Palynziq - patient leaflet, side effects, dosage

- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

• 1. What Palynziq is and what it is used for

• 2. What you need to know before you use Palynziq

• 3. How to use Palynziq

• 4. Possible side effects

• 5. How to store Palynziq

• 6. Contents of the pack and other information

1. What Palynziq is and what it is used for

Palynziq contains the active substance pegvaliase, an enzyme that can break down a substance called phenylalanine in the body. Palynziq is a treatment for patients aged 16 years and older with phenylketonuria (PKU), a rare inherited disorder that causes phenylalanine from proteins in food to build up in the body. People who have PKU have high levels of phenylalanine and this can lead to serious health problems. Palynziq reduces the levels of phenylalanine in the blood of patients who have PKU whose blood phenylalanine levels cannot be kept below 600 micromol/l by other means such as by diet.

2. What you need to know before you use Palynziq

Do not use Palynziq

• – if you have a severe allergy to pegvaliase or any other ingredients of this medicine, or another medicine that contains polyethylene glycol (PEG) (listed in section 6).

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before using Palynziq.

Allergic reactions

You may have allergic reactions when being treated with Palynziq. Your doctor will tell you how to manage your allergic reactions based on the severity of the reaction, and will prescribe you additional medicines to manage the reaction.

Before using Palynziq, tell your doctor if you cannot use or do not want to use an adrenaline injection device to treat a severe allergic reaction to Palynziq.

Palynziq can cause severe allergic reactions that may be life-threatening and these can happen any time after a Palynziq injection.

• Stop injecting Palynziq if any of the following symptoms occur.

• – Swelling of the face, eyes, lips, mouth, throat, tongue, hands and/or feet

• – Trouble breathing or wheezing

• – Throat tightness or choking feeling

• – Trouble swallowing or speaking

• – Feeling dizzy or fainting

• – Losing control of urine or stools

• – Rapid heartbeat

• – Hives (like an itchy, bumpy skin rash) that spreads quickly

• – Flushing

• – Severe stomach cramps or pain, vomiting, or diarrhoea

• Use adrenaline injection device as instructed by your doctor and seek urgent medical assistance.

Your doctor will prescribe an adrenaline injection device to use for a severe allergic reaction. Your doctor will train you and someone helping you on when and how to use adrenaline. Keep the adrenaline injection device with you at all times.

For at least the first 6 months of treatment, someone must be with you when you are self-injecting Palynziq. This person must stay with you for at least 1 hour after your injection to watch you for signs and symptoms of a severe allergic reaction and, if needed, give you an injection of adrenaline and call for emergency medical help.

If you have a severe allergic reaction, do not continue to use Palynziq until you have talked with the doctor who prescribes you Palynziq. Tell your doctor that you had a severe allergic reaction. Your doctor will tell you if you can continue Palynziq treatment.

Time needed to lower your blood phenylalanine levels

Your doctor will start you on Palynziq at a low dose and will increase your dose slowly. It will take time to find the dose that works best to lower your blood phenylalanine levels. Most people respond within 18 months, but it can sometimes take up to 30 months.

Injection of other medicines that contain PEG while using Palynziq

Palynziq includes an ingredient called polyethylene glycol (PEG). If you inject Palynziq with another injectable medicine that contains PEG, such as PEGylated medroxyprogesterone acetate, you may have an allergic reaction. Tell your doctor or pharmacist if you are injecting, have recently injected or might inject any other medicines.

Blood phenylalanine levels that are too low

You may have blood phenylalanine levels that are too low when using Palynziq. Your doctor will check your blood phenylalanine levels monthly. If your blood phenylalanine levels are too low, your doctor may ask you to change your diet and/or will lower your dose of Palynziq. Your doctor will check your blood phenylalanine levels every 2 weeks until your blood phenylalanine levels return to normal.

Children and adolescents

It is not known if Palynziq is safe and effective in children and adolescents less than 16 years of age with PKU and therefore should not be used in people aged less than 16 years.

Other medicines and Palynziq

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

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before using this medicine.

Palynziq is not recommended during pregnancy unless your condition requires treatment with Palynziq and other ways of controlling your blood phenylalanine levels do not work. If your phenylalanine levels are too high or too low during pregnancy, this may harm you or your baby. You and your doctor will decide the best way for you to manage your blood phenylalanine levels. It is very important to keep your phenylalanine levels under control before and during pregnancy.

It is not known if Palynziq passes into breast milk or if it will affect your baby. Talk to your healthcare provider about the best way to feed your baby if you use Palynziq.

It is not known if Palynziq has an effect on fertility. Animal studies suggest that women may have difficulty becoming pregnant if their phenylalanine levels are abnormally low.

Driving and using machines

Palynziq can affect your ability to drive and use machines if you have a severe allergic reaction.

Palynziq contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per pre-filled syringe, that is to say essentially ‘sodium-free’.

3. How to use Palynziq

Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.

Palynziq is given as an injection under the skin (subcutaneous injection).

Dose

• You will start Palynziq at the lowest dose. You will use the 2.5 mg syringe once a week for at least the first 4 weeks. The 2.5 mg syringe has a white plunger.
• Your doctor will then slowly increase your dose and/or how often you inject Palynziq. Your doctor will tell you how long to stay at each dose. Slowly increasing your dose over time allows your body to adjust to this medicine.
• The goal is to reach a daily dose that lowers your blood phenylalanine levels to within the target range of 120 to 600 micromol/l and does not cause too many side effects. Patients usually need a daily dose of 20 mg, 40 mg, or 60 mg to reach their target blood phenylalanine le­vel.

Example of steps to reach your blood phenylalanine goal

Palynziq dose and how often to take it	Syringe colour
2.5 mg once a week	White plunger
2.5 mg two times a week
10 mg once a week	Green plunger
10 mg twice a week
10 mg four times a week
10 mg daily
20 mg daily	Blue plunger
40 mg daily (2 injections of 20 mg pre-filled syringe)1
60 mg daily (3 injections of 20 mg pre-filled syringe)1

1 If you need more than one injection to receive your daily dose,

all injections should be done at the same time of day and injection sites should be at least 5 centimetres away from each other. Do not divide your daily dose throughout the day.

• Your doctor will continue to check your blood phenylalanine levels during treatment and may adjust your dose of Palynziq or ask you to change your diet.
• Your doctor will need to check your blood phenylalanine monthly to see if this medicine is working for you.

Starting Palynziq

• Your healthcare provider will give you the Palynziq injection until you (or a caregiver) can do it yourself.
• Your doctor will prescribe medicines for you to take before your Palynziq injection, such as paracetamol, fexofenadine, and/or ranitidine. These medicines help to reduce the symptoms of an allergic reaction.
• A healthcare provider will monitor you for at least 1 hour after you get Palynziq for signs and symptoms of an allergic reaction.
• Your doctor will also prescribe adrenaline injection device to use for any severe allergic reactions. Your healthcare provider will also tell you which signs and symptoms to look out for and what to do if you have a severe allergic reaction.
• Your doctor will show you how and when to use the adrenaline injection device. Keep it with you at all times.

Continuing Palynziq

• This medicine comes in pre-filled syringes with 3 different strengths (2.5 mg-white plunger, 10 mg-green plunger, or 20 mg-blue plunger). You may need more than one pre-filled syringe for your prescribed dose. Your healthcare provider will tell you which syringe, or a combination of syringes, to use and will show you (or a caregiver) how to inject Palynziq.
• The “Instructions for Use” (section 7 of this leaflet) shows you:

o how to prepare and inject Palynziq and

o how to throw away Palynziq syringes properly after you use them

• Your doctor will tell you how long to continue taking medicines such as paracetamol, fexofenadine, and/or ranitidine before you take Palynziq.
• For at least the first 6 months of Palynziq treatment, you must have someone with you when you self-inject Palynziq, and for at least 1 hour after your injection to watch for signs and symptoms of a severe allergic reaction and, if needed, give you an injection of adrenaline and call for emergency medical help.

o Your doctor will train them on the signs and symptoms of a severe allergic reaction and how to give an injection of adrenaline.

o Your doctor will tell you if you need an observer for longer than 6 months.

• Do not change your protein intake unless your doctor tells you to.

If you use more Palynziq than you should

If you use more Palynziq than you should, tell your doctor. See section 4 for details on what to do based on your symptoms.

If you forget to use Palynziq

If you miss a dose, take your next dose at the regular time. Do not take two doses of Palynziq to make up for a missed dose.

If you stop taking Palynziq

If you stop taking Palynziq treatment, your blood phenylalanine levels are likely to increase. Talk to your doctor before stopping Palynziq treatment.

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

4. Possible side effects

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

Allergic reactions occur very commonly (may affect more than 1 in 10 people) and range in severity. Symptoms of allergic reaction can include skin rash, itching, swelling of head or face, itchy or runny eyes, cough, trouble breathing, and wheezing. Your doctor will tell you how to manage any allergic reactions based on their severity, and will prescribe you additional medicines to manage the reaction. Some of these allergic reactions can be more serious, as described below, and will require immediate attention.

Serious side effects include:

• – Sudden severe allergic reactions: (Common – may affect up to 1 in 10people). Stop injecting Palynziq if you notice any serious sudden signs of allergy or combination of signs listed below. o Swelling of the face, eyes, lips, mouth, throat, tongue, hands and/or feet o Trouble breathing or wheezing

o Throat tightness or a choking feeling o Trouble swallowing or speaking

o Feeling dizzy or fainting

o Losing control of urine or stools

o Rapid heartbeat

o Hives (like an itchy, bumpy skin rash) that spreads quickly

o Flushing

o Severe stomach cramps or pain, vomiting, or diarrhoea

Use adrenaline injection device as instructed by your doctor and seek urgent medical assistance. Your doctor will prescribe an adrenaline injection device to use for a severe allergic reaction. Your doctor will train and instruct you and someone helping you on when and how to use adrenaline. Keep the adrenaline injection device with you at all times.

Contact your doctor immediately if you have the following:

• – A type of allergic reaction called serum sickness which includes a combination of fever (high temperature), rash, muscle and joint aches (Common – may affect up to 1 in 10 people)

Other side effects

Very common: may affect more than 1 in 10 people

• – skin redness, swelling, bruising, tenderness, or pain where you injected Palynziq

• – joint pain

• – decrease in complement factors C3 and C4 proteins (which are parts of your immune system) in blood test

• – allergic reaction

• – too low levels of phenylalanine in blood tests

• – headache

• – skin rash

• – stomach pain

• – feeling sick, also called nausea

• – vomiting

• – hives (raised itchy rash on the skin)

• – itchiness

• – thinning or loss of hair

• – cough

• – increase in c-reactive protein (CRP) in blood test (CRP is a protein that indicates that you have

inflammation)

• – swollen glands in the neck, armpit or groin

• – skin redness

• – muscle pain

Common: may affect up to 1 in 10 people

• – trouble breathing

• – joint stiffness

• – joint swelling

• – muscle stiffness

• – skin rash with small bumps

• – blistering or peeling of the outer layer of the skin

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed inBy reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Palynziq

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

Do not use this medicine after the expiry date which is stated on the syringe label, tray cover, and carton after “EXP”. The expiry date refers to the last day of that month.

Store in a refrigerator (2°C – 8°C). Do not freeze.

If needed, you may store Palynziq in its sealed tray outside the refrigerator (below 25°C) for up to a single period of 30 days away from sources of heat. Record the date removed from refrigeration on the unopened product tray. Once stored outside of refrigeration, the product must not be returned to the refrigerator.

Do not use this medicine if the pre-filled syringe is damaged or you notice the solution is discoloured, cloudy, or if you can see particles.

Use safe disposal procedures for syringes. 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 Palynziq contains

• – The active substance is pegvaliase.

Each 2.5 mg pre-filled syringe contains 2.5 mg pegvaliase in 0.5 ml solution.

Each 10 mg pre-filled syringe contains 10 mg pegvaliase in 0.5 ml solution.

Each 20 mg pre-filled syringe contains 20 mg pegvaliase in 1 ml solution.

• – The other ingredients are trometamol, trometamol hydrochloride, sodium chloride (see section 2 for further information), trans -cinnamic acid, water for injections.

What Palynziq looks like and contents of the pack

Palynziq solution for injection (injection) is a clear to slightly opalescent, colourless to pale yellow solution. The pre-filled syringe includes an automatic needle guard.

Pre-filled syringe 2.5 mg (white plunger):

Each 2.5 mg carton contains 1 pre-filled syringe.

Pre-filled syringe 10 mg (green plunger):

Each 10 mg carton contains 1 pre-filled syringe.

Pre-filled syringe 20 mg (blue plunger):

Each 20 mg carton contains 1 or 10 pre-filled syringes.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

BioMarin International Limited

Shanbally, Ringaskiddy

County Cork

Ireland

P43 R298

This leaflet was last revised in MM/YYYY.

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: There are also links to other websites about rare diseases and treatments.

7. Instructions for use

BEFORE YOU START

Read this Instructions for use before you start using the Palynziq pre-filled syringe and each time you get a new prescription. There may be new information. Also, talk to your healthcare provider about your medical condition or your treatment.

Follow these instructions carefully while you are using Palynziq. If your healthcare provider decides that you or your caregiver can give your injections of Palynziq at home, your healthcare provider will show you or your caregiver how to inject Palynziq before you inject it for the first time. Do not inject Palynziq until your healthcare provider has shown you or your caregiver how to inject Palynziq.

Talk to your healthcare provider if you have any questions about how to inject Palynziq the right way.

Do not share your pre-filled syringes with anyone else.

For storage instructions, refer to section 5 “How to store Palynziq ” of this leaflet.

Important things to know about using your Palynziq pre-filled syringe:

• Use each Palynziq pre-filled syringe once only. Do not use a Palynziq syringe more than

once.

• Never pull back on the plunger.
• Do not remove the needle cap until you are ready to inject.

Figure A below shows what the pre-filled syringe looks like before use.

Figure A

Select the correct Palynziq pre-filled syringe(s) for your dose:

When you receive your Palynziq pre-filled syringe(s), check that the name “Palynziq” appears on the carton(s).

• Palynziq pre-filled syringes come in 3 different strengths: 2.5 mg, 10 mg, and 20 mg.
• You may need more than one pre-filled syringe for your prescribed dose. Your healthcare

provider will tell you which syringe, or combination of syringes, to use. Ask your healthcare provider if you have any questions.

• Before you inject Palynziq, check each carton and syringe to make sure you have the right pre-filled syringe for your prescribed dose.

Figure B

PREPARING FOR INJECTION

Step 1: Collect supplies:

Gather your supplies for the injection and place them on a clean flat surface. Take out the required number of cartons needed for your dose from the refrigerator.

Supplies you will need for your Palynziq Injection:

• Palynziq pre-filled syringe(s) in sealed tray(s). Each tray contains 1 syringe.
• gauze pad or cotton ball
• 1 alcohol pad
• 1 bandage
• 1 sharps disposal or puncture resistant container

Step 2: Remove Palynziq tray(s) from carton and check expiry date:

• – Take out the cartons needed for your dose from the refrigerator. Check the expiry date on the carton. If the expiry date has passed, do not use the pre-filled syringe in that carton.

• – Open each carton and take out the sealed tray you need for your dose.

• – Place each sealed tray on a clean, flat surface out of reach of children and pets.

• – Put the carton with any remaining trays back in the refrigerator. If a refrigerator is not available, see section 5 “How to store Palynziq ” in this leaflet.

Step 3: Allow Palynziq tray(s) to sit at room temperature for 30 minutes before opening:

Let the sealed tray(s) sit at room temperature for at least 30 minutes. Injecting cold Palynziq can be uncomfortable.

• - Do not warm up the pre-filled syringe in any other way. Do not use a microwave and do not place in hot water.

Step 4: Remove syringe from tray:

Peel the cover from the tray. Hold the middle of the pre-filled syringe body and take out the pre-filled syringe from the tray (see Figure C).

• Do not use the pre-filled syringe if it looks damaged or used. Use a new pre-filled syringe for your injection.
• Do not remove the needle cap from your pre-filled syringe.
• Do not shake or roll the syringe in your hands.

Step 5: Check syringe strength and check for particles:

Check the syringe label to make sure you have the correct strength for your prescribed dose. Look at the liquid through the viewing window (see Figure D). The liquid should look clear and colourless to pale yellow. It is normal to see an air bubble.

• Do not flick or try to push the bubble out.
• Do not use the pre-filled syringe if the liquid is cloudy, discoloured, or has lumps or particles in it. Use a new pre-filled syringe for your injection.

INJECTING PALYNZIQ

Step 6: Choose your injection site.

The recommended injection sites are:

• Front middle of the thighs.
• Lower part of the abdomen except for the 5 centimetre area around the belly button (navel).

If a caregiver is giving the injection, the top of the buttocks and the back of the upper arms may also be used (see Figure E).

Note:

• Do not inject into moles, scars, birthmarks, bruises, rashes, or areas where the skin is hard, tender, red, damaged, burned, inflamed, or tattooed.
• If you need more than 1 injection for your daily dose, the injection sites should be at least 5 centimetres away from each other (see Figures E and F).
• Each day, change (rotate) your injection sites. Choose an injection site that is at least 5 centimetres away from the injection site(s) you used the day before. It can be on the same part of the body or a different part of the body (see Figures E and F).

Step 7: Wash your hands well with soap and water (see Figure G).

Step 8: Clean the chosen site with an alcohol pad. Let the skin air dry for at least 10 seconds before injecting (see Figure H).

• Do not touch the cleaned injection site.
• Do not remove the needle cap until you are ready to inject Palynziq.
• Before injecting, check to make sure the needle is not damaged or bent.

Inject Palynziq

Step 9: Hold the body of the pre-filled syringe with one hand with the needle facing away from you (see Figure I).

• Do not use the pre-filled syringe if it has been dropped. Use a new pre-filled syringe for your injection.

Step 10: Pull the needle cap straight off the needle (see Figure J).

• Do not twist the needle cap during removal.
• Do not hold the pre-filled syringe by the

plunger or plunger head while taking the needle cap off.

You may see a drop of liquid on the tip of the needle. This is normal. Do not wipe it away. Throw the needle cap away in a sharps disposal or puncture-resistant container.

Step 11: Hold the body of the pre-filled syringe in 1 hand between your thumb and index finger. Use your other hand to pinch up the skin around the injection site. Hold the skin firmly (see Figure K).

• Do not touch the plunger head while inserting the needle into the skin.

Step 12: Use a quick motion to fully insert the needle into the pinched skin at a 45 to 90 degree angle (see Figure L).

Release the pinch of skin. Use that hand to hold the bottom of the syringe steady. Place the thumb of your other hand on the plunger head (see Figure L).

Step 13: Use your thumb to push in the plunger slowly and steadily as far as it will go to inject all the medicine (see Figure M). More pressure may be needed to inject all the medicine for the 10 mg and 20 mg strengths.

Step 14: Slowly move your thumb up to release the plunger allowing the needle to automatically be covered by the syringe body (see Figure N).

Treat injection site

Step 15: Treat injection site (if needed).

If you see drops of blood at the injection site, press a sterile cotton ball or gauze over the injection site and hold for about 10 seconds. You may cover the injection site with an adhesive bandage if needed.

If more than one syringe is needed:

Step 16: If your health care provider tells you to use more than one syringe for your dose, repeat Steps 4 to 15 listed above for each syringe that you use.

• Note: Do not inject multiple injections in the same spot. The injection sites should be at least 5 centimetres away from each other. See Step 6 for choosing an injection site.
• If multiple syringes are needed for a single dose, you should inject at the same time of day. Doses should not be divided over the course of the day

AFTER THE INJECTION

Dispose of the used syringes

Put your used needles and syringes in a sharps disposal or puncture-resistant container right away after use. Check with your doctor, pharmacist or nurse about the right way to throw away the container. Use safe disposal procedures for syringes.

ANNEX IV

Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s)

Scientific conclusions

Taking into account the PRAC Assessment Report on the PSUR(s) for pegvaliase, the scientific conclusions of CHMP are as follows:

In view of available data on dyspnoea from clinical trials and spontaneous reports and in view of a plausible mechanism of action, the PRAC considers a causal relationship between pegvaliase and dyspnoea is at least a reasonable possibility. The PRAC concluded that the product information of products containing pegvaliase should be amended accordingly.

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

Grounds for the variation to the terms of the marketing authorisation(s)

On the basis of the scientific conclusions for pegvaliase the CHMP is of the opinion that the benefitrisk balance of the medicinal product(s) containing pegvaliase is unchanged subject to the proposed changes to the product information.

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

53

Blood phenylalanine level prior to initiating treatment with Palynziq.

Based on the mixed model repeated measures (MMRM) method, with treatment arm, visit, and treatment arm-by-visit interaction (the time profile of blood phenylalanine changes is assessed separately for each treatment arm) as factors adjusting for baseline blood phenylalanine concentration.

Nine patients were excluded from the Week 8 analysis from the Palynziq treatment arms (20 mg/day or 40 mg/day): 4 patients did not complete the RDT due to adverse events (1 patient discontinued treatment and 3 patients transitioned to the long-term extension period) and the remaining 5 patients who did not complete phenylalanine assessment within the window for Week 8 (Day 43 to 56).

Five patients were excluded from the Week 8 analysis from the placebo arms (20 mg/day or