenuous activities of your finger until instructed further by your doctor. Your
doctor may recommend you perform a series of finger flexion and extension exercises several times a
day for several months.
If you receive more Xiapex than you should
As this product is administered to you by your doctor it is very unlikely that you will be given an
incorrect dosage. In the unlikely event that your doctor administers a higher dosage than
recommended, you may experience an increase in the severity of possible side effects listed in section
4 “Possible Side Effects” of this Package Leaflet.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
Clinical study experience with Xiapex is currently limited to up to 3 injections per cord and up to a
total of 8 injections in the hands.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Xiapex can cause side effects, although not everybody gets them.
Please consult a doctor immediately if you experience any signs or symptoms of a serious allergic
reaction, e.g., wide spread redness or rash, swelling, tightness in the throat or difficulty breathing.
You must not be given Xiapex
if you know that you have had a serious allergic reaction to
collagenase or any of the other ingredients.
Most of the side effects that occurred in the clinical studies were mild or moderate in severity and
were localised to the hand treated.
The following side effects have been seen with Xiapex:
Very common side effects: affects more than 1 user in 10:
reactions at the injection site like bleeding, pain, swelling, tenderness and bruising
itching in the hand
feeling of pain in the hand, wrist or arm
swollen or enlarged glands near the elbow or under the arm
swelling in the hand or arm
Common side effects: affects 1 to 10 users in 100:
reactions at the injection site like pain, warmth, swelling, presence of a blister, redness of skin
and/or skin rash
skin wound at the site of injection
painful glands near the elbows or under the arm
joint swelling and pain
burning sensation, partial loss of sensitivity, feeling of “pins and needles” or numbness
dizziness, headache, nausea
increased perspiration
27
Uncommon side effects: affects 1 to 10 users in 1000:
rupture of a tendon, ligament injury
low blood platelet count
swelling of the eyelid
allergic reaction
chronic pain
discomfort, injury, paralysis of the limb
tremor/shaking
fainting
vomiting, diarrhoea, upper abdominal pain
rash, eczema
stiffness, creaking of the joints
muscle spasm, muscle weakness, musculoskeletal stiffness or discomfort
feeling of pain in the groin, shoulder, chest wall, or neck
swelling
fever, general pain, discomfort, tiredness, feeling hot, malaise, flu-like illness
reactions at the site of injection including peeling of the skin, skin discoloration, infection,
pain, skin tightness, numbness, irritation or nodules, scab, wound
increased liver enzymes
agitation, disorientation, irritability, restlessness, difficulty sleeping
shortness of breath, hyperventilation
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE XIAPEX
Keep out of the reach and sight of children.
Your doctor must not use Xiapex after the expiry date which is stated on the carton and vial label after
EXP. The expiry date refers to the last day of that month.
Xiapex has to be stored in a refrigerator at 2ºC-8ºC and should not be frozen.
After reconstitution, immediate use of the medicine is recommended. Reconstituted Xiapex can be
kept at ambient room temperature (20ºC-25ºC) for up to one hour or refrigerated at 2ºC-8˚C for up to
4 hours prior to administration. If refrigerated, the reconstituted solution must be allowed to return to
ambient room temperature (20ºC-25ºC) for approximately 15 minutes before use.
Your doctor must not use Xiapex if the reconstituted solution is discolored or contains particles. The
solution must be clear, colourless with no lumps or flakes or particles.
Your doctor will take care of storing, handling and disposing of Xiapex. Medicines must not be
disposed of via wastewater or household waste. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Xiapex contains
The active substance is collagenase
clostridium histolyticum
. Each vial of Xiapex contains 0.9 mg of
collagenase
clostridium histolyticum
. The other ingredients are sucrose, trometamol and hydrochloric
acid.
The solvent contains calcium chloride dihydrate, sodium chloride
and water for injections.
28
What Xiapex looks like and contents of the pack
Xiapex is supplied as a white powder in a 3 ml type I clear glass vial with rubber stopper, aluminium
seal and flip-off plastic cap.
The solvent that is used to dissolve the powder is supplied as a clear liquid in a 5 ml type I clear glass
vial with rubber stopper, aluminium seal and flip-off plastic cap.
Xiapex is supplied in a single use pack containing 1 vial of Xiapex powder and 1 vial of 3 ml solvent.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Pfizer Limited, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom.
Manufacturer
Pfizer Manufacturing Belgium NV, Rijksweg 12, 2870 Puurs, Belgium.
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien Luxembourg/Luxemburg
Pfizer S.A./N.V. Pfizer S.A.
Tél/Tel: +32 (0)2 554 62 11 Tél/Tel: +32 (0)2 554 62 11
България Magyarország
Пфайзер Люксембург САРЛ, Клон България Pfizer Kft.
Тел.: +359 2 970 4333
Tel.: + 36 1 488 37 00
Česká republika
Malta
Pfizer s.r.o.
V.J. Salomone Pharma Ltd.
Tel: +420 283 004 111
Tel: + 356 21 22 01 74
Danmark
Nederland
Pfizer ApS
Pfizer bv
Tlf: +45 44 20 11 00
Tel: +31 (0)10 406 43 01
Deutschland
Norge
Pfizer Pharma GmbH
Pfizer AS
Tel: +49 (0)30 550055 51000
Tlf: +47 67 52 61 00
Eesti
Österreich
Pfizer Luxembourg SARL Eesti filiaal
Pfizer Corporation Austria Ges.m.b.H.
Tel: +372 6 405 328
Tel: +43 (0)1 521 15-0
Pfizer Hellas A.E.
Pfizer Polska Sp. z o.o.
Τηλ: +30 210 6785800
Tel.: +48 22 335 61 00
España
Portugal
Pfizer S.A.
Laboratórios Pfizer, Lda.
Tel: +34 91 490 99 00
Tel: +351 21 423 5500
France
România
Pfizer
Pfizer România S.R.L.
Tél: +33 (0)1 58 07 34 40
Tel: +40 (0)21 207 28 00
29
Ελλάδα
Polska
Ireland
Slovenija
Pfizer Healthcare Ireland
Pfizer Luxembourg SARL, Pfizer, podružnica za
svetovanje s področja farmacevtske dejavnosti,
Ljubljana
Tel: 1800 633 363 (toll free)
Tel: + 386 (0)1 52 11 400
+44 (0)1304 616161
Ísland
Slovenská republika
Icepharma hf
Pfizer Luxembourg SARL, organizačná zložka
Sími: + 354 540 8000
Tel: + 421-2-3355 5500
Italia
Suomi/Finland
Pfizer Italia S.r.l.
Pfizer Oy
Tel: +39 06 33 18 21
Puh/Tel: +358 (0)9 43 00 40
Κύπρος
Sverige
Geo. Pavlides & Araouzos Ltd,
Pfizer AB
Τηλ: +35722818087
Tel: +46 (0)8 550 520 00
Latvija
United Kingdom
Pfizer Luxembourg SARL filiāle Latvijā
Pfizer Limited
Tel: +371 670 35 775
Tel: +44 (0)1304 616161
Lietuva
Pfizer Luxembourg SARL filialas Lietuvoje
Tel. +3705 2514000
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/.
--------------------------------------------------------------------------------------------------------------------------
The following information is intended for medical or healthcare professionals only:
Instructions for use and handling
1. Preparation - Reconstitution procedure
The single dose vial containing Xiapex and the single dose vial containing the solvent for solution for
injection for reconstitution must be refrigerated. Prior to use, the vial containing Xiapex and the vial
containing the solvent for solution for reconstitution must be removed from the refrigerator and
allowed to stand at room temperature for at least 15 minutes and no longer than 60 minutes
.
Using an aseptic technique, the following procedure for reconstitution must be followed:
1. Confirm the joint to be treated (metacarpophalangeal [MP] or proximal interphalangeal [PIP]) as
the volume of solvent required for reconstitution is determined by the type of joint (PIP joint requires
a smaller volume for injection).
2. Remove the flip-off plastic caps from both vials and swab the rubber stopper and surrounding
surface of the vial containing Xiapex and the vial containing the solvent for reconstitution with sterile
alcohol (no other antiseptics must be used).
30
3. Use only the supplied solvent for reconstitution; it contains calcium which is required for the
activity of Xiapex. Using a sterile syringe calibrated with 0.01 ml graduations, withdraw the
appropriate amount of solvent
supplied in order to deliver as follows:
0.39 ml of solvent for cords affecting a MP joint or
0.31 ml of solvent for cords affecting a PIP joint
4. Inject the solvent slowly into the sides of the vial containing the lyophilised powder of Xiapex. Do
not invert the vial or shake the solution. Slowly swirl the solution to ensure that all of the lyophilised
powder has gone into solution. Remove and discard the syringe and needle used for reconstitution.
5. Inspect the solution visually for particulate matter and discoloration prior to administration. The
reconstituted solution of Xiapex must be clear. If the solution contains particles, is cloudy or
discoloured, do not inject it.
6. Reconstituted Xiapex can be kept at ambient room temperature (20ºC-25ºC) for up to one
hour or refrigerated (2ºC-8˚C) for up to 4 hours prior to administration. If refrigerated, the
reconstituted solution must be allowed to return to ambient room temperature (20ºC-25ºC) for
approximately 15 minutes before use.
2. Injection procedure
Administration of a local anaesthetic medicinal product prior to injection of Xiapex is not
recommended, as it may interfere with proper placement of the injection.
1.
Reconfirm the cord to be injected. The site chosen for injection must be the area where the
contracting cord is maximally separated from the underlying flexor tendons and where the skin is
not intimately adhered to the cord.
2.
Prepare the skin with an antiseptic and allow it to dry.
3.
Using a sterile, hubless syringe with 0.01 ml graduations and a permanently fixed, 26 or 27 gauge,
12 or 13 mm needle (not supplied), withdraw the adequate
volume of reconstituted solution
for
a 0.58 mg dose of Xiapex required for injection to deliver:
0.25 ml of reconstituted Xiapex for cords affecting a MP joint or
0.20 ml of reconstituted Xiapex for cords affecting a PIP joint.
4.
Use caution with cords as they approach the PIP flexion crease area. If injecting into a cord
affecting the PIP joint of the fifth (little) finger, care must be taken to inject as close to the palmar
digital crease as possible and not to insert more than 2 mm to 3 mm in depth. For PIP joints do not
inject more than 4 mm distal to the palmar digital crease.
5.
With your non-dominant 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 minimise the potential for injection of Xiapex into tissues other than the cord.
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. See Figure 1 below for an illustration of the injection
technique.
31
6.
After confirming that the needle is correctly placed in the cord, inject approximately one-third of
the dose.
7.
Next, keeping the needle under the skin at all times, 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.
8.
Again keeping the needle under the skin at all times, 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 (see Figure 2).
The figures 1 and 2 below are for illustrative purposes only and may not be representative of the
precise location of anatomical structures in an individual patient.
Figure 1: Illustration of the injection technique.
Figure 2: Three step injection of Xiapex into the cord.
32
9.
Wrap the patient’s treated hand with a soft, bulky, gauze dressing.
10.
Discard the unused portion of the reconstituted solution and solvent after injection. Do not store,
pool, or use any vials containing unused reconstituted solution or solvent.
11.
Patients should be instructed:
Not to flex or extend the fingers of the injected hand to reduce extravasation of Xiapex out
of the cord until the finger extension procedure is completed.
Not attempt to disrupt the injected cord by self manipulation at any time.
To elevate the injected hand as much as possible until the day after the finger extension
procedure.
To promptly contact their doctor if there is evidence of infection (e.g., fever, chills,
increasing redness or oedema) or trouble bending the finger after the swelling goes down
(symptoms of tendon rupture).
To return to see their physician the next day for an examination of the injected hand and a
possible finger extension procedure to disrupt the cord.
3. Finger extension procedure
1.
At the follow-up visit the day after injection, determine if the contracture has resolved. If a cord
contracture remains, a passive finger extension procedure will be performed in an attempt to
disrupt the cord.
2.
Local anaesthesia may be used, if needed, during the finger extension procedure.
3.
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 to 20 seconds. For cords affecting the
PIP joint, perform the finger extension procedure when the MP joint is in the flexed position.
4.
If the first finger extension procedure does not result in disruption of the cord, a second and third
attempt can be performed at 5- to 10-minute intervals. No more than 3 attempts are recommended
to disrupt a cord.
5.
If the cord has not disrupted after 3 attempts of extension, a follow-up visit may be scheduled
approximately 4 weeks after the injection. If, at that subsequent visit the contracted cord persists,
an additional injection and finger extension procedure may be performed.
6.
Following the finger extension procedure(s) and fitting patient with a splint (with treated joint in
maximum extension), patients should be instructed to:
Not perform strenuous activity with the injected hand until advised to do so.
Wear the splint at bedtime for up to 4 months.
Perform a series of finger flexion and extension exercises several times a day for several
months.
33
Source: European Medicines Agency
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