Voxzogo

Package leaflet: Information for the user

Voxzogo 0.4 mg powder and solvent for solution for injection, 0.56 mg powder and solvent for solution for injection, 1.2 mg powder and solvent for solution for injection

vosoritide
This medicinal product is subject to additional monitoring. This will allow rapid identification of new safety information. You can help by reporting any side effects you or your child 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 using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you/your child have any questions, consult your doctor.
• This medicine has been prescribed for you or your child only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful.
• If you/your child experience any side effect, including those not listed in this leaflet, consult your doctor. See section 4.

Contents of this leaflet

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

1. What Voxzogo is and what it is used for

What Voxzogo is
Voxzogo contains the active substance vosoritide. It is similar to a protein in the body called
C-type natriuretic peptide (CNP). Vosoritide is produced using recombinant technology, which employs
bacteria that have been modified to include the gene for producing the protein.

What Voxzogo is used for
This medicine is used for the treatment of achondroplasia in patients aged 4 months and older whose
bones are still growing. Achondroplasia is a genetic disorder that affects the growth of nearly all
bones in the body, including those of the skull, spine, arms, and legs, resulting in very short stature
with a characteristic appearance.
The product is indicated only in cases of achondroplasia caused by FGFR3 gene mutations confirmed by
genetic testing.

How Voxzogo works
The active substance in Voxzogo acts directly on the growth plates of bones to promote new bone growth.

2. What you need to know before using Voxzogo

Do not use Voxzogo

• if you/your child are allergic to vosoritide or to any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
Talk to your doctor before using Voxzogo:

• if you/your child have significant heart disease or blood pressure problems
• if you/your child are taking or have recently taken medicines that lower blood pressure. If any of the above conditions apply to you or your child, or if you are unsure, consult your doctor before using Voxzogo.

Effects on blood pressure
Voxzogo can reduce blood pressure. As a result, you may experience dizziness, nausea, or fatigue. Blood pressure usually returns to normal within 90 minutes after injection of Voxzogo. If these effects occur and are severe, inform your doctor.
Drinking plenty of fluids at the time of injection may reduce the likelihood of these effects. It is recommended that patients consume a light snack and drink sufficient fluids (e.g., water, milk, or juice) approximately 30 minutes before the injection.

Children and adolescents
There is insufficient information on the use of this medicine in children under 4 months of age; therefore, its use is not recommended.

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

Pregnancy and breastfeeding
If you/your daughter are being treated with this medicine and are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor before using this medicine.
The use of this medicine is not recommended during pregnancy and breastfeeding.

Driving, cycling, and operating machinery
This medicine may cause dizziness, confusion, fatigue, or nausea shortly after injection. In such cases, you must not drive, cycle, engage in physical activity, or operate machinery for about one hour after the injection, or until you feel better.

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

3. How to use Voxzogo

Voxzogo injection must be administered by the person caring for the patient.
Do not inject Voxzogo to your child until you have received proper training from a healthcare professional.
Always use this medicine exactly as instructed by the doctor. If you have any doubts, consult your doctor or pharmacist.

Dosage
Your doctor will determine the correct dose based on your body weight or your child’s body weight. Your doctor will tell you how much injectable solution to administer. If you have any doubts, consult your doctor or pharmacist.
Table 1 shows the daily injection volume you or your child should receive according to body weight.
The amount to be injected may be shown as different volumes depending on the type of syringe included in the package (millilitres (mL) or Units (U)). Make sure you have the correct dose for the syringe you are using.

Table 1: Single dose volumes by body weight in mL and volumes in Units (U)

You/your child should eat a light snack and drink enough water, milk, or juice about 30 minutes before the injection. This may reduce side effects such as dizziness, fatigue, or nausea (feeling unwell).

How to use Voxzogo
Inject Voxzogo slowly under the skin (subcutaneous injection).
The injection should be given at approximately the same time each day.
It is recommended to administer the injection at a different site each day and not to use the same site for 2 consecutive days. Do not inject the medicine into moles, scars, birthmarks, or areas where the skin is tender, bruised, red, or hardened.

If you use more Voxzogo than you should
If you inject more Voxzogo than prescribed, contact your doctor immediately.

If you forget to use Voxzogo
If your child misses a dose, the injection should be administered if less than 12 hours have passed since the scheduled time. If more than 12 hours have passed since the scheduled dose time, do not inject the missed dose. Wait until the next day and continue with the usual dose at the regular time.

If you stop using Voxzogo
Always consult your child’s paediatrician before deciding to stop treatment. If you/your child have any doubts about using this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Very common side effects
May affect more than 1 in 10 people:

• low blood pressure (temporary effects include dizziness, tiredness or nausea shortly after injection)
• vomiting
• reactions at the injection site: redness, itching, inflammation, swelling, bruising, skin rash, hives, pain. Reactions at the injection site are generally mild and resolve spontaneously within a few hours.
• elevated levels of blood alkaline phosphatase (detected by blood tests).

Common side effects
May affect up to 1 in 10 people:

• feeling faint or confused, and fainting
• dizziness
• nausea
• tiredness

Uncommon side effects
May affect up to 1 in 100 people:

• abnormal growth of body or facial hair in men or women (hypertrichosis)

Reporting of side effects
If you/your child experience any side effects, including those not listed in this leaflet, please inform your doctor or nurse. You may also report side effects directly through the national reporting system detailed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Voxzogo

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton after “Exp./EXP”. The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C – 8 °C). Do not freeze. Keep in the original packaging to protect from light.
Voxzogo may be stored at room temperature (below 30 °C) for up to 90 days, but not beyond the expiry date. Do not return Voxzogo to the refrigerator after storage at room temperature. Record on the carton the date when Voxzogo was removed from the refrigerator for storage at room temperature.
Use Voxzogo immediately after reconstitution in solution. In any case, it must be administered within 3 hours after preparation. Do not use this medicine if the injectable solution is cloudy or contains particles.
Do not dispose of medicines via household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

What Voxzogo contains

• The active substance is vosoritide.
  • Each vial containing 0.4 mg of powder reconstituted in 0.5 mL of solvent corresponds to a concentration of 0.8 mg/mL.
  • Each vial containing 0.56 mg of powder reconstituted in 0.7 mL of solvent corresponds to a concentration of 0.8 mg/mL.
  • Each vial containing 1.2 mg of powder reconstituted in 0.6 mL of solvent corresponds to a concentration of 2 mg/mL.
• The other components are citric acid (E 330), sodium citrate (E 331), trehalose dihydrate, mannitol (E 421), methionine, polysorbate 80 (E 433).
• The solvent is water for injections.

Description of the appearance of Voxzogo and contents of the pack
Voxzogo powder and solvent for injectable solution is supplied as:

• a white to yellow powder for injectable solution in a glass vial, and
• a clear, colourless solvent (water for injections) to dissolve the powder.

After dissolving the powder in the solvent, the solution is a clear, colourless to yellow liquid.
Each box contains:

• 10 vials of Voxzogo
• 10 pre-filled syringes of water for injections
• 10 single-use needles
• 10 single-use syringes

Marketing Authorisation Holder and Manufacturer
BioMarin International Limited
Shanbally, Ringaskiddy
County Cork
Ireland
P43 R298
More detailed information on this medicinal product is available on the website of the European Medicines Agency: https://www.ema.europa.eu. In addition, links to other websites on rare diseases and related therapeutic treatments are provided.
Instructions for using the syringe graduated in millilitres (mL)
Read these instructions for use before using Voxzogo and each time you receive a
new supply. There may be new information.
Materials supplied for injection of Voxzogo (see Figure A)
Figure A
Voxzogo vial Solvent needle Solvent syringe
(blue wing retracts needle) (contains water for injections
for reconstitution of Voxzogo)

Syringe for injection

Consult your doctor or healthcare provider if you are unsure about the recommended dose or how to use the solvent needle and injection syringe.
Materials required but not supplied in the package (see Figure B)
If you do not have these materials, contact your pharmacist.
Figure B
Alcohol wipes Sharps container Gauze or plaster

PREPARATION FOR INJECTION
Before starting, prepare a clean work surface and wash your hands.

Step 1: On a clean, flat surface, open the closure cap of the vial and clean the top with an alcohol swab. Do not touch the vial stopper with your fingers after cleaning it with an alcohol swab.
Step 2: Gently bend the closure cap to detach it from the solvent syringe.
Step 3: Rotate the solvent needle onto the solvent syringe until no further rotation is possible.
Step 4: Remove the needle cap and insert the needle into the vial, placing it in the center of the stopper. Slowly push the plunger down to inject all the liquid. Be careful not to press the blue tab until Step 5.
Step 5: Remove the needle from the vial, then press the blue tab to pull back (retract) the needle. Dispose of the needle and syringe in a sharps container. See Step 19 and “How to dispose of (discard) Voxzogo”. Do not use the solvent syringe to administer the injection. WARNING: Be careful not to touch the tip of the needle.
Step 6: Gently rotate the vial until the powder is completely dissolved and a clear solution is obtained. Do not shake the vial. Check that the medicine is from transparent to yellow, not cloudy, and contains no particles.
Step 7: Remove the needle cap from the injection syringe and insert the needle into the vial, placing it in the center of the stopper. Be careful not to bend the needle. WARNING: Do not recap the needle.
Step 8: Carefully hold the vial and syringe and invert the vial with the needle still inserted. The vial should be positioned above the syringe. Be careful not to bend the needle.
Step 9: Keep the tip of the needle in the medicine and slowly pull back the plunger to draw the prescribed dose into the syringe. Check the amount to be drawn up in the prescribing information. WARNING: Draw up the prescribed dose.
Step 10: Gently tap the syringe to remove any large air bubbles. Then slowly push the large air bubbles back into the vial.
Step 11: Repeat Steps 9 and 10 until the correct prescribed dose is in the syringe without large air bubbles. Verify that the dose in the syringe matches the prescribed dose. Measure from the base of the plunger, as illustrated. WARNING: Eliminate any large air bubbles. One or two small air bubbles are acceptable.
Step 12: Confirm that the syringe contains the prescribed dose, then remove the vial and prepare to inject the dose. WARNING: Before removing the vial, confirm that the amount drawn matches the prescribed dose.

SELECTION AND PREPARATION OF THE INJECTION SITE

Step 13: Voxzogo must be injected only into the fatty layer under the skin (subcutaneous use). •Do not inject through clothing. •Do not inject in the same spot for two consecutive times. •Do not inject into sore, bruised, red, hard, or scarred skin.	The following injection sites are recommended: •upper back area of the arms or •thighs or •abdomen (5 cm away from the navel) or •buttocks
Step 14: Clean the injection site with an alcohol wipe and let it air dry. Do not touch the area again before administering the injection.

ADMINISTRATION OF THE VOXZOGO INJECTION

Step 15: After cleaning the injection site with an alcohol swab, pinch the skin around the chosen injection site.
Step 16: Quickly and completely insert the needle into the skin at a 45-degree angle.
Step 17: Release the skin fold and slowly and completely push the plunger. Inject the full dose.
Step 18: Continue pushing the plunger until the needle retracts into the syringe.
Step 19: Dispose of the vial, syringes, and used needles in a sharps container. For more information, see “How to dispose of Voxzogo”.

After injecting Voxzogo

• Check the injection site. If a small amount of blood is present at the injection site, press a gauze pad over it for a few seconds or apply a plaster.
• Do not rub the injection site.
• Check for any signs of low blood pressure, such as dizziness, fatigue, or nausea. If these symptoms are present, contact your doctor or healthcare provider, then lie down on your back with pillows under your legs to keep them elevated.

How to dispose of (discard) Voxzogo
Immediately after use, place used or expired vials, needles, and syringes into a sharps disposal container.
If you do not have a sharps disposal container, you may use a household container that:

• is made of heavy-duty plastic
• can be securely closed with a tight-fitting, puncture-resistant lid to prevent leakage or escape of sharps
• remains upright and stable during use
• does not leak, and
• is properly labeled to warn of hazardous waste inside.

When the sharps disposal container is nearly full, follow local guidelines for proper disposal.
Do not throw any medicines, vials, syringes, or loose needles into household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

Instructions for using the syringe graduated in Units (U)
Read these instructions for use before using Voxzogo and each time you receive a
new supply. There may be new information.
The solvent needles and administration syringes provided in this package are new components marked with "Units" (U) for measuring the recommended dose. Your doctor will tell you the recommended dose based on your weight range.

Materials provided for Voxzogo injection (see Figure A)
Figure A
Voxzogo vial Solvent needle Solvent syringe
(contains Water for Injections for reconstitution of Voxzogo)

Injection syringe

Your dose can be administered using the injection syringe shown in Figure A. Measurements with this syringe are equivalent to those of an mL syringe as follows: 0.1 mL = 10 Units.
Contact your doctor or healthcare provider if you are unsure about the recommended dose or how to use the solvent needle and injection syringe.

Materials required but not provided in the pack (see Figure B)
If you do not have these materials, speak to your pharmacist.
Figure B
Alcohol swabs Sharps disposal container Gauze or plaster

PREPARATION FOR INJECTION
Before starting, prepare a clean work surface and wash your hands.

Step 1: On a clean, flat surface, open the closure cap of the vial and wipe the top with an alcohol swab. Do not touch the vial stopper with your fingers after cleaning it with an alcohol swab.
Step 2: Gently bend the closure cap to detach it from the solvent syringe.
Step 3: Rotate the solvent needle onto the solvent syringe until no further rotation is possible.
Step 4: Remove the needle cap and insert the needle into the vial, in the center of the stopper. Slowly push the plunger down to inject all the liquid.
Step 5: Remove the needle from the vial. Dispose of the needle and syringe in a sharps container. See Step 18 and “How to dispose of (discard) Voxzogo”. Do not use the solvent syringe to administer the injection. WARNING: Be careful not to touch the needle tip.
Step 6: Gently rotate the vial until the powder is completely dissolved and a clear solution is obtained. Do not shake the vial. Check that the medicine is from transparent to yellow, not cloudy, and contains no particles.
Step 7: Remove the needle cap from the injection syringe and insert the needle into the vial, in the center of the stopper. Be careful not to bend the needle. WARNING: Do not recap the needle.
Step 8: Carefully hold the vial and syringe and invert the vial with the needle still inserted. The vial should be on top. Be careful not to bend the needle.

Step 9: Keep the tip of the needle in the medicine and slowly pull back the plunger to draw the prescribed dose into the syringe. Check the amount to be drawn up in the prescribing information. WARNING: Check the syringe provided in the pack and draw up the prescribed dose.
Step 10: Gently tap the syringe to remove any large air bubbles. Then slowly push the air bubbles back into the vial.
Step 11: Repeat steps 9 and 10 until the correct prescribed dose is in the syringe, without large air bubbles. Check that the dose in the syringe matches the prescribed dose. Measure from the base of the plunger, as illustrated. WARNING: Remove any large air bubbles. One or two small air bubbles are acceptable.
Step 12: Confirm that the syringe contains the prescribed dose, then remove the vial and prepare to inject the dose. WARNING: Before removing the vial, confirm that the amount corresponds to the prescribed dose.

SELECTION AND PREPARATION OF THE INJECTION SITE

Step 13: Voxzogo must be injected only into the fatty layer beneath the skin (subcutaneous use). •Do not inject through clothing. •Do not inject in the same spot for two consecutive injections. •Do not inject into painful, bruised, red, hard, or scarred skin.	The following injection sites are recommended: •upper outer area of the arms or •thighs or •abdomen (at least 5 cm away from the navel) or •buttocks
Step 14: Clean the injection site with an alcohol swab and let it air dry. Do not touch the area again before administering the injection.

ADMINISTRATION OF THE VOXZOGO INJECTION

Step 15: After cleaning the injection site with an alcohol swab, pinch the skin around the chosen injection site.
Step 16: Quickly and completely insert the needle into the skin at a 45-degree angle.
Step 17: Release the skin fold and slowly and completely push the plunger. Inject the full dose.
Step 18: Dispose of the vial, syringes, and used needles in a sharps container. For more information, see “How to dispose of (discard) Voxzogo”.

After injecting Voxzogo

• Check the injection site. If a small amount of blood is present at the injection site, press a gauze pad over it for a few seconds or apply a plaster.
• Do not rub the injection site.
• Check for any signs of low blood pressure, such as dizziness, fatigue, or nausea. If these symptoms occur, contact your doctor or a healthcare professional, then lie down on your back with pillows under your legs to keep them elevated.

How to dispose of (discard) Voxzogo
Immediately after use, place used or expired vials, needles, and syringes into a sharps container.
If you do not have a sharps container, you may use a household container that:

• is made of strong plastic
• can be tightly closed with a puncture-resistant protective lid to prevent sharp or pointed objects from escaping
• remains upright and stable during use
• does not leak, and
• is properly labelled to warn of the presence of hazardous waste inside.

When the sharps container is nearly full, follow local guidelines for proper disposal.
Do not dispose of any medicines, vials, syringes, or loose needles in household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

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

Scientific conclusions
Taking into account the assessment by the Pharmacovigilance Risk Assessment Committee (PRAC) of the Periodic Safety Update Report(s) (PSUR) for vosoritide, the scientific conclusions of the PRAC are as follows:
In light of available data on the risk of hypertrichosis from clinical trials and spontaneous reports, including cases with a close temporal relationship and no alternative explanations, although no data on the biological mechanism are available, the PRAC considers that a causal relationship between vosoritide and hypertrichosis is at least a reasonable possibility. The PRAC concluded that the product information for medicines containing vosoritide should therefore be amended accordingly.

Having reviewed the PRAC's recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the general conclusions and the reasoning of the recommendation.

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