Xiapex

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  • Xiapex
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Staðsetning

  • Fáanlegt í:
  • Xiapex
    Evrópusambandið
  • Tungumál:
  • enska

Meðferðarupplýsingar

  • Meðferðarhópur:
  • Other drugs for disorders of the musculoskeletal system
  • Lækningarsvæði:
  • Dupuytren Contracture
  • Ábendingar:
  • Xiapex is indicated for:The treatment of Dupuytren’s contracture in adult patients with a palpable cord.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.
  • Vörulýsing:
  • Revision: 18

Staða

  • Heimild:
  • EMA - European Medicines Agency
  • Leyfisstaða:
  • Authorised
  • Leyfisnúmer:
  • EMEA/H/C/002048
  • Leyfisdagur:
  • 27-02-2011
  • EMEA númer:
  • EMEA/H/C/002048
  • Síðasta uppfærsla:
  • 30-03-2019

Opinber matsskýrsla

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United Kingdom

An agency of the European Union

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+44 (0)20 3660 6000

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+44 (0)20 3660 5555

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www.ema.europa.eu/contact

© European Medicines Agency, 2015. Reproduction is authorised provided the source is acknowledged.

EMA/748449/2015

EMEA/H/C/002048

EPAR summary for the public

Xiapex

collagenase clostridium histolyticum

This is a summary of the European public assessment report (EPAR) for Xiapex. It explains how the

Committee for Medicinal Products for Human Use (CHMP) assessed the medicine to reach its opinion in

favour of granting a marketing authorisation and its recommendations on the conditions of use for

Xiapex.

What is Xiapex?

Xiapex is a powder and solvent that are made up into a solution for injection. It contains the active

substance collagenase clostridium histolyticum.

What is Xiapex used for?

Xiapex is used to treat Dupuytren’s contracture and Peyronie’s disease in adults.

Dupuytren’s contracture is a condition where one or more fingers are bent forwards toward the palm

and cannot be fully straightened. It is caused by a thickening of the tissues under the skin of the palm

that form ‘cords’ pulling down on the fingers. Xiapex is to be used in patients with cords in their palms

that are thick enough to be felt through the skin.

Peyronie’s disease is a condition in which men develop plaques of fibrous, scar-like tissue in their

penis, causing it to become abnormally curved, and sometimes leading to pain or difficulty in sexual

intercourse. Xiapex is used in patients with plaques that can be felt through the skin and in whom the

abnormal curvature of the penis is at least 30 degrees at the start of therapy.

The medicine can only be obtained with a prescription.

How is Xiapex used?

Xiapex must be given by a doctor trained in the use of the medicine and experienced in diagnosing and

managing Dupuytren’s contracture or male genital problems.

Xiapex

EMA/748449/2015

Page 2/3

For Dupuytren’s contracture, the doctor injects the appropriate dose of Xiapex directly into a cord in

the patient’s palm. Around 24 hours after the injection, the finger can then be straightened by the

doctor, by performing a ‘finger extension procedure’ whereby it is stretched out for around 10 to 20

seconds to help disrupt the cord. Up to 2 cords or 2 affected joints in the same hand can be treated at

a time. If injection and finger extension have not brought about a satisfactory response, the procedure

may be repeated at monthly intervals up to a maximum of 3 injections per cord.

For patients with Peyronie’s disease, Xiapex is given for up to 4 treatment cycles each lasting about 6

weeks. In each cycle, the dose of Xiapex is injected into the plaque causing the deformity followed by a

second injection given 1 to 3 days after the first. A ‘penile modeling procedure’ is then performed by

the doctor after a further 1 to 3 days to gently stretch and bend the plaque in the opposite direction to

the abnormal curvature. Patients should subsequently continue modeling procedures daily at home as

instructed for the rest of the cycle.

For more information on the use of Xiapex, including instructions on finger extension and penile

modeling procedures, see the summary of product characteristics (also part of the EPAR).

How does Xiapex work?

The cords in the palm of patients with Dupuytren’s contracture and the plaques in Peyronie’s disease

are made of fibres of a protein called collagen. Xiapex contains a mixture of two ‘collagenases’,

enzymes that break up collagen. When injected into a cord or a plaque, the collagenases break up the

collagen fibres. This weakens and disrupts the cord or plaque.

The collagenases in Xiapex are extracted from the bacterium Clostridium histolyticum.

How has Xiapex been studied?

Xiapex was compared with placebo (a dummy treatment) in two main studies involving a total of 374

adult patients with Dupuytren’s contracture. The patients were treated with three injections and their

hands were examined three months after the last injection to see how much the finger joints could be

straightened out. The main measure of effectiveness was the proportion of patients whose main

affected joint could be straightened so that it was bent forwards by no more than 5 degrees.

For Peyronie’s disease, Xiapex was compared with placebo in two further studies involving 832 men.

Patients received up to 4 treatment cycles, each involving two injections and subsequent modeling

procedures, and the effects were measured on follow-up after 1 year. The main measures of

effectiveness were the reduction in the abnormal curvature of the penis and the extent to which the

condition was bothersome to the patient.

What benefit has Xiapex shown during the studies?

Xiapex was shown to be more effective at treating Dupuytren’s contracture than placebo. Among

patients who completed the first study, 64% (130 out of 203) of those receiving Xiapex could

straighten their fingers to an angle of 5 degrees or less compared with 7% (7 out of 103) of patients

receiving placebo. In the second study the figures were 44% (20 out of 45) for the Xiapex group and

5% (1 out of 21) for the placebo group.

Xiapex was also more effective than placebo in treating Peyronie’s disease, producing a 38% and 31%

improvement in abnormal curvature in the two studies, compared with 21% and 15% respectively for

placebo. There was also a greater improvement with Xiapex than placebo in patient-reported scores of

how bothersome the condition was after treatment.

Xiapex

EMA/748449/2015

Page 3/3

What is the risk associated with Xiapex?

The most common side effects seen with Xiapex were local injection site reactions such as swelling,

bruising, bleeding and pain. Injection site reactions were very common, occurring in the vast majority

of patients. These reactions were mostly mild to moderate in severity and generally subsided within

one to two weeks. Xiapex must not be used to treat Peyronie’s disease if the plaque affects the urethra

(the tube that carries urine and semen to the outside). For the full list of all side effects and

restrictions with Xiapex, see the package leaflet.

Why has Xiapex been approved?

The CHMP decided that Xiapex’s benefits are greater than its risks and recommended that it be given

marketing authorisation.

What measures are being taken to ensure the safe and effective use of

Xiapex?

A risk management plan has been developed to ensure that Xiapex is used as safely as possible. Based

on this plan, safety information has been included in the summary of product characteristics and the

package leaflet for Xiapex, including the appropriate precautions to be followed by healthcare

professionals and patients.

The company that markets Xiapex must also ensure that all doctors expected to use the medicine are

properly trained on the use of the medicine and experienced in diagnosing and managing Dupuytren’s

contracture or Peyronie’s disease. The company must carry out an educational programme for doctors

on the correct use and the potential side effects associated with the medicine.

Other information about Xiapex

The European Commission granted a marketing authorisation valid throughout the European Union for

Xiapex on 28 February 2011.

The full EPAR for Xiapex can be found on the Agency’s website ema.europa.eu/Find medicine/Human

medicines/European Public Assessment Reports. For more information about treatment with Xiapex,

read the package leaflet (also part of the EPAR) or contact your doctor or pharmacist.

This summary was last updated in 11-2015.

Upplýsingar um fylgiseðil sjúklinga: samsetning, vísbendingar, aukaverkanir, skammtar, milliverkanir, aukaverkanir, meðgöngu, brjóstagjöf

B. PACKAGE LEAFLET

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 because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor.

If you get any side effects, talk to your doctor. This includes any possible side effects not listed

in this leaflet. See section 4.

What is in this leaflet

What Xiapex is and what it is used for

What you need to know before you are given Xiapex

How Xiapex is used

Possible side effects

How to store Xiapex

Contents of the pack and other information

1.

What Xiapex is and what it is used for

Xiapex is used for the treatment of two different conditions:

Dupuytren’s contracture in adult

patients with a palpable cord

Peyronie’s disease in adult men

Dupuytren’s contracture

This 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.

Peyronie’s disease

This is a condition where adult men have a ‘plaque’ that can be felt and a curve to their penis. The

disease can cause a change in the shape of the erect penis due to the abnormal build-up of scar tissue,

known as a plaque, within the stretchy fibres of the penis. The plaque may interfere with the ability to

get a straight erection because the plaque will not stretch as much as the rest of the penis. Men with

Peyronie’s disease may have an erection that is curved or bent.

The active substance in Xiapex is collagenase

clostridium histolyticum

, and this collagenase is

produced using the microorganism

Clostridium histolyticum

. Xiapex is injected by your doctor into

the cord in your finger/hand or plaque in your penis and works by breaking down the collagen in the

cord or plaque.

For Dupuytren’s disease, Xiapex breaks down the collagen forming the cord and thereby releasing the

contracture completely or partly and enabling your finger(s) to be straighter.

For Peyronie’s disease, Xiapex breaks down the collagen in the plaque that is causing your erect penis

to curve, which may help the previously bent erection to become straighter and enable you to feel less

bothered by your disease. The reduction of the curve achieved will vary between individuals.

2.

What you need to know before you are given Xiapex

You must not be given Xiapex:

If you are allergic to collagenase

clostridium histolyticum

or any of the other ingredients of this

medicine (listed in section 6).

For Peyronie’s disease if the treatment of your plaque involves the tube (called the urethra) that

your urine passes through.

Warnings and precautions

Talk to your doctor or pharmacist before you are given Xiapex.

Allergic reactions

Severe

allergic reactions can happen in patients who receive Xiapex, because it contains proteins

foreign to the human body.

Call your doctor right away if you have any of these symptoms of an allergic reaction after an

injection of Xiapex:

hives

swollen face

breathing trouble

chest pain

The potential for a serious allergic reaction or the development of a musculoskeletal syndrome upon

repeated use of Xiapex 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.

Before you are given this medicine,

make sure your doctor knows:

if you have had an allergic reaction to a previous Xiapex injection.

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.

If you are treated for Dupuytren’s contracture

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.

Tell your doctor if you have previously received or are thinking about receiving Xiapex to treat a

condition known as Peyronie's disease. This condition affects adult men, who have a ‘plaque’ that can

be felt and a curve to their erect penis.

If you are treated for Peyronie’s disease

This medicine must only be injected into the plaque in your penis by your doctor.

Penile fracture (corporal rupture) or other serious injury to the penis

Receiving an injection of Xiapex may cause damage to the tubes in your penis called the corpora.

After treatment with Xiapex, one of these tubes may break during an erection. This is called a

corporal rupture or penile fracture.

After treatment with Xiapex, blood vessels in your penis may also break, causing blood to collect

under the skin (which is called a haematoma).

Symptoms of penile fracture (corporal rupture) or other serious injury to your penis may include:

a popping sound or sensation in an erect penis

sudden loss of the ability to maintain an erection

pain in your penis

purple bruising and swelling of your penis

difficulty urinating or blood in the urine

Call your doctor right away if you experience any of the symptoms of penile fracture or serious

injury to your penis listed above, as this may require surgical intervention.

Do not have sex or have any other sexual activity for at least 2 weeks

after the second injection of

a treatment cycle with Xiapex and after any pain and swelling has gone away.

Tell your doctor if you are thinking about receiving or have previously received Xiapex to treat a

condition known as Dupuytren’s contracture. In this condition, a cord forms in the tissue in the palm

of the hand and causes one or more fingers to bend toward the palm so that they cannot be

straightened.

Children and adolescents

There is no relevant use of Xiapex in children and adolescents aged 0-18 years for the treatment of

Dupuytren’s contracture or Peyronie’s disease.

Other medicines and Xiapex

Tell your doctor if you are taking, have recently taken or might take any other medicines. This

includes 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. There are no known interactions with

concomitant use of medicines for erectile dysfunction and Xiapex treatment.

Pregnancy and breast-feeding

Dupuytren’s contracture

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask

your doctor or pharmacist for advice before you are given this medicine.

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.

There is no experience in the use of Xiapex in breast-feeding women therefore the use of Xiapex is

not recommended during breast-feeding.

Peyronie's disease

This condition does not occur in females.

Driving and using machines

If you experience dizziness, numbness or altered sensation, and headache immediately after an

injection of Xiapex you must avoid potentially hazardous tasks such as driving or using machines

until these effects have passed or until advised by your doctor.

Swelling and pain may impair the use of the treated hand in Dupuytren’s disease.

Xiapex contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially ‘sodium- free’.

3.

How Xiapex is used

Only doctors that have been appropriately trained in the correct use of Xiapex and are experienced in

the management of Dupuytren’s or Peyronie’s disease are allowed to give you treatment.

You will be given Xiapex as an injection directly into the area that is causing your finger/penis to

bend (intralesional injection). Your doctor will perform all injections of Xiapex.

The recommended dose of your prescribed medicine is 0.58 mg.

Dupuytren’s contracture

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 approximately 24-72 hours 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.

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. Injections in up to two cords or two affected joints in the same hand

can be administered during a treatment visit. If the disease has resulted in multiple contractures,

additional cords may be treated at other treatment visits approximately 4 weeks apart, 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.

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.

Peyronie’s disease

Your doctor will inject Xiapex into the plaque that is causing your penis to curve.

Xiapex is given as part of a treatment cycle. In each treatment cycle, you will receive one

injection of Xiapex, followed by a second injection on a separate day (1 to 3 days later).

After each injection of Xiapex, your penis may be wrapped with a bandage. Your doctor will

tell you when to remove the dressing.

One to three days after the second injection of Xiapex in a treatment cycle, you will need to

return to your doctor for a manual procedure that will help stretch and help straighten your

penis. Your doctor will tell you when to come back for this.

Your doctor will show you how to gently stretch and straighten your penis the right way. For

further information see

“Instructions on how to gently stretch your penis”

“Instructions

on how to gently straighten your penis” at the end of the Patient leaflet.

You should only gently stretch your penis when you do not have an erection.

You should

gently stretch your penis 3 times a day for 6 weeks after each treatment cycle.

You should only gently straighten your penis if you have an erection that happens without

any sexual activity (spontaneous erection).

You should gently straighten your penis 1 time a

day for 6 weeks after each treatment cycle.

Your doctor will tell you when you can resume sexual activity after each treatment cycle.

Your doctor will also tell you when to come back if more treatment cycles are needed.

Clinical study experience with Xiapex is currently limited to four treatment cycles in which a total of

8 injections may be administered into the plaque causing the curvature.

Tell your doctor right away if you have trouble stretching or straightening your penis, or if you have

pain or other concerns.

If you receive more Xiapex than you should

As this medicine is administered to you by your doctor it is very unlikely that you will be given an

incorrect dose. In the unlikely event that your doctor administers a higher dose than recommended,

you may experience an increase in the severity of possible side effects listed in section 4 “Possible

Side Effects”.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Allergic reaction

Severe allergic reaction has been reported uncommonly (1 case). 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.

Dupuytren’s contracture

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 administered in up to two cords or joints per

treatment visit:

Very common side effects

(may affect more than 1 in 10 people):

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

(may affect up to 1 in 10 people):

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

skin wound, blood blister

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

Uncommon side effects

(may affect up to 1 in 100 people):

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, increased sensitivity to stimuli

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

cold intolerance of the treated fingers

reactions at the site of injection including peeling of the skin, skin discolouration, infection,

pain, skin tightness, numbness, irritation or nodules, scab, wound

increased liver enzymes

agitation, disorientation, irritability, restlessness, difficulty sleeping

shortness of breath, hyperventilation

inflammation of the lymph nodes (lymphadenitis), inflammation of lymphatic channels

(lymphangitis) leading to reddened skin with elevated borders, tender and warm, usually

accompanied by a red streak, enlarged lymph nodes

Peyronie’s disease

Penile Fracture (corporal rupture) or other serious injury to the penis

Penile Fracture (corporal rupture) or other serious injury to the penis has uncommonly occurred.

Call your doctor right away if you experience any of the symptoms of penile fracture or other

serious injury to your penis which are as follows:

a popping sound or sensation in an erect penis,

sudden loss of the ability to maintain an erection, pain in your penis, purple bruising and swelling of

your penis, difficulty urinating or blood in the urine, a collection of blood under the skin at the

injection site.

Most of the side effects that occurred in the clinical studies were mild or moderate in severity and

most resolved within 2 weeks of the injection.

The following side effects have been seen with Xiapex:

Very common side effects

(may affect more than 1 in 10 people)

:

bruising or swelling of the penis and pain in the penis

a small collection of blood under the skin at the injection site

Common side effects

(may affect up to 1 in 10 people)

:

reactions at the injection site such as presence of a blister, swelling, itching or a solid raised

area under the skin

pain at the injection site and above the penis

blister or redness/discolouration of the penis

genital itchiness

painful erection, painful sex and erectile dysfunction.

Uncommon side effects

(may affect up to 1 in 100 people)

:

lymph node pain and swollen lymph nodes

increased white blood cells

fast heart rate

ringing in the ear

abdominal swelling

constipation

feeling hot

injection site rash

fever

weakness

chills

flu-like illness

drainage from a blister on the penis

tenderness

allergic reaction

fungal skin infection

infection

upper respiratory infection

skin cut

open wound

collection of blood outside of a blood vessel on scrotum

joint injury

popping sound/sensation indicating penile fracture

blood sugar increased

blood pressure increased

water retention

back pain

groin pain and discomfort

thickening near ligament at base of penis

tenderness in ligament at base of penis

headache

dizziness

unpleasant taste

abnormal sensation

burning sensation

increased/decreased sensitivity to stimuli to senses

abnormal dreams

depression

avoidance of sex

painful/increased urination

scar tissue in penis

penis disorder

worsening of Peyronie’s disease

sexual dysfunction

scrotal redness, swelling and pain

genital discomfort and bruising

pelvic pain

penis size reduced

formation of a blood clot inside the penile vein

cough

small area of inflammation

night sweats

sore on the skin of the penis

skin rash producing redness

skin disorder/irritation

collection of blood outside the blood vessels

bruising

disease of the lymph vessels

superficial vein inflammation

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. You can also report side effects directly via the national reporting system

listed in Appendix V. By reporting side effects you can help provide more information on the safety

of this medicine.

5.

How to store Xiapex

Keep this medicine out of the sight and reach of children.

Your doctor must not use this medicine 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.

Store in a refrigerator at 2ºC-8ºC. Do not freeze.

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 discoloured 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. Do not throw away any

medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you

no longer use. These measures will help protect the environment.

6.

Contents of the pack and other 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 2.4% w/w (for pH

adjustment).

The solvent contains calcium chloride dihydrate, sodium chloride

and water for injections.

What Xiapex looks like and contents of the pack

Xiapex is a powder and solvent for solution for injection. The white lyophilized powder is supplied 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 a clear colourless liquid. 3 ml solution is supplied in

a 5 ml type I clear glass vial with rubber stopper, aluminium seal and flip-off plastic cap.

Xiapex is supplied in a pack containing 1 vial of Xiapex powder and 1 vial of solvent.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Swedish Orphan Biovitrum AB (publ), SE-112 76 Stockholm, Sweden

Manufacturer

Swedish Orphan Biovitrum AB (publ), SE-112 76 Stockholm, Sweden

This leaflet was last revised 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 Peyronie’s disease patients only:

Instructions on how to gently stretch your penis

Gently stretch your penis 3 times a day. Only stretch your penis if your penis is not hard (erect).

With one hand, hold the tip of your penis with your fingers. With the other hand, hold the base

of your penis with the fingers (see illustration below).

Gently pull your penis away from your body to its full length and hold the stretch for

30 seconds.

Let go of the tip of your penis and let your penis return to its normal length.

Instructions on how to gently straighten your penis

Gently straighten your penis one time a day. Only straighten your penis if you have an erection

that happens without any sexual activity (spontaneous erection). Bending your penis should not

cause any pain or discomfort.

With one hand hold your penis. With your other hand, gently bend your penis in the opposite

direction of the curve (see illustration below). Hold the penis in this more straightened position

for 30 seconds, then let go.

-------------------------------------------------------------------------------------------------------------------------

The following information is intended for healthcare professionals only:

Instructions for use and handling

Dupuytren’s contracture

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.

Before use, remove the vial containing the lyophilized powder of Xiapex and the vial

containing the diluent for reconstitution from the refrigerator and allow the two vials to stand at

room temperature for at least 15 minutes and no longer than 60 minutes. Visually inspect the

vial containing Xiapex. The cake of lyophilized powder should be intact and white in colour.

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).

After removal of the flip-off cap from each vial, using aseptic technique swab the rubber

stopper and surrounding surface of the vial containing Xiapex and the vial containing the

diluent for reconstitution with sterile alcohol (no other antiseptics should be used).

Use only the supplied diluent for reconstitution. The diluent contains calcium which is required

for the activity of Xiapex.

Using a 1 ml syringe with 0.01 ml graduations with a 27-gauge 12-13 mm needle (not

supplied), withdraw the correct volume of the

diluent supplied

0.39 ml of solvent for cords affecting a MP joint in Dupuytren’s contracture

0.31 ml of solvent for cords affecting a PIP joint in Dupuytren’s contracture

Inject the diluent slowly into the sides of the vial containing the lyophilized powder of Xiapex.

Do not invert the vial or shake the solution. Slowly swirl the solution to ensure that all of the

lyophilized powder has gone into solution.

The reconstituted Xiapex solution can be kept at room temperature (20º to 25ºC) for up to one

hour or refrigerated at 2º to 8°C for up to 4 hours prior to administration. If the reconstituted

Xiapex solution is refrigerated, allow this solution to return to room temperature for

approximately 15 minutes before use.

Discard the syringe and needle used for reconstitution and the diluent vial.

When administering two injections in the same hand during a treatment visit, use a new syringe

and separate vial of reconstituted solution (containing 0.58 mg of Xiapex) for the second

injection. Repeat steps 1 through 8.

2.

Identification of treatment area

Prior to each treatment cycle, identify the treatment area as follows:

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).

3.

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.

The reconstituted Xiapex solution should be clear. Inspect the solution visually for particulate

matter and discolouration prior to administration. If the solution contains particulates, is

cloudy, or is discoloured, do not inject the reconstituted solution.

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.

When administering two injections in the same hand during a treatment visit, begin with the

affected finger in the most ulnar aspect of the hand and continue toward the radial aspect

(eg, fifth finger to index finger). Within each finger, begin with the affected joint in the

most proximal aspect of the finger and continue toward the distal aspect (eg, MP to PIP).

For each injection, follow steps 4-10.

Apply antiseptic at the site of the injection and allow the skin to dry.

Using a new 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.

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.

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.

After confirming that the needle is correctly placed in the cord, inject approximately one-third

of the dose.

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.

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.

Wrap the patient’s treated hand with a soft, bulky, gauze dressing.

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.

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 approximately 24-72 hours after each injection for an

examination of the injected hand and a possible finger extension procedure to disrupt the

cord.

4.

Finger extension procedure

At the follow-up visit approximately 24-72 hours 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.

If cords of two affected joints in one finger were treated, perform the finger extension

procedure on the cord affecting the MP joint before performing the procedure on the cord

affecting the PIP joint.

Local anaesthesia may be used, if needed, during the finger extension procedure.

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.

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 per

affected joint are recommended to disrupt a cord.

If the cord has not disrupted after 3 attempts of extension per cord, 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.

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.

-------------------------------------------------------------------------------------------------------------------------

The following information is intended for healthcare professionals only:

Instructions for use and handling

Peyronie’s disease

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.

Before use, remove the vial containing the lyophilized powder of Xiapex and the vial

containing the diluent for reconstitution from the refrigerator and allow the two vials to stand at

room temperature for at least 15 minutes and no longer than 60 minutes. Visually inspect the

vial containing Xiapex. The cake of lyophilized powder should be intact and white in colour.

After removal of the flip-off cap from each vial, using aseptic technique swab the rubber

stopper and surrounding surface of the vial containing Xiapex and the vial containing the

diluent for reconstitution with sterile alcohol (no other antiseptics should be used).

Use only the supplied diluent for reconstitution. The diluent contains calcium which is required

for the activity of Xiapex.

Using a 1 ml syringe with 0.01 ml graduations with a 27-gauge 12-13 mm needle (not

supplied), withdraw the correct volume of the

diluent supplied

0.39 ml of solvent for the penile plaque in Peyronie’s disease

Inject the diluent slowly into the sides of the vial containing the lyophilized powder of Xiapex.

Do not invert the vial or shake the solution. Slowly swirl the solution to ensure that all of the

lyophilized powder has gone into solution.

The reconstituted Xiapex solution can be kept at room temperature (20º to 25ºC) for up to one

hour or refrigerated at 2º to 8°C for up to 4 hours prior to administration. If the reconstituted

Xiapex solution is refrigerated, allow this solution to return to room temperature for

approximately 15 minutes before use.

Discard the syringe and needle used for reconstitution and the diluent vial.

2.

Identification of treatment area

Prior to each treatment cycle, identify the treatment area as follows:

Induce a penile erection

Locate the plaque at the point of maximum concavity (or focal point) in the bend of the

penis

Mark the point with a surgical marker. This indicates the target area in the plaque for

Xiapex deposition

3.

Injection procedure

The reconstituted Xiapex solution should be clear. Inspect the solution visually for particulate

matter and discolouration prior to administration. If the solution contains particulates, is

cloudy, or is discoloured, do not inject the reconstituted solution.

Apply antiseptic at the site of the injection and allow the skin to dry.

Administer suitable local anaesthetic, if desired.

Using a new hubless syringe containing 0.01 ml graduations with a permanently fixed 27-gauge

12 or 13 mm needle (not supplied), withdraw a volume of 0.25 ml of

reconstituted solution

(containing 0.58 mg of Xiapex).

The penis should be in a flaccid state before Xiapex is injected. Place the needle tip on the side

of the target plaque in alignment with the point of maximal concavity. Orient the needle so that

it enters the plaque from the side, NOT downwards or perpendicularly towards the corpora

cavernosum.

Insert and advance the needle transversely through the width of the plaque, towards the

opposite side of the plaque without passing completely through it. Proper needle position is

tested and confirmed by carefully noting resistance to minimal depression of the syringe

plunger.

With the tip of the needle placed within the plaque, initiate injection, maintaining steady

pressure to slowly inject the drug into the plaque. Withdraw the needle slowly so as to deposit

the full dose along the needle track within the plaque. For plaques that are only a few

millimetres in width, the distance of withdrawal of the syringe may be very minimal. The goal

is always to deposit the full dose entirely within the plaque.

Upon complete withdrawal of the needle, apply gentle pressure at the injection site. Apply a

dressing as necessary.

Discard the unused portion of the reconstituted solution and diluent after each injection. Do not

store, pool, or use any vials containing unused reconstituted solution or diluent.

The second injection of each treatment cycle should be made approximately 2 to 3 mm apart

from the first injection.

4.

Penile modelling procedure

Penile modelling helps relieve curvature deformity and straighten the penile shaft. At a follow-up visit

1 to 3 days after the second injection of each treatment cycle, perform a penile modelling procedure

(as described below) on the flaccid penis to stretch and elongate the plaque that Xiapex has disrupted:

Administer suitable local anaesthetic, if desired.

Wearing gloves, grasp the plaque or indurated portion of the flaccid penis about 1 cm

proximal and distal to the injection site. Avoid direct pressure on the injection site.

Using the target plaque as a fulcrum point, use both hands to apply firm, steady pressure

to elongate and stretch the plaque. The goal is to gradually create bending opposite to the

patient’s penile curvature, with stretching to the point of moderate resistance. Hold

pressure for 30 seconds then release.

After a 30 second rest period, repeat the penile modelling technique for a total of 3

modelling attempts at 30 seconds for each attempt.

The patient should then be instructed to self-perform penile modelling activities at home each day for

the 6-week period following the physician penile plaque modelling visit of each treatment cycle,

according to the detailed instructions provided in the package leaflet.

ANNEX IV

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS

OF THE MARKETING AUTHORISATION

Scientific conclusions

Taking into account the PRAC Assessment Report on the PSUR for collagenase clostridium

histolyticum (treatment of Dupuytren's contracture and treatment of Peyronie's disease), the scientific

conclusions of CHMP are as follows:

The MAH submitted with this PSUR a cumulative review of reported cases of cold intolerance

covering this PSUR’s period. Cumulatively 5 cases of temperature intolerance, 5 cases of peripheral

coldness, 3 cases of peripheral vascular disorder and 5 cases of Raynaud’s phenomenon were

reported. Two of these cases had a positive dechallenge, 8 had a negative dechallenge/remain

unresolved, and in 8 cases the outcome is unknown. From available information it can be seen that the

fingers which were treated are affected, and that in response to cold weather become white and/or

cold. The phenomenon developed in some cases after several months after injection. However,

development of peripheral coldness can be considered a serious side effect with influence on the

ability to work for some patients. Symptoms can include pain, altered sensation or colour changes and

it can cause debilitating morbidity affecting patients’ lives. It is also known for fasciectomy and might

be present after chirurgical intervention or trauma on the upper limbs. In addition two cases were

reported in the literature following collagenase clostridium histolyticum treatment of Dupuytrens

contracture with new onset of cold intolerance. The pathophysiology of cold sensitivity as a complex

of symptoms occurring after injuries is not well understood, and to date there are no known therapies

which can prevent development of the syndrome or manage it. The symptoms tend either to disappear

or exacerbate with time passing. Based on the available evidence the PRAC concluded that ‘cold

intolerance of the treated fingers’ should be added as a new adverse drug reaction with a frequency

‘uncommon’ in section 4.8 of the SmPC and section 4 of the Package Leaflet.

The CHMP agrees with the scientific conclusions made by the PRAC.

Grounds for the variation to the terms of the marketing authorisation

On the basis of the scientific conclusions for collagenase clostridium histolyticum (treatment of

Dupuytren's contracture and treatment of Peyronie's disease) the CHMP is of the opinion that the

benefit-risk balance of the medicinal product containing collagenase clostridium histolyticum

(treatment of Dupuytren's contracture and treatment of Peyronie's disease) is unchanged subject to the

proposed changes to the product information.

The CHMP recommends that the terms of the marketing authorisation should be varied.