Xiapex 0.9 mg powder and solvent for solution for injection

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.

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.

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?.

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.

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.

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 andor 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

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 tremorshaking 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.

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.

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 chlorideand water for injections.

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:

BelgiëBelgiqueBelgien Pfizer S.A.N.V. TélTel 32 02 554 62 11 LuxembourgLuxemburg Pfizer S.A. TélTel 32 02 554 62 11

, . 359 2 970 4333 Magyarország Pfizer Kft. Tel. 36 1 488 37 00

eská republika Pfizer s.r.o. Tel 420 283 004 111 Malta V.J. Salomone Pharma Ltd. Tel 356 21 22 01 74

Danmark Pfizer ApS Tlf 45 44 20 11 00 Nederland Pfizer bv Tel 31 010 406 43 01

Deutschland Pfizer Pharma GmbH Tel 49 030 550055 51000 Norge Pfizer AS Tlf 47 67 52 61 00

Eesti Pfizer Luxembourg SARL Eesti filiaal Tel 372 6 405 328 Österreich Pfizer Corporation Austria Ges.m.b.H. Tel 43 01 521 15-0

Pfizer Hellas A.E. 30 210 6785800 Polska Pfizer Polska Sp. z o.o. Tel. 48 22 335 61 00

España Pfizer S.A. Tel 34 91 490 99 00 Portugal Laboratórios Pfizer, Lda. Tel 351 21 423 5500

France Pfizer Tél 33 01 58 07 34 40 România Pfizer România S.R.L. Tel 40 021 207 28 00

Ireland Pfizer Healthcare Ireland Slovenija Pfizer Luxembourg SARL, Pfizer, podrunica za svetovanje s podroja farmacevtske dejavnosti, Ljubljana Tel 386 01 52 11 400 Tel 1800 633 363 toll free 44 01304 616161

Ísland Icepharma hf Sími 354 540 8000 Slovenská republika Pfizer Luxembourg SARL, organizaná zloka Tel 421-2-3355 5500

Italia Pfizer Italia S.r.l. Tel 39 06 33 18 21 SuomiFinland Pfizer Oy PuhTel 358 09 43 00 40

Geo. Pavlides Araouzos Ltd, 35722818087 Sverige Pfizer AB Tel 46 08 550 520 00

Latvija United Kingdom Pfizer Luxembourg SARL filile Latvij Tel 371 670 35 775 Pfizer Limited Tel 44 01304 616161

Lietuva
Pfizer Luxembourg SARL filialas Lietuvoje
Tel. +3705 2514000

This leaflet was last approved in

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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).

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.

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.

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.