ONPATTRO 2 mg/mL concentrate for infusion solution

2. What you need to know before you receive Onpattro

You must not receive Onpattro

• if you have ever had a severe allergic reaction to patisiran or any of the other ingredients of this medicine (listed in section 6). If you are not sure, talk to your doctor or nurse before receiving Onpattro.

Warnings and precautions

Infusion-related reactions

Onpattro is given as an infusion into a vein (called "intravenous infusion"). During treatment with Onpattro, infusion-related reactions can occur. Before each infusion, you will be given medicines that reduce the risk of infusion-related reactions (see "Medicines given during treatment with Onpattro" in section 3).

Tell your doctor or nurse immediately if you experience any signs of an infusion-related reaction. These signs are listed at the beginning of section 4.

If you experience an infusion-related reaction, your doctor or nurse may slow down the infusion and you may need to take other medicines to control the symptoms. When these reactions stop or improve, your doctor or nurse may decide to restart the infusion.

Vitamin A deficiency

Treatment with Onpattro reduces the amount of vitamin A in the blood. Your doctor will measure your vitamin A levels. If your vitamin A levels are low, your doctor will wait until they return to normal and until any symptoms due to vitamin A deficiency have resolved before you start treatment with Onpattro. Symptoms of vitamin A deficiency may include:

• Decreased night vision, dry eyes, poor vision, and blurred or cloudy vision.

If you have vision problems or any other eye problems while using Onpattro, talk to your doctor. Your doctor may refer you to an eye specialist for a check-up if necessary.

Your doctor will ask you to take a vitamin A supplement every day during treatment with Onpattro.

Levels of vitamin A that are too high or too low can harm the development of the fetus. Therefore, women of childbearing age must not be pregnant when starting treatment with Onpattro and must use effective contraceptive methods (see section "Pregnancy, breastfeeding, and contraception" below).

Tell your doctor if you plan to become pregnant. Your doctor may advise you to stop taking Onpattro. Your doctor will make sure your vitamin A levels have returned to normal before you try to become pregnant.

Tell your doctor if you have an unplanned pregnancy. Your doctor may advise you to stop taking Onpattro. During the first 3 months of pregnancy, your doctor may advise you to stop taking the vitamin A supplement. During the last 6 months of pregnancy, you should restart the vitamin A supplement if your vitamin A levels in the blood have not returned to normal, due to a higher risk of vitamin A deficiency during the last 3 months of pregnancy.

Children and adolescents

Onpattro is not recommended for children and adolescents under 18 years of age.

Other medicines and Onpattro

Tell your doctor or nurse if you are using, have recently used, or might use any other medicines. It is important that you tell your doctor or nurse if you are taking any of the following medicines, as your doctor may need to change the dose:

• Bupropion, a medicine used to treat depression or to help you stop smoking.
• Efavirenz, a medicine used to treat HIV and AIDS.

Pregnancy, breastfeeding, and contraception

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, ask your doctor for advice before taking this medicine.

Women of childbearing age

Onpattro will reduce the level of vitamin A in your blood, which is important for the normal development of the fetus. If you are a woman of childbearing age, you must use an effective contraceptive method during treatment with Onpattro. Talk to your doctor or nurse about suitable contraceptive methods. Pregnancy must be excluded before starting treatment with Onpattro.

Pregnancy

Do not use Onpattro if you are pregnant, unless your doctor has told you to. If you are of childbearing age and plan to use Onpattro, you must use effective contraceptive methods.

Breastfeeding

The components of Onpattro may pass into breast milk. Talk to your doctor about stopping breastfeeding or stopping Onpattro.

Driving and using machines

Onpattro is not expected to affect your ability to drive or use machines. Your doctor will tell you if your condition allows you to drive and use machines safely.

Onpattro contains sodium

This medicine contains 3.99 milligrams (mg) of sodium (the main component of cooking/table salt) per milliliter (ml). This is equivalent to 0.2% of the maximum recommended daily intake of sodium for an adult.

3. How Onpattro is administered

How much Onpattro is administered

• Your doctor will calculate how much Onpattro you will receive based on your body weight.
• The usual dose of Onpattro is 300 micrograms per kilogram (kg) of body weight given every 3 weeks.

How Onpattro is administered

• Onpattro will be given to you by a doctor or nurse.
• It is given as an infusion into a vein ("intravenous infusion") usually over about 80 minutes.

If you do not have problems with infusions at the clinic, your doctor may discuss the possibility of a healthcare professional giving you the infusions at home.

Medicines given during treatment with Onpattro

About 60 minutes before each Onpattro infusion, you will be given medicines that reduce the risk of infusion-related reactions (see section 4). These include antihistamines, a corticosteroid (a medicine that reduces inflammation), and a pain reliever.

How long you will use Onpattro

Your doctor will tell you how long you need to receive Onpattro. Do not stop treatment with Onpattro unless your doctor tells you to.

If you receive more Onpattro than you should

This medicine will be given to you by a doctor or nurse. In the unlikely event that you receive too much (an overdose), your doctor or nurse will check if you have any side effects.

If you miss a dose of Onpattro

If you miss a visit to receive Onpattro, ask your doctor or nurse when to schedule the next treatment.

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

4. Possible side effects

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

Infusion-related reactions

Infusion-related reactions are very common (may affect more than 1 in 10 people).

Tell your doctor or nurse immediately if you experience any of the following signs of an infusion-related reaction during treatment. You may need to slow down or stop the infusion and take other medicines to treat the reaction.

• Stomach pain
• Nausea
• Body pain, such as back, neck, or joint pain
• Headache
• Feeling tired (fatigue)
• Chills
• Dizziness
• Cough, shortness of breath, or other respiratory problems
• Redness of the face or body (flushing), warmth of the skin, rash, or itching
• Chest pain or discomfort
• Fast heart rate
• Low or high blood pressure, some patients have fainted during the infusion due to low blood pressure.
• Pain, redness, warmth, or swelling at the infusion site or near it
• Swelling of the face
• Changes in the sound or tone of the voice (hoarseness)

Other side effects

Tell your doctor or nurse immediately if you notice any of the following side effects:

Very common:may affect more than 1 in 10 people

• Swelling of the arms or legs (peripheral edema)

Common:may affect up to 1 in 10 people

• Joint pain (arthralgia)
• Muscle spasms
• Indigestion (dyspepsia)
• Shortness of breath (dyspnea)
• Redness of the skin (erythema)
• Feeling dizzy or faint (vertigo)
• Stuffy or runny nose (rhinitis)
• Irritation or infection of the respiratory tract (sinusitis, bronchitis)

Uncommon:may affect up to 1 in 100 people

• Leakage of the medicine into the tissue around the infusion site, which can cause swelling or redness

Tell your doctor or nurse immediately if you notice any of the above side effects.

Reporting of side effects

If you experience any side effects, talk to your doctor or nurse, even if they are not listed in this leaflet. You can also report side effects directly through the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Onpattro

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 carton after EXP. The expiry date is the last day of the month shown.

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

If you do not have access to a refrigerator, Onpattro can be stored at room temperature (up to 25°C) for a maximum of 14 days.

Medicines should not be disposed of via wastewater or household waste. Your healthcare professional will dispose of any unused medicines. This will help protect the environment.

6. Container Contents and Additional Information

Onpattro Composition

• The active ingredient is patisiran.
• Each ml contains patisiran sodium equivalent to 2 mg of patisiran.
• Each vial contains patisiran sodium equivalent to 10 mg of patisiran.
• The other components are DLin-MC3-DMA ((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl-4-(dimethylamino)butanoate), PEG2000-C-DMG (α-(3'-{[1,2-di(myristyloxy)propanoyl]amino}propyl)-ω-methoxy, polyoxyethylene), DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), cholesterol, disodium phosphate heptahydrate, anhydrous potassium dihydrogen phosphate, sodium chloride, and water for injectable preparations (see "Onpattro contains sodium" in section 2).

Onpattro Appearance and Container Contents

• Onpattro is a homogeneous, opalescent, white or off-white concentrate for solution for infusion (sterile concentrate).
• Onpattro is supplied in cardboard boxes containing one vial each.

Marketing Authorization Holder and Manufacturer

Alnylam Netherlands B.V.

Antonio Vivaldistraat 150

1083 HP Amsterdam

Netherlands

For further information on this medicinal product, please contact the local representative of the marketing authorization holder:

Date of Last Revision of this Leaflet: 05/2024

Other Sources of Information

Detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu/.

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This information is intended solely for healthcare professionals:

Required Premedication

All patients must receive premedication before administration of Onpattro to reduce the risk of infusion-related reactions (IRRs). On the day of Onpattro infusion, at least 60 minutes before the start of the infusion, the following medications should be administered:

• Intravenous corticosteroid (10 mg of dexamethasone or equivalent)
• Oral paracetamol (500 mg)
• Intravenous H1 blocker (50 mg of diphenhydramine or equivalent)
• Intravenous H2 blocker (20 mg of famotidine or equivalent)

In the event of unavailable or intolerance to intravenous premedication, an oral equivalent may be administered.

If clinically indicated, the corticosteroid may be gradually reduced in decrements not exceeding 2.5 mg to a minimum dose of 5 mg of dexamethasone (intravenous, IV) or equivalent. The patient must have received at least 3 consecutive Onpattro infusions without experiencing IRRs before each reduction in corticosteroid premedication.

Additional doses or higher doses of one or more premedication medications may be administered to reduce the risk of IRRs, if necessary.

Preparation of the Infusion Solution

This medicinal product is for single use only.

Onpattro must be diluted with a 9 mg/ml (0.9%) sodium chloride solution before intravenous infusion. The diluted infusion solution must be prepared by a healthcare professional using an aseptic technique as follows:

• Remove Onpattro from the refrigerator. Do not shake or agitate.
• Discard the vial if it has been frozen.
• Perform a visual inspection for particles and coloration. Do not use if there is coloration or foreign particles. Onpattro is a homogeneous, opalescent, white or off-white solution. A white or off-white coating may be observed on the inner surface of the vial, normally at the interface between the liquid and the headspace. The presence of the white or off-white coating does not affect the quality of the product.
• Calculate the required volume of Onpattro based on the recommended dosage according to weight.
• Withdraw the entire contents of one or more vials into a single sterile syringe.
• Filter Onpattro through a sterile polyethersulfone (PES) syringe filter (0.45 microns) into a sterile container.
• Withdraw the required volume of filtered Onpattro from the sterile container with a sterile syringe.
• Dilute the required volume of filtered Onpattro in an infusion bag containing a 9 mg/ml sodium chloride solution (0.9%) to a total volume of 200 ml. Use infusion bags that do not contain di(2-ethylhexyl) phthalate (DEHP).
• Gently invert the bag to mix the solution. Do not shake. Do not mix or dilute with other medications.
• Discard unused portions of Onpattro. Disposal of unused medicinal products and materials that have come into contact with them should be done in accordance with local regulations.
• Onpattro does not contain preservatives. The diluted solution should be administered immediately after preparation. If not used immediately, store the diluted solution in the infusion bag at room temperature (up to 30°C) or between 2°C and 8°C for a maximum of 16 hours (including infusion time). Do not freeze.

Administration

Onpattro is for intravenous use.

• Onpattro must be diluted before intravenous infusion.
• A dedicated line with an infusion set containing an integrated PES filter (1.2 microns) should be used. Infusion sets must not contain di(2-ethylhexyl) phthalate (DEHP).
• The diluted Onpattro solution should be infused intravenously over approximately 80 minutes at an initial infusion rate of approximately 1 ml/min for the first 15 minutes, followed by an increase to approximately 3 ml/min for the remainder of the infusion. The infusion duration may be extended in the event of IRRs.
• Onpattro should be administered through a secure and free-flowing venous access line. The infusion site should be monitored for possible infiltration during administration. If extravasation is suspected, it should be managed according to local standard practice for non-vesicant substances.
• The patient should be monitored during the infusion and, if clinically indicated, after the infusion.
• Once the infusion is complete, the intravenous administration set should be flushed with a 9 mg/ml sodium chloride solution (0.9%) to ensure that all of the medicinal product has been administered.