TEGSEDI

B. PACKAGE LEAFLET

Package leaflet: Information for the user

Tegsedi 284 mg solution for injection in pre-filled syringe

inotersen
Please read this entire leaflet carefully before using this medicine, as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, consult your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you personally. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any adverse reactions, including those not listed in this leaflet, inform your doctor or nurse. See section 4.

Contents of this leaflet

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

1. What Tegsedi is and what it is used for

Tegsedi contains the active substance inotersen. It is used to treat adults with hereditary transthyretin amyloidosis. Hereditary transthyretin amyloidosis is a genetic disease that causes an accumulation of small fibres of the protein transthyretin in the body's organs, impairing their normal function. Tegsedi is used when the disease causes symptoms of polyneuropathy (nerve damage).
Inotersen is a type of medicine called an antisense oligonucleotide inhibitor. It works by reducing the production of transthyretin in the liver, thereby decreasing the risk of transthyretin fibres depositing in the body's organs and causing symptoms.

2. What you need to know before using Tegsedi

Do not use Tegsedi if:

• you are allergic to inotersen or to any of the other ingredients of this medicine (listed in section 6)
• blood tests show you have an abnormally low platelet count, the blood cells that clump together to help blood clot
• kidney function tests or urine protein tests show signs of severe kidney problems
• you have severe liver impairment (hepatic insufficiency).

Warnings and precautions
Before starting treatment with Tegsedi, your doctor will assess your blood cell levels, liver and kidney function, vitamin A levels, and protein levels in your urine. You may also be given a pregnancy test to ensure the result is negative. Unless otherwise directed by your doctor, you will only be treated with Tegsedi if all these test results are within acceptable ranges and your pregnancy test is negative. Your doctor will repeat these tests regularly during treatment. It is important that you undergo these blood and urine tests regularly for as long as you are receiving Tegsedi.
Thrombocytopenia
Tegsedi can reduce the blood cells responsible for blood clotting (platelets), which may cause a condition called thrombocytopenia at any time during treatment with Tegsedi (see section 4). If, as in thrombocytopenia, the number of platelets is too low, blood may not clot quickly enough to stop bleeding. This can lead to bruising and more serious problems such as excessive bleeding and internal bleeding. Your doctor will check your platelet levels in the blood before starting Tegsedi and regularly throughout the entire treatment period. It is important that you have these blood tests regularly while being treated with Tegsedi due to the risk of severe bleeding caused by low platelet counts. If you stop treatment with Tegsedi, your blood levels should be monitored 8 weeks after treatment ends.
Contact your doctor immediately if you notice unexplained bruising or a skin rash with small red spots (called petechiae), bleeding from cuts that does not stop or oozes, bleeding gums or nosebleeds, blood in the urine or stool, or bleeding in the whites of the eyes. Seek immediate medical help if you experience neck stiffness or an unusual and severe headache, as these symptoms may be caused by bleeding in the brain.
Glomerulonephritis/kidney problems
Glomerulonephritis is a kidney disease in which the kidneys stop functioning properly due to inflammation and kidney damage. Some patients treated with inotersen have developed this condition.
Symptoms of glomerulonephritis include foamy urine, pink or brown-colored urine, blood in the urine, and reduced urine output compared to usual.
Some patients treated with inotersen have also shown worsening kidney function in the absence of glomerulonephritis.
Your doctor will check your kidney function before starting and regularly during treatment with Tegsedi. It is important that you have these blood tests regularly while being treated with Tegsedi due to the risk of kidney problems. If you stop treatment with Tegsedi, kidney function should be checked 8 weeks after treatment ends. If you develop glomerulonephritis, your doctor will prescribe appropriate treatment.
Vitamin A deficiency
Tegsedi can reduce vitamin A (also known as retinol) levels in the body. Your doctor will measure your levels, and if your vitamin A levels are already low, they must be corrected and any symptoms resolved before you can start treatment with Tegsedi. Symptoms indicating low vitamin A levels include:

• dry eyes, poor vision, reduced night vision, blurred or hazy vision.

Contact your doctor if you experience vision problems or any other eye problems while using Tegsedi. Your doctor may refer you to a specialist for an eye examination if necessary.
During treatment with Tegsedi, your doctor will instruct you to take a daily vitamin A supplement.
Both excessively high and low vitamin A levels can harm fetal development. Therefore, women of childbearing potential must exclude the possibility of pregnancy before starting treatment with Tegsedi and must use effective contraception (see section “Pregnancy and breastfeeding” below).
If you are planning a pregnancy, you must stop taking inotersen, including vitamin A supplementation, and ensure your vitamin A levels have normalized before attempting conception.
If you become pregnant unexpectedly, you must stop treatment with inotersen. However, due to the prolonged activity of Tegsedi, you may continue to have reduced vitamin A levels. It is not known whether continuing vitamin A supplementation at a dose of 3,000 IU per day could be harmful to the fetus during the first trimester of pregnancy, but this dose should not be exceeded. You should resume vitamin A supplementation during the second and third trimesters if your vitamin A levels have not yet normalized, due to the increased risk of vitamin A deficiency in the third trimester.
Liver injury and monitoring
Tegsedi can cause serious liver problems. Before starting treatment with inotersen, a blood test will be required to check whether the liver is functioning properly. In addition, you will need to have these blood tests periodically during treatment with this medicine. It is important to have these periodic blood tests for the entire duration of treatment with Tegsedi.
Liver transplant rejection
Talk to your doctor before using Tegsedi if you have previously received a liver transplant. Cases of liver transplant rejection have been reported in patients treated with Tegsedi. Your doctor will monitor you regularly for this during treatment with Tegsedi.
Children and adolescents
Tegsedi must not be used in children or adolescents under 18 years of age.
Other medicines and Tegsedi
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. It is important to inform your doctor if you have previously been treated with any of the following medicines:

• medicines that prevent blood clots or reduce platelet count in the blood, e.g. acetylsalicylic acid, heparin, warfarin, clopidogrel, rivaroxaban, and dabigatran.
• medicines that may alter kidney function or damage the kidneys, e.g. sulfonamides (used as antibacterials), anilides (used to treat fever and pain), aldosterone antagonists (used as diuretics), and natural opium alkaloids and other opioids (used as painkillers).

Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding, consult your doctor before using this medicine.
Women of childbearing potential
Tegsedi reduces the level of vitamin A in the body, which is important for normal fetal development during pregnancy. It is not known whether vitamin A supplementation can fully compensate for the risk of vitamin A deficiency affecting the fetus (see “Warnings and precautions” above). If you are a woman of childbearing potential, you must use effective contraception and exclude the possibility of pregnancy before starting treatment with Tegsedi.
Pregnancy
You must not use Tegsedi during pregnancy unless specifically instructed by your doctor.
Breastfeeding
Inotersen may be excreted in breast milk. A risk to the breastfed newborn cannot be excluded. Consult your doctor regarding the need to discontinue breastfeeding or treatment with Tegsedi.
Driving and using machines
Tegsedi has not shown any effects on the ability to drive vehicles or operate machinery.
Tegsedi contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per 1.5 mL, i.e., it is essentially “sodium-free”.

3. How to use Tegsedi

Use this medicine exactly as your doctor has instructed you. If you have any doubts, consult your doctor or pharmacist.
The recommended dose of Tegsedi is 284 mg of inotersen.
Doses must be administered once weekly. All subsequent doses should be injected once weekly, always on the same day.

Route and method of administration
Tegsedi is administered only by subcutaneous injection (subcutaneous use).

Instructions for use
Before using the pre-filled syringe, your doctor must show you or the person assisting you the correct way to use it. Ask your doctor any questions you or the person assisting you may have.
Read the instructions for use before using the pre-filled syringe for the first time and each time you receive a new prescription. They may contain new information.

Guide to parts
Before use After use
Plunger

Grip
Safety spring
(inside the
barrel)
Barrel
Inspection
window
After use, the safety
Needle
spring activates
automatically and the
Cap
needle retracts.
of the
needle

Each pre-filled syringe contains a single dose and is for single use only.

WARNINGS
Do not remove the needle cap until you reach step 6 of these instructions and are ready to inject Tegsedi. Do not share the syringe with other people or reuse the syringe. Do not use if the pre-filled syringe has fallen on a hard surface or is damaged. Do not freeze the pre-filled syringe. If any of the above conditions occurs, dispose of the pre-filled syringe in a puncture-resistant sharps container and use a new syringe.
PREPARATION
1. Gather the necessary supplies
1 pre-filled syringe from the refrigerator -1 alcohol wipe (not supplied) -1 gauze pad or cotton ball (not supplied) -1 puncture-resistant sharps container (not supplied) Do not inject the medicine until all the supplies listed above have been gathered.
2. Prepare to use the pre-filled syringe
Remove the plastic tray from the packaging and check the expiration date. Do not use if the expiration date has passed. •Wait 30 minutes for the syringe to reach room temperature (20–25 °C) before proceeding with the injection. Do not heat the pre-filled syringe in any other way. For example, do not heat in a microwave oven or in warm water, or place near other heat sources. •Remove the pre-filled syringe from the tray by holding it by the barrel. Do not move the plunger.
3. Check the medicine in the pre-filled syringe
	Look through the inspection window to check that the solution is clear and colorless or pale yellow. It is normal for air bubbles to be present in the solution. No action is needed. Do not use if the solution appears cloudy, has changed color, or contains particles. If any of these conditions occurs, dispose of the pre-filled syringe in a puncture-resistant sharps container and use a new syringe.
4. Choose the injection site
	Select an injection site on the abdomen (stomach) or the front of the thigh. The injection may also be administered on the outer upper arm if Tegsedi is being given by another person. Do not inject within 3 cm of the navel. Do not inject in the same site repeatedly. Do not inject in areas where the skin is bruised, tender, red, or hardened. Do not inject in tattoos, scars, or damaged skin. Do not inject through clothing.
5. Clean the injection site
	Wash hands with soap and water. Using circular motions, clean the injection site with an alcohol wipe. Allow the skin to air dry. Do not touch the area again before the injection.
INJECTION
6. Remove the needle cap
	Hold the pre-filled syringe by the barrel, directing the needle away from yourself. Remove the needle cap by pulling it straight off with a firm motion. Do not unscrew it. A drop of liquid may appear at the tip of the needle. This is normal. Keep your hands away from the plunger to avoid pushing it before you are ready for injection. Do not remove the needle cap until just before injection. Do not pull off the cap while holding the pre-filled syringe by the plunger. Always hold the syringe by the barrel. Do not let the needle touch any surface. Do not remove any air bubbles from the pre-filled syringe. Do not recap the needle on the pre-filled syringe.
7. Insert the needle
	Hold the pre-filled syringe in one hand. Hold the skin around the injection site as instructed by your healthcare provider, gently pinching the skin at the injection site or administering the injection without pinching, as directed. Slowly insert the needle completely into the chosen injection site at a 90° angle. Do not hold the pre-filled syringe by the plunger or press on the plunger to insert the needle.
8. Begin the injection
With a slow and steady motion, depress the plunger	Completely depress the plunger slowly and steadily until all the medicine is injected. Ensure that the needle remains fully inserted into the injection site while injecting the medicine. It is important to depress the plunger completely. While depressing the plunger, you may hear a "click." This is normal. This sound does not indicate the end of the injection. You may feel some resistance in the plunger toward the end of the injection. You may need to apply slightly more pressure to ensure the plunger is fully depressed. Do not release the plunger.
9. Hold the plunger down
Keep the plunger fully depressed and wait 5 seconds Wait 5 seconds	At the end of the injection, firmly push the plunger. Keep the plunger fully depressed and wait 5 seconds. If you release the plunger too quickly, some of the medicine may be lost. When the plunger begins to rise automatically, this indicates that it has been fully depressed. If the plunger does not begin to rise automatically, press it again.

10. Completing the injection

Slowly release your thumb from
the plunger and allow the safety
spring to push the plunger
automatically upward.

The needle should now be retracted
Release the
safely inside the pre-filled
plunger
syringe, and the safety spring
should be visible outside the
plunger.
When the plunger reaches the
bottom, the injection is complete.
If the plunger does not rise
automatically when you slowly
release your thumb, this means
the safety spring has not activated.
In this case, press the plunger
again, but with greater force.
Do not pull the plunger
up manually. Remove the entire
pre-filled syringe by lifting it
upward.
Do not attempt to recap the
retracted needle.
Do not rub the injection site.

DISPOSAL AND CARE
Disposing of the used pre-filled syringe

Place the used pre-filled syringe
immediately into a designated
sharps disposal container after
use. Do not throw the pre-filled
syringe into household waste.

If you use more Tegsedi than you should
Contact your doctor or pharmacist or go to the Emergency Room immediately, even if you do not have
any symptoms.

If you forget to use Tegsedi
If you miss a dose of Tegsedi, take the next dose as soon as possible, unless the next dose is due within two days, in which case the missed dose should be skipped and the next dose administered as scheduled.
Do not take a double dose to make up for the missed dose.

If you stop treatment with Tegsedi
Do not stop using Tegsedi unless your doctor tells you to do so.
If you have any doubts about how to use this medicine, consult your doctor, pharmacist, or
nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Serious side effects
If you experience any of the following side effects, stop using Tegsedi and contact your doctor immediately:

• symptoms that could indicate glomerulonephritis (a disease that prevents the kidneys from functioning properly), such as foamy urine, pink or brown urine, blood in the urine, or reduced amount of urine compared to usual. Glomerulonephritis is a common side effect of inotersen (may affect up to 1 in 10 people).
• symptoms that could indicate thrombocytopenia (a disorder that prevents blood from clotting due to low platelet levels), such as unexplained bruising or a skin rash with small red spots (called petechiae), bleeding from cuts that does not stop or oozes, bleeding gums or nosebleeds, blood in the urine or stools, or bleeding in the whites of the eyes. Low platelet levels are a very common side effect of inotersen (may affect more than 1 in 10 people).
• symptoms that could indicate liver damage, such as yellowing of the eyes or skin, or dark urine, possibly accompanied by itching of the skin, pain in the upper right part of the stomach (abdomen), loss of appetite, bleeding or bruising more easily than usual, or feeling unusually tired. Seek immediate medical help if you experience neck stiffness or an unusual and severe headache, as these symptoms may be caused by brain bleeding.

Other side effects
Very common (may affect more than 1 in 10 people)

• Reduction in red blood cells that may cause pale skin, weakness, or shortness of breath (anaemia)
• Headache
• Vomiting or nausea
• Increased body temperature
• Feeling cold (chills) or shivering
• Pain, redness, itching, or bruising at the injection site
• Swelling of ankles, feet, or fingers (peripheral oedema)

Common (may affect up to 1 in 10 people)

• Increase in the number of white blood cells called eosinophils in the blood (eosinophilia)
• Decreased appetite
• Feeling faint or dizzy, especially when standing up (low blood pressure, hypotension)
• Bruising
• Collection of blood within tissues, potentially appearing similar to a severe bruise (haematoma)
• Itching
• Skin rash
• Kidney damage leading to reduced kidney function or kidney failure
• Abnormal results in blood and urine tests (may indicate liver or kidney damage)
• Flu-like symptoms, such as high temperature, body aches, and chills (flu-like illness)
• Swelling at the injection site or change in skin colour

Uncommon (may affect up to 1 in 100 people)

• Allergic reaction

Reporting of side effects
If you get any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist. 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 Tegsedi

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton, tray, and pre-filled syringe after "Exp" or "EXP". The expiry date refers to the last day of that month.
Store in the refrigerator (2 °C – 8 °C).
Do not freeze.
Tegsedi may be stored outside the refrigerator for up to 6 weeks at temperatures below 30°C. If stored outside the refrigerator and not used within 6 weeks, it must be discarded.
Keep in the original packaging to protect the medicine from light.
Do not use this medicine if you notice that the solution is cloudy or contains particles.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Tegsedi contains

• The active substance is inotersen.
• Each mL contains 189 mg of inotersen (as inotersen sodium). Each pre-filled syringe contains 284 mg of inotersen (as inotersen sodium) in 1.5 mL of solution.
• The other components are water for injections, sodium hydroxide, and hydrochloric acid (see “Tegsedi contains sodium” in section 2).

Description of the appearance of Tegsedi and contents of the pack
Tegsedi is a clear, colourless to pale yellow injectable solution in a pre-filled syringe (injection).
Tegsedi is available in packs of 1 or 4 pre-filled syringes.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
Akcea Therapeutics Ireland Ltd
St. James House,
72 Adelaide Road, Dublin 2
D02 Y017, Ireland

Manufacturer
ABF Pharmaceutical Services GmbH
Brunnerstraße 63/18-19
1230 Wien
Austria

More detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu