Xenpozyme

Package leaflet: Information for the patient

Xenpozyme 4 mg powder for concentrate for solution for infusion, 20 mg powder for concentrate for solution for infusion

olipudase alfa
This medicinal product is subject to additional monitoring. This will allow for rapid identification of new safety information. You can help by reporting any side effects you experience while taking this medicine. See the end of section 4 for information on how to report side effects.
Please read all of this leaflet carefully before receiving this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or nurse.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor or nurse. See section 4.

Contents of this leaflet

1. What Xenpozyme is and what it is used for
2. What you need to know before receiving Xenpozyme
3. How Xenpozyme is administered
4. Possible side effects
5. How to store Xenpozyme
6. Contents of the pack and other information

1. What Xenpozyme is and what it is used for

What Xenpozyme is
Xenpozyme contains an enzyme called olipudase alfa.
What Xenpozyme is used for
Xenpozyme is used to treat a hereditary disorder called acid sphingomyelinase deficiency (ASMD). It is used in children and adults with type A/B or type B ASMD to treat signs and symptoms of ASMD not related to the central nervous system.
How Xenpozyme works
In patients with ASMD, the enzyme acid sphingomyelinase does not function properly. This results in the accumulation of a substance called sphingomyelin, which damages organs such as the spleen, liver, heart, lungs, and blood. Olipudase alfa works in the same way as the natural enzyme and therefore acts as a replacement, reducing the accumulation of sphingomyelin in organs and treating the signs and symptoms of the disease.

2. What you need to know before receiving Xenpozyme

Do not receive Xenpozyme

• If you have experienced life-threatening allergic (anaphylactic) reactions to olipudase alfa (see section “Warnings and precautions” below) or to any of the other components of this medicine (listed in section 6).

Warnings and precautions
You may experience side effects known as infusion-associated reactions that could be caused by the infusion (intravenous drip) of the medicine. These side effects may occur during administration of Xenpozyme or within 24 hours after the infusion.
They may include allergic reactions (see section 4) and symptoms such as headache, itchy skin rash (urticaria), fever, nausea, vomiting, and skin itching.
If you think you are having an infusion-associated reaction, inform your doctor immediately.
If you experience a severe allergic reaction during the infusion, your doctor will stop the infusion and provide you with appropriate medical treatment. Your doctor will then evaluate the risks and benefits of administering further doses of Xenpozyme.
If you experience a mild or moderate infusion-associated reaction, your doctor or nurse may temporarily stop the infusion, reduce the infusion rate and/or reduce the dose.
Your doctor may also administer (or have administered) other medications to prevent or manage potential allergic reactions.
Before starting treatment, your doctor will order blood tests to monitor liver function (by measuring liver enzyme levels), and subsequently at regular intervals as doses are adjusted (see section 3).

Other medicines and Xenpozyme
Inform your doctor or nurse if you are taking, have recently taken, or might take any other medicines.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor or nurse before taking this medicine.
Experience with the use of Xenpozyme in pregnant women is limited. Xenpozyme, if taken by a woman during pregnancy, may be harmful to the fetus. Xenpozyme should be used during pregnancy only if clearly necessary. Women of childbearing potential must use effective contraceptive methods during treatment and, in case Xenpozyme is discontinued, for 14 days after the last dose.
It is not known whether Xenpozyme passes into human breast milk. Xenpozyme has been detected in animal milk. Inform your doctor if you are breastfeeding or intend to breastfeed. Your doctor will then help you decide whether to discontinue breastfeeding or discontinue taking Xenpozyme, taking into account the benefits of breastfeeding for the child and the benefits of Xenpozyme for the mother.

Driving and using machines
Xenpozyme may have a slight effect on the ability to drive and use machines, as it may cause low blood pressure (which may make you feel faint).

Xenpozyme contains sodium
This medicine contains 0.60 mg of sodium (a main component of table salt) per 4 mg vial or 3.02 mg of sodium per 20 mg vial. This corresponds, respectively, to 0.03% and 0.15% of the maximum recommended daily dietary intake for an adult or adolescent, and to ≤ 0.08% and ≤ 0.38% of the maximum acceptable daily sodium intake for children under 16 years of age.

3. How Xenpozyme is administered

Xenpozyme is administered via intravenous infusion (drip) under the supervision of a healthcare
professional experienced in treating ASMD or other metabolic disorders.
The recommended dose is based on body weight and is given every two weeks.
Treatment starts with a low dose of the medicine, which is gradually increased.
The infusion usually takes between 3 and 4 hours, but may be shorter or longer at the doctor’s discretion; it may also be shorter during the dose escalation period.

Adult patients
The recommended starting dose of Xenpozyme is 0.1 mg per kg of body weight. This dose is
progressively increased at each subsequent administration until reaching the recommended dose of 3 mg per kg of body weight, given every two weeks. It generally takes up to 14 weeks to reach the recommended dose, but it may take longer at the doctor’s discretion.

Children
The recommended starting dose of Xenpozyme is 0.03 mg per kg of body weight. Subsequent doses should be progressively increased until reaching the recommended dose of 3 mg per kg of body weight every two weeks. It generally takes up to 16 weeks to reach the recommended dose, but it may take longer at the doctor’s discretion.

Home infusion
If you are receiving a stable dose and tolerate Xenpozyme infusions well, your doctor may consider home infusion. The decision to switch to home infusion must be made following evaluation and recommendation by your doctor. If you experience a side effect during a Xenpozyme infusion, the person administering the infusion at home may stop the infusion and initiate appropriate medical treatment.

Instructions for proper use
Xenpozyme is administered by intravenous infusion (intravenous drip). It is supplied as a powder that must be mixed with sterile water before administration.

If you are given more Xenpozyme than you should
Inform your doctor immediately if you suspect any deviation from the usual infusion.

If you miss an infusion of Xenpozyme
It is important to receive the infusion every two weeks. An infusion is considered missed if it is not administered within 3 days of the scheduled dose. Depending on the number of missed doses, your doctor may need to restart treatment at a lower dose.
If you have missed an infusion or are unable to attend a scheduled appointment, contact your doctor immediately.

If you have any doubts about how to use this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Cases of infusion-related reactions have been observed while patients were receiving the medicine or within 24 hours after the infusion.
The most serious side effects may include severe and sudden allergic reactions, itchy rash (urticaria), skin rash, increased liver enzymes, and irregular heartbeat.
You must inform your doctor immediately if you experience an infusion-related reaction or an allergic reaction.
If you experience an infusion reaction, you may be given other medicines to treat or help prevent future reactions. If the infusion reaction is severe, your doctor may stop the Xenpozyme infusion and start appropriate medical treatment.

Very common (may affect more than 1 in 10 people):

• headache
• raised itchy rash (urticaria)
• fever, increased body temperature
• nausea
• abdominal pain (stomach pain)
• vomiting
• itchy skin
• muscle pain
• skin rash
• increased blood test values indicating inflammation
• upper abdominal pain
• redness of the skin

Common (may affect up to 1 in 10 people):

• itchy eyes or red eyes
• joint pain
• fatigue
• abnormal blood tests for liver function
• diarrhoea
• low blood pressure
• difficulty breathing
• abdominal discomfort
• skin rash (various types of rash, sometimes with itching)
• back pain
• pain
• chills
• feeling of intense warmth
• wheezing
• irritation of the throat and vocal cords
• liver pain
• skin lesions (such as raised solid spots or flat red areas)
• bone pain
• weakness
• severe allergic reactions
• eye discomfort
• rapid heartbeat
• forceful heartbeat, which may be fast or irregular
• tightness and swelling of the throat
• stomach pain
• rapid swelling under the skin in areas such as the face, throat, arms, and legs, which can be life-threatening if swelling of the throat obstructs the airways
• catheter site-related reactions, including pain, tingling, or swelling
• abnormal blood test values indicating inflammation

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or nurse. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Xenpozyme

Keep this medicine out of the sight and reach of children.
Do not use Xenpozyme after the expiry date stated on the label and on the carton. The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C – 8 °C).
After dilution, it is recommended to use the solution immediately.
If not used immediately, the reconstituted solution can be stored for up to 24 hours at a temperature between 2 °C and 8 °C or up to 12 hours at room temperature (up to 25 °C).
After dilution, the solution may be stored for a maximum of 24 hours at 2 °C – 8 °C.
Do not dispose of any medicine via wastewater or household waste. Ask your doctor or nurse how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Xenpozyme contains

• The active substance is olipudase alfa. One vial contains 4 mg or 20 mg of olipudase alfa.
• The other components are:
• L-methionine
• disodium phosphate heptahydrate
• sodium dihydrogen phosphate monohydrate
• sucrose
  See section 2: Xenpozyme contains sodium.

Description of the appearance of Xenpozyme and contents of the pack
Xenpozyme is a lyophilised powder for concentrate for solution for infusion in a vial (4 or 20 mg/vial).
It is a white to off-white lyophilised powder.
After reconstitution with sterile water, a clear, colourless solution is obtained. This solution must be further diluted before infusion.

Marketing Authorisation Holder
Sanofi B.V., Paasheuvelweg 25, 1105 BP Amsterdam, The Netherlands

Manufacturer
Genzyme Ireland Limited, IDA Industrial Park, Old Kilmeaden Road, Waterford, Ireland

For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien Lietuva
Sanofi Belgium Swixx Biopharma UAB
Tél/Tel: +32 (0)2 710 54 00 Tel: +370 5 236 91 40

България Luxembourg/Luxemburg
Swixx Biopharma EOOD Sanofi Belgium
Тел.: +359 (0)2 4942 480 Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien)

Česká republika Magyarország
Sanofi s.r.o. SANOFI-AVENTIS Zrt.
Tel: +420 233 086 111 Tel.: +36 1 505 0050

Danmark Malta
Sanofi A/S Sanofi S.r.l.
Tlf: +45 45 16 70 00 Tel: +39 02 39394275

Deutschland Nederland
Sanofi-Aventis Deutschland GmbH Sanofi B.V.
Tel.: 0800 04 36 996 Tel: +31 20 245 4000
Tel. aus dem Ausland: +49 69 305 70 13

Eesti Norge
Swixx Biopharma OÜ sanofi-aventis Norge AS
Tel: +372 640 10 30 Tlf: +47 67 10 71 00

Ελλάδα Österreich
Sanofi-Aventis Μονοπρόσωπη AEBE sanofi-aventis GmbH
Τηλ: +30 210 900 16 00 Tel: +43 1 80 185 – 0

España Polska
sanofi-aventis, S.A. Sanofi Sp. z o.o.
Tel: +34 93 485 94 00 Tel.: +48 22 280 00 00

France Portugal
Sanofi Winthrop Industrie Sanofi - Produtos Farmacêuticos, Lda
Tél: 0 800 222 555 Tel: +351 21 35 89 400
Appel depuis l’étranger: +33 1 57 63 23 23

Hrvatska România
Swixx Biopharma d.o.o. Sanofi Romania SRL
Tel: +385 1 2078 500 Tel: +40 (0) 21 317 31 36

Ireland Slovenija
sanofi-aventis Ireland Ltd. T/A SANOFI Swixx Biopharma d.o.o.
Tel: +353 (0) 1 403 56 00 Tel: +386 1 235 51 00

Ísland Slovenská republika
Vistor ehf. Swixx Biopharma s.r.o.
Sími: +354 535 7000 Tel: +421 2 208 33 600

Italia Suomi/Finland
Sanofi S.r.l. Sanofi Oy
Tel: 800 536389 Puh/Tel: +358 (0) 201 200 300

Κύπρος Sverige
C.A. Papaellinas Ltd. Sanofi AB
Τηλ: +357 22 741741 Tel: +46 (0)8 634 50 00

Latvija
Swixx Biopharma SIA
Tel: +371 6 616 47 50

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu.

This leaflet is available in all languages of the European Union/European Economic Area on the European Medicines Agency website and on the website www.xenpozyme.info.sanofi, or by scanning the QR code shown below (and on the outer carton) with a smartphone.

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The following information is intended for healthcare professionals only:
Preparation of the solution for administration
The powder for concentrate for solution for infusion must be reconstituted with water for injections, diluted with 9 mg/mL (0.9%) sodium chloride injection solution, and then administered by intravenous infusion.
The reconstitution and dilution steps must be carried out under aseptic conditions. During preparation of the infusion solution, do not use any filter devices. During reconstitution and dilution, avoid foaming.

1. Based on the patient's body weight and prescribed dose, determine the number of vials to be reconstituted.
   Patient's weight (kg) × dose (mg/kg) = patient's dose (in mg). For example, when using a 20 mg vial: patient's dose (in mg) divided by 20 mg/vial = number of vials to reconstitute. If the number of vials includes a fraction, round up to the next whole number.

2. Remove the required number of vials from the refrigerator and allow them to stand for approximately 20–30 minutes to reach room temperature.

3. Reconstitute each vial by injecting:

• 1.1 mL of water for injections into the 4 mg vial
• 5.1 mL of water for injections into the 20 mg vial
  using a slow, dropwise addition technique against the inner wall of the vial.

4. Gently tilt and rotate each vial. Each vial will yield a clear, colourless solution at a concentration of 4 mg/mL.

5. Visually inspect the reconstituted solution in the vials for presence of particulate matter and discolouration. The Xenpozyme solution must be clear and colourless. Do not use vials showing opaque particles or discolouration.

6. Withdraw the volume of reconstituted solution corresponding to the prescribed dose from the appropriate number of vials and dilute with 9 mg/mL (0.9%) sodium chloride injection solution in a syringe or infusion bag, depending on the infusion volume (see Table 1 for the recommended total infusion volume based on age and/or patient weight).

Table 1 – Recommended infusion volumes

• In pediatric patients, for final infusion volumes varying according to body weight (see Table 1):
  • in a 10 mL empty syringe, prepare an infusion solution at 0.1 mg/mL by adding 0.25 mL (1 mg) of the reconstituted solution prepared in step 3) and 9.75 mL of sodium chloride 9 mg/mL (0.9%) injectable solution
  • calculate the volume (mL) required to achieve the patient's dose (mg). Example: 0.3 mg ÷ 0.1 mg/mL = 3 mL
• Dilution instructions for a total volume between ≥5 mL and ≤20 mL, using a syringe:
  • slowly inject the required volume of reconstituted solution against the inner wall of the empty syringe
  • slowly add sufficient sodium chloride 9 mg/mL (0.9%) injectable solution to achieve the required total infusion volume (avoid formation of foam inside the syringe).
• Dilution instructions for a total volume ≥50 mL, using an infusion bag:

empty infusion bag:
o in a sterile, appropriately sized infusion bag, slowly inject the required volume of reconstituted solution from step 3)
o slowly add sufficient sodium chloride 9 mg/mL (0.9%) injectable solution to achieve the required total infusion volume (avoid formation of foam inside the bag)
pre-filled infusion bag:
o withdraw from the pre-filled infusion bag containing sodium chloride 9 mg/mL (0.9%) injectable solution the volume of normal saline required to obtain the final volume specified in Table 1
o slowly add into the infusion bag the required volume of the reconstituted solution from step 3) (avoid formation of foam inside the bag).
7) To mix, gently invert the syringe or infusion bag. Do not shake.
As this is a protein solution, slight flocculation (described as fine translucent fibers) may occasionally occur after dilution.
8) During administration, the diluted solution must be filtered through a low protein-binding in-line filter, 0.2 μm.
9) After completion of the infusion, the infusion line should be flushed with sodium chloride 9 mg/mL (0.9%) injectable solution at the same infusion rate used for the final part of the infusion.

ANNEX IV
SCIENTIFIC CONCLUSIONS AND REASONS FOR THE VARIATION OF THE TERMS
OF THE MARKETING AUTHORISATION

Scientific Conclusions
Taking into account the evaluation by the Pharmacovigilance Risk Assessment Committee (PRAC) of the Periodic Safety Update Report (PSUR) for olipudase alfa, the PRAC's scientific conclusions are as follows:
In light of new data on anaphylactic reactions from spontaneous reports, including a case with positive re-challenge despite desensitisation, the PRAC considers that new information on the occurrence of anaphylactic reactions has become available and should be made available to prescribers. The PRAC concluded that the product information for medicinal products containing olipudase alfa should be updated accordingly.
Having reviewed the PRAC recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the overall conclusions and reasoning of the recommendation.

Reasons for the variation of the terms of the marketing authorisation
Based on the scientific conclusions regarding olipudase alfa, the CHMP considers that the benefit-risk balance of the medicinal product containing olipudase alfa remains unchanged, subject to the proposed amendments to the product information.
The CHMP recommends a variation to the terms of the marketing authorisation.