Consumer medicine information

Onpattro

Patisiran

BRAND INFORMATION

Brand name

Onpattro

Active ingredient

Patisiran

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Onpattro.

SUMMARY CMI

Onpattro®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using Onpattro?

Onpattro contains the active ingredient patisiran. Onpattro is used to treat an illness which runs in families called hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis).

For more information, see Section 1. Why am I using Onpattro? in the full CMI.

2. What should I know before I use Onpattro?

Do not use if you have ever had an allergic reaction to patisiran or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Onpattro? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Onpattro and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How Onpattro is given?

  • The usual dose of Onpattro is 300 micrograms per kilogram (kg) of body weight given once every 3 weeks.
  • Onpattro will be given to you by a doctor or nurse. It is given as a drip into a vein (‘intravenous infusion’) usually over about 80 minutes.

More instructions can be found in Section 4. How Onpattro is given? in the full CMI.

5. What should I know while using Onpattro?

Things you should do
  • Tell your doctor if you are pregnant or breastfeeding, or are planning to become pregnant
  • Remind any doctor, dentist, or pharmacist you visit that you are using Onpattro.
Things you should not do
  • Your doctor will tell you how long you need to receive Onpattro. Do not stop treatment with Onpattro unless your doctor tells you to.
Driving or using machines
  • Onpattro is believed to have no or negligible influence on the ability to drive or use machines. Your doctor will tell you whether your condition allows you to drive vehicles and use machines safely.
Looking after your medicine
  • Keep this medicine where young children cannot reach it.
  • Do not use this medicine after the expiry date which is stated on the carton after ‘EXP’. The expiry date refers to the last day of that month.
  • Store in a refrigerator (2°C to 8°C). Do not freeze.
  • If refrigeration is not available, Onpattro can be stored at room temperature (up to 25°C) for up to 14 days. Onpattro must be discarded if not used within the 14 day period.

For more information, see Section 5. What should I know while using Onpattro? in the full CMI.

6. Are there any side effects?

Tell your doctor or nurse straight away if you get any of the following signs of an infusion-related reaction during treatment. The infusion may need to be slowed down or stopped, and you may need to take other medicines to manage the reaction. You may experience stomach pain, feeling sick (nausea), body aches or pain, headache, feeling tired, chills, dizziness, cough, hoarseness, feeling short of breath or other breathing problems, reddening of the face or body (flushing), warm skin, rash or itching, chest discomfort or chest pain, rapid heart rate or low or high blood pressure (some patients have fainted during the infusion due to low blood pressure), pain, redness, burning sensation, or swelling at or near the infusion site or swelling of the face.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

Onpattro®

Active ingredient(s): patisiran

Consumer Medicine Information (CMI)

This leaflet provides important information about using Onpattro. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Onpattro.

Where to find information in this leaflet:

1. Why am I using Onpattro?
2. What should I know before I use Onpattro?
3. What if I am taking other medicines?
4. How Onpattro is given?
5. What should I know while using Onpattro?
6. Are there any side effects?
7. Product details

1. Why am I using Onpattro?

Onpattro contains the active ingredient patisiran.

This medicine is used to treat an illness which runs in families called hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis).

  • hATTR amyloidosis is caused by problems with a protein in the body called ‘transthyretin’ (TTR).
  • This protein is made mostly in the liver and carries vitamin A and other substances around the body.
  • In people with this illness, abnormally shaped TTR proteins clump together to make deposits called ‘amyloid’.
  • Amyloid can build up around the nerves, heart, and other places in the body, preventing them from working normally. This causes the symptoms of the illness.

Onpattro works by lowering the amount of TTR protein that the liver makes.

  • This means there is less TTR protein in the blood that can form amyloid.
  • This can help to reduce the effects of this illness.

Onpattro is used in adults only.

2. What should I know before I use Onpattro?

Warnings

Do not use Onpattro if:

  • you are allergic to patisiran, or any of the ingredients listed at the end of this leaflet.

Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

  • have any other medical conditions
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Infusion-related reactions

Onpattro is given as a drip into a vein (called an ‘intravenous infusion’). Reactions to this infusion may happen during treatment with Onpattro. Before each infusion you will be given medicines that help to lower the chance of infusion related reactions (see “How Onpattro is given” in section 4).

Tell your doctor or nurse straight away if you get any signs of an infusion-related reaction. These signs are listed in section 6.

If you have an infusion-related reaction, your doctor or nurse may slow down or stop your infusion, and you may need to take other medicines to control the symptoms. When these reactions stop, or get better, your doctor or nurse may decide to start the infusion again.

Vitamin A deficiency

Treatment with Onpattro lowers the amount of vitamin A in your blood. Your doctor will measure your vitamin A levels, and if they are too low they should have returned to normal and any symptoms due to vitamin A deficiency should have resolved before you start treatment with Onpattro. Symptoms of vitamin A deficiency may include:

  • Decrease in night vision, dry eyes, poor vision, hazy or cloudy vision

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

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

Both too high and too low levels of vitamin A can harm the development of your unborn child. Therefore, women of childbearing age should not be pregnant when starting treatment with Onpattro and should practise effective contraception (see section “Pregnancy and breastfeeding”below).

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

You should not use Onpattro if you are pregnant, unless advised by your doctor.

Onpattro will reduce the level of vitamin A in your blood, which is important for normal development of your unborn child. If you are a woman of child-bearing age, you should practise effective contraception during treatment with Onpattro. Talk to your doctor or nurse about suitable methods of contraception. Pregnancy should be excluded before starting treatment with Onpattro.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Ingredients of Onpattro may pass into breast milk. Talk to your doctor about stopping breast-feeding or treatment with Onpattro.

Use in children and adolescents

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

Onpattro contains sodium

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

3. What if I am taking other medicines?

Tell your doctor, nurse or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

It is important to tell your doctor, nurse or pharmacist 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 to stop smoking
  • Efavirenz, a medicine used to treat HIV infection and AIDS

Check with your doctor, nurse or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Onpattro.

4. How Onpattro is given?

How much to give

  • Your doctor will work out how much Onpattro to give you - this will depend on your body weight.
  • The usual dose of Onpattro is 300 micrograms per kilogram (kg) of body weight given once every 3 weeks.

How Onpattro is given

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

If you do not have problems with your infusions in the clinic, your doctor may talk with you about a healthcare professional giving you your infusions at home.

Medicines given during treatment with Onpattro

Before each infusion of Onpattro, you will be given medicines that help to lower the risk of infusion-related reactions. These include antihistamines, a corticosteroid (a medicine that suppresses inflammation), and a pain reliever.

How long to 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 miss your dose of Onpattro

If you miss an appointment to have Onpattro, ask your doctor or nurse when to book your next treatment.

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

If you are given too much Onpattro

This medicine will be given to you by your doctor or nurse. In the unlikely event that you are given too much (an overdose) your doctor or nurse will check you for side effects.

In the unlikely event that you are not with a healthcare professional, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Onpattro?

Things you should do

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

If you are a woman of child-bearing age, you should practise effective contraception during treatment with Onpattro.

Tell your doctor if you are planning to become pregnant.

Your doctor may tell you to stop taking Onpattro. Your doctor will ensure that your vitamin A levels have returned to normal before you try to become pregnant.

Call your doctor straight away if you:

  • get any signs of an infusion-related reaction. These signs are listed in section 6 Are there any side effects > Infusion related reactions.
  • if you have an unplanned pregnancy. Your doctor may tell you to stop taking Onpattro. During the first 3 months of your pregnancy, your doctor may tell you to stop your vitamin A supplement. During the last 6 months of your pregnancy, you should resume vitamin A supplementation if the vitamin A levels in your blood have not yet returned to normal, because of an increased risk of vitamin A deficiency during the last 3 months of your pregnancy.

Remind any doctor, dentist or pharmacist you visit that you are using Onpattro.

Things you should not do

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

Driving or using machines

Onpattro is believed to have no or negligible influence on the ability to drive or use machines. Your doctor will tell you whether your condition allows you to drive vehicles and use machines safely.

Looking after your medicine

  • Do not use this medicine after the expiry date which is stated on the carton after ‘EXP’. The expiry date refers to the last day of that month.
  • Store in a refrigerator (2°C to 8°C). Do not freeze.
  • If refrigeration is not available, Onpattro can be stored at room temperature (up to 25°C) for up to 14 days. Onpattro must be discarded if not used within the 14 day period.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

Medicines should not be disposed of via wastewater or household waste. Your healthcare professional will throw away any medicines that are no longer being used. These measures will help protect the environment.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor, nurse, or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Other side effects:
  • Muscle spasms
  • Indigestion (dyspepsia)
  • Feel like the room is spinning (vertigo)
  • Irritation or infection of the airways (sinusitis, bronchitis)
  • Redness of the skin (erythema)
  • Pain in the joints (arthralgia)
  • Stuffy or runny nose (rhinitis)
Speak to your doctor or nurse if you have any of these less serious side effects.

Serious side effects

Serious side effectsWhat to do
  • Infusion-related reactions:
    - Cough, feeling short of breath, or other breathing problems
    - Changes to the sound or tone of your voice (hoarseness)
    - Reddening of the face or body (flushing), warm skin, rash or itching
    - Chest discomfort or chest pain
    - Rapid heart rate
    - Low or high blood pressure; some patients have fainted during the infusion due to low blood pressure
    - Pain, redness, burning sensation, or swelling at or near the infusion site
    - Swelling of the face
    - Stomach pain
    - Feeling sick (nausea)
    - Body aches or pain, including pain in the back, neck, or joints
    - Headache
    - Feeling tired (fatigue)
    - Chills
    - Dizziness
  • Swelling of the arms or legs (peripheral oedema)
  • Shortness of breath (dyspnoea)
  • Leakage of the drug into the surrounding tissue at the site of infusion, which may cause swelling or redness (extravasation)
Tell your doctor or nurse straight away if you notice any of these serious side effects.

Tell your doctor, nurse or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Onpattro contains

Active ingredient
(main ingredient)		Patisiran
Other ingredients
(inactive ingredients)
  • DLin-MC3-DMA ((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl-4-(dimet hylamino) butanoate)
  • PEG2000-C-DMG (1,2-Dimyristoyl-sn-glycero-3-carboxaminopropylpolyethylene glycol 2000 methyl ether)
  • Distearoylphosphatidylcholine [DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine)]
  • Cholesterol
  • Dibasic sodium phosphate heptahydrate
  • Monobasic potassium phosphate
  • Sodium chloride
  • Water for injections
Potential allergensN/A

Do not take this medicine if you are allergic to any of these ingredients.

What Onpattro looks like

Onpattro is presented in vials containing patisiran sodium equivalent to 10 mg patisiran. Each mL contains patisiran sodium equivalent to 2 mg patisiran.

Onpattro is a white to off-white, opalescent, homogeneous concentrated injection for infusion.

Aust R 380813.

Who sponsors Onpattro

Medison Pharma Australia Pty Ltd
1 Bligh Street
Sydney
NSW 2000
Australia

Phone: 1800 566 020
Email: [email protected]
www.medisonpharma.com.au

This leaflet was prepared in July 2024.

Published by MIMS September 2024

BRAND INFORMATION

Brand name

Onpattro

Active ingredient

Patisiran

Schedule

S4

 

1 Name of Medicine

Patisiran.

2 Qualitative and Quantitative Composition

Each mL contains patisiran sodium equivalent to 2 mg patisiran.
Each vial contains patisiran sodium equivalent to 10 mg patisiran formulated as lipid nanoparticles.

Excipients with known effect.

Each mL of concentrate contains 3.99 mg sodium.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Concentrated injection for infusion (sterile concentrate).
White to off-white, opalescent, homogeneous solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Onpattro is indicated for the treatment of hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) in adult patients with stage 1 or stage 2 polyneuropathy.

4.2 Dose and Method of Administration

Therapy should be initiated under the supervision of a physician knowledgeable in the management of amyloidosis.

Dosage.

The recommended dose of Onpattro is 300 microgram per kg body weight administered via intravenous (IV) infusion once every 3 weeks.
Dosing is based on actual body weight. For patients weighing ≥ 100 kg, the maximum recommended dose is 30 mg.
Vitamin A supplementation at approximately 2500 IU vitamin A per day is advised for patients treated with Onpattro (see Section 4.4 Special Warnings and Precautions for Use).

Required premedication.

All patients should receive premedication prior to Onpattro administration to reduce the risk of infusion-related reactions (IRRs) (see Section 4.4 Special Warnings and Precautions for Use). Each of the following medicinal products should be given on the day of Onpattro infusion at least 60 minutes prior to the start of infusion:
Intravenous corticosteroid (dexamethasone 10 mg, or equivalent);
Oral paracetamol (500 mg);
Intravenous H1 blocker (diphenhydramine 50 mg, or equivalent);
Intravenous H2 blocker (famotidine 20 mg, or equivalent).
For premedications not available or not tolerated intravenously, equivalents may be administered orally.
If clinically indicated, the corticosteroid may be tapered in decrements no greater than 2.5 mg to a minimum dose of 5 mg of dexamethasone (IV), or equivalent. The patient should receive at least 3 consecutive IV infusions of Onpattro without experiencing IRRs before each reduction in corticosteroid premedication.
Additional or higher doses of one or more of the premedications may be administered to reduce the risk of IRRs, if needed (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Missed dose.

If a dose is missed, Onpattro should be administered as soon as possible.
If Onpattro is administered within 3 days of the missed dose, dosing should be continued according to the patient's original schedule.
If Onpattro is administered more than 3 days after the missed dose, dosing should be continued every 3 weeks thereafter.

Special populations.

Elderly patients.

No dose adjustment is required in patients ≥ 65 years of age (see Section 5.2 Pharmacokinetic Properties).

Hepatic impairment.

No dose adjustment is necessary in patients with mild hepatic impairment (bilirubin ≤ 1 x ULN and AST > 1 x ULN, or bilirubin > 1.0 to 1.5 x ULN and any AST; see Section 5.2 Pharmacokinetic Properties).

Renal impairment.

No dose adjustment is necessary in patients with mild or moderate renal impairment (estimated glomerular filtration rate [eGFR] ≥ 30 to < 90 mL/min/1.73 m2; see Section 5.2 Pharmacokinetic Properties).

Paediatric population.

The safety and efficacy of Onpattro in children or adolescents < 18 years of age have not been established. No data are available.

Method of administration.

Onpattro is for intravenous use. It is for single use only.

Dilution.

Onpattro must be diluted with sodium chloride 9 mg/mL (0.9%) solution prior to intravenous infusion. The diluted solution for infusion should be prepared by a healthcare professional using aseptic technique as follows:
Remove Onpattro from the refrigerator. Do not shake or vortex.
Discard vial if it has been frozen.
Inspect visually for particulate matter and discolouration. Do not use if discolouration or foreign particles are present. Onpattro is a white to off-white, opalescent, homogeneous solution. A white to off-white coating may be observed on the inner surface of the vial, typically at the liquid-headspace interface. Product quality is not impacted by presence of the white to off-white coating.
Calculate the required volume of Onpattro based on the recommended weight-based dosage (see Section 4.2 Dose and Method of Administration).
Withdraw the entire contents of one or more vials into a single sterile syringe.
Filter Onpattro through a sterile 0.45 micron polyethersulfone (PES) syringe filter into a sterile container.
Withdraw the required volume of filtered Onpattro from the sterile container using a sterile syringe.
Dilute the required volume of filtered Onpattro into an infusion bag containing sodium chloride 9 mg/mL (0.9%) solution for a total volume of 200 mL. Use infusion bags that are free of di(2-ethylhexyl)phthalate (DEHP).
Gently invert the bag to mix the solution. Do not shake. Do not mix or dilute with other medicinal products.
Discard any unused portion of Onpattro. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Infusion process.

A dedicated line with an infusion set containing a 1.2 micron polyethersulfone (PES) inline infusion filter must be used. The infusion sets and lines must be free of di(2-ethylhexyl)phthalate (DEHP).
The diluted solution of Onpattro 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 duration of infusion may be extended in the event of an IRR (see Section 4.4 Special Warnings and Precautions for Use).
Onpattro must be administered through a free-flowing venous access line. The infusion site should be monitored for possible infiltration during administration. Suspected extravasation should be managed according to local standard practice for non-vesicants.
The patient should be observed during the infusion and, if clinically indicated, following the infusion (see Section 4.4 Special Warnings and Precautions for Use).
After completion of the infusion, the intravenous administration set should be flushed with sodium chloride 9 mg/mL (0.9%) solution to ensure that all medicinal product has been administered.
Infusion of Onpattro at home may be considered for patients who have tolerated at least 3 infusions well in the clinic. The decision for a patient to receive home infusions should be made after evaluation and recommendation by the treating physician. Home infusions should be performed by a healthcare professional.

4.3 Contraindications

Severe hypersensitivity (e.g. anaphylaxis) to the active substance or any of the excipients listed in Section 6.1 List of Excipients.

4.4 Special Warnings and Precautions for Use

Infusion-related reactions.

IRRs have been observed in patients treated with Onpattro. In patients experiencing an IRR, the majority experienced the first IRR within the first 2 infusions (see Section 4.8 Adverse Effects (Undesirable Effects)). Across clinical studies, the most common symptoms (reported in ≥ 2% of patients) of IRRs were flushing, back pain, nausea, abdominal pain, dyspnoea, and headache. IRRs may also include hypotension and syncope.
To reduce the risk of IRRs, patients should receive premedications on the day of Onpattro infusion, at least 60 minutes prior to the start of infusion (see Section 4.2 Dose and Method of Administration). If an IRR occurs, slowing or interrupting the infusion and institution of medical management (e.g. corticosteroids or other symptomatic treatment) should be considered, as clinically indicated. If the infusion is interrupted, resumption of the infusion at a slower infusion rate may be considered after symptoms have resolved. The Onpattro infusion should be discontinued in the case of a serious or life-threatening IRR.
Some patients who experience IRRs may benefit from a slower infusion rate or additional or higher doses of one or more of the premedications with subsequent infusions to reduce the risk of IRRs.

Vitamin A deficiency.

By reducing serum TTR protein, Onpattro treatment leads to a decrease in serum vitamin A (retinol) levels (see Section 5.1 Pharmacodynamic Properties). Serum vitamin A levels below the lower limit of normal should be corrected and any ocular symptoms or signs due to vitamin A deficiency should be evaluated prior to initiation of treatment with Onpattro.
Patients receiving Onpattro should take oral supplementation of approximately 2500 IU vitamin A per day to reduce the potential risk of ocular toxicity due to vitamin A deficiency. Referral for ophthalmological assessment is recommended if patients develop ocular symptoms suggestive of vitamin A deficiency, including reduced night vision or night blindness, persistent dry eyes, eye inflammation, corneal inflammation or ulceration, corneal thickening or corneal perforation.
Serum vitamin A levels should not be used to guide vitamin A supplementation during treatment with Onpattro.
During the first 60 days of pregnancy, both too high or too low vitamin A levels may be associated with an increased risk of foetal malformation. Therefore, pregnancy should be excluded before initiating Onpattro and women of childbearing potential should practise effective contraception. If a woman intends to become pregnant, Onpattro and vitamin A supplementation should be discontinued, and serum vitamin A levels should be monitored and have returned to normal before conception is attempted.
In the event of an unplanned pregnancy, Onpattro should be discontinued (see Section 4.6 Fertility, Pregnancy and Lactation). Vitamin A supplementation should be discontinued during the first trimester, unless the pregnant woman has clinical signs of vitamin A deficiency. If such signs are present, vitamin A supplementation should not exceed 2500 IU per day. Thereafter, vitamin A supplementation of 2500 IU per day should be resumed in the second and third trimesters if serum vitamin A levels have not returned to normal, because of the increased risk of vitamin A deficiency in the third trimester.

Use in hepatic impairment.

Onpattro has not been studied in patients with moderate or severe hepatic impairment and should not be used in these patients unless the anticipated clinical benefit outweighs the potential risk (see Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

Onpattro has not been studied in patients with severe renal impairment or end-stage renal disease and should not be used in these patients unless the anticipated clinical benefit outweighs the potential risk (see Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

There are no special precautions for the use of Onpattro in the elderly.

Paediatric use.

The safety and efficacy of Onpattro in children or adolescents < 18 years of age have not been established. No data are available.

Effects on laboratory tests.

Serum TTR is a carrier of retinol binding protein, which facilitates transport of vitamin A in the blood. Treatment with Onpattro reduces serum TTR levels, which results in reduced levels of retinol binding protein and vitamin A in the serum. However, transport and tissue uptake of vitamin A can occur through alternative mechanisms in the absence of retinol binding protein. As a result, during treatment with Onpattro, laboratory tests for serum vitamin A do not reflect the total amount of vitamin A in the body and should not be used to guide vitamin A supplementation (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties).

Excipients.

This medicinal product contains 3.99 mg sodium per mL, equivalent to 0.2% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal clinical drug interaction studies have been performed. The pharmacokinetics of Onpattro components are not expected to be affected by inhibitors or inducers of cytochrome P450 enzymes or to cause drug-drug interactions, except for induction and time-dependent inhibition of CYP2B6 in vitro. The net effect on CYP2B6 substrates (e.g. bupropion and efavirenz) in vivo is unknown.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on the effects of Onpattro on human fertility.
Intravenous (IV) administration of patisiran-LNP (lipid nanoparticle) (up to 0.3 mg/kg) or a rodent-specific (pharmacologically active) surrogate (0.1 mg/kg) to male rats every two weeks prior to and throughout mating to untreated females produced no adverse effects on fertility. Maximum exposures to the components of the test items were subclinical.
Intravenous administration of patisiran-LNP (up to 1.5 mg/kg) or a rodent-specific (pharmacologically active) surrogate (1.5 mg/kg) to female rats every week for two weeks prior to mating and continuing throughout organogenesis resulted in no adverse effects on fertility. Maximum exposures to the components of the test items were similar to or marginally above clinical exposures at the maximum recommended human dose (MRHD).
Intravenous administration of patisiran-LNP (up to 2 mg/kg) to adult monkeys every three weeks for 39 weeks produced no adverse effects on male reproductive organs or on sperm morphology or count. Maximum exposures were similar to clinical exposures to patisiran at the MRHD. Maximum exposures to the lipid components were 7 to 9 times the clinical exposures to these components at the MRHD.
(Category D)

Pregnancy.

There are no data on the use of Onpattro in pregnant women.
Onpattro treatment leads to a decrease in serum vitamin A levels. Vitamin A is essential for normal embryofetal development; however, excessive levels of vitamin A are associated with adverse developmental effects.
Animal studies are insufficient with respect to developmental toxicity. Intravenous administration of patisiran-LNP (up to 1.5 mg/kg) or a rodent-specific (pharmacologically active) surrogate (1.5 mg/kg) to female rats every week for two weeks prior to mating and continuing throughout organogenesis resulted in no adverse effects on embryofetal development. Maximum exposures to the components of the test items were subclinical.
Intravenous administration of patisiran-LNP (up to 0.6 mg/kg) to pregnant rabbits every week during the period of organogenesis produced no adverse effects on embryofetal development. Maximum exposure to the components of the test items were subclinical. In a separate study, patisiran-LNP (up to 2 mg/kg), administered to pregnant rabbits every week during the period of organogenesis, resulted in embryofetal mortality and reduced fetal body weight at doses ≥ 1 mg/kg, which were associated with maternal toxicity.
Intravenous administration of patisiran-LNP (up to 1.5 mg/kg) or a rodent-specific surrogate (1.5 mg/kg) to pregnant rats every week throughout pregnancy and lactation resulted in no adverse developmental effects on the offspring.
Maximum exposures to the components of the test items were subclinical or similar to clinical exposures at the MRHD in the above animal studies.

Women of childbearing potential.

Treatment with Onpattro reduces serum levels of vitamin A. Both too high or too low vitamin A levels may be associated with an increased risk of fetal malformation. Therefore, pregnancy should be excluded before initiation of treatment and women of childbearing potential should use effective contraception. If a woman intends to become pregnant, Onpattro and vitamin A supplementation should be discontinued and serum vitamin A levels should be monitored and have returned to normal before conception is attempted.
Due to the potential teratogenic risk arising from unbalanced vitamin A levels, Onpattro should not be used during pregnancy, unless the clinical condition of the woman requires treatment. As a precautionary measure, vitamin A and thyroid stimulating hormone (TSH) levels should be obtained early in pregnancy. Close monitoring of the fetus should be carried out in the event of an unplanned pregnancy, especially during the first trimester (see Section 4.4 Special Warnings and Precautions for Use). Women of childbearing potential have to use effective contraception during treatment with Onpattro.
 No studies have been conducted to assess the presence of components of Onpattro in human milk, the effects on the breastfed child or the effects on milk production. In lactating rats, patisiran was not present in milk, although small amounts of the lipid components DLin-MC3-DMA and PEG2000-C-DMG were present (up to 7% of concomitant maternal plasma concentrations). There were no adverse effects on the pups.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Onpattro, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

4.7 Effects on Ability to Drive and Use Machines

On the basis of the pharmacodynamic and pharmacokinetic profiles, Onpattro is considered to have no or negligible influence on the ability to drive or use machines.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The most frequently occurring adverse reactions reported in Onpattro-treated patients in clinical trials were peripheral oedema (29.7%) and infusion-related reactions (18.9%). The only adverse reaction resulting in the discontinuation of Onpattro was an infusion-related reaction (0.7%).

Tabulated list of adverse reactions.

The adverse reactions are presented as MedDRA preferred terms under the MedDRA System Organ Class (SOC) by frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency of the adverse reactions is expressed according to the following categories: Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100). See Table 1.

Description of selected adverse reactions.

Infusion-related reactions.

Symptoms of IRRs include, but are not limited to: arthralgia or pain (including back, neck, or musculoskeletal pain), flushing (including erythema of face or skin warm), nausea, abdominal pain, dyspnoea or cough, dysphonia, chest discomfort or chest pain, headache, rash, pruritus, chills, dizziness, fatigue, increased heart rate or palpitations, hypotension which may include syncope, hypertension, facial oedema.
In clinical studies, all patients received premedication with a corticosteroid, paracetamol, and H1 and H2 blockers to reduce the risk of IRRs. In the double-blind placebo-controlled study, 18.9% of Onpattro-treated patients experienced IRRs, compared to 9.1% of placebo-treated patients. In Onpattro-treated patients, all IRRs were either mild (95.2%) or moderate (4.8%) in severity. Among Onpattro-treated patients who experienced an IRR, 78.6% experienced the first IRR within the first 2 infusions. The frequency of IRRs decreased over time. Some patients still experienced IRRs after 18 months of treatment, and in a few patients, IRRs continued to be frequent. Few IRRs led to infusion interruption. IRRs resulted in permanent discontinuation of Onpattro in < 1% of patients in clinical studies. For clinical management of IRRs, see Section 4.4. Special Warnings and Precautions for Use.

Peripheral oedema.

In the placebo-controlled study, peripheral oedema was reported in 29.7% of Onpattro-treated patients and 22.1% of placebo-treated patients. All events were mild or moderate in severity and did not lead to treatment discontinuation. In Onpattro-treated patients, the events decreased in frequency over time.

Extravasation.

Extravasation was observed in < 0.5% of infusions in clinical studies. Signs and symptoms included phlebitis or thrombophlebitis, infusion or injection site swelling, dermatitis (subcutaneous inflammation), cellulitis, erythema or injection site redness, burning sensation, or injection site pain.

Other special population(s).

Liver transplant recipients.

In an open-label study in 23 patients with hATTR amyloidosis and polyneuropathy progression after receiving a liver transplant, the safety profile was consistent with the experience in previous clinical studies of patients with hATTR amyloidosis (see Section 5.1 Pharmacodynamic Properties).

Immunogenicity.

Anti-drug antibodies to Onpattro were evaluated by measuring antibodies specific to PEG2000-C-DMG, a lipid component exposed on the surface of Onpattro. In the placebo-controlled and open-label clinical studies, 7 of 194 (3.6%) patients with hATTR amyloidosis developed antidrug antibodies during treatment with Onpattro. One additional patient had pre-existing antidrug antibodies. Anti-drug antibody titres were low and transient with no evidence of an effect on clinical efficacy, the safety profile, or the pharmacokinetic or pharmacodynamic profiles of Onpattro.

Reporting of suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and given symptomatic treatment, as appropriate.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other nervous system drugs; ATC code: N07XX12.

Mechanism of action.

Onpattro contains patisiran, a double-stranded small interfering ribonucleic acid (siRNA) that targets a genetically conserved sequence in the 3' untranslated region of a number of variant and wild-type TTR mRNA. Patisiran is formulated as lipid nanoparticles to deliver the siRNA to hepatocytes, the primary source of TTR protein in the circulation. Through a process called RNA interference (RNAi), patisiran causes the catalytic degradation of TTR mRNA in the liver, resulting in a reduction of serum TTR protein.

Pharmacodynamic effects.

Mean serum TTR was reduced by approximately 80% within 10 to 14 days after a single dose with 300 microgram per kg Onpattro. With repeat dosing every 3 weeks, mean reductions of serum TTR after 9 and 18 months of treatment were 83% and 84%, respectively. Serum TTR reduction was maintained with continued dosing.
Serum TTR is a carrier of retinol binding protein, which facilitates transport of vitamin A in the blood. Mean reductions in serum retinol binding protein of 45% and serum vitamin A of 62% were observed over 18 months (see Section 4.4 Special Warnings and Precautions for Use).

Clinical trials.

The efficacy of Onpattro was studied in a randomised, double-blind, placebo-controlled study in 225 hATTR amyloidosis patients with a TTR variant and symptomatic polyneuropathy. Patients were randomised 2:1 to receive 300 microgram per kg Onpattro or placebo via intravenous infusion once every 3 weeks for 18 months. All patients received premedication with a corticosteroid, paracetamol, and H1 and H2 blockers.
In the study, 148 patients received Onpattro and 77 patients received placebo. The median patient age at baseline was 62 (range 24 to 83) years and 74% of patients were male, 26% were female. Thirty-nine (39) different TTR variants were represented; the most common (≥ 5%) were V30M (43%), A97S (9%), T60A (7%), E89Q (6%), and S50R (5%). Approximately 10% of patients had the V30M variant and early onset of symptoms (< 50 years of age). At baseline, 46% of patients had stage 1 disease (unimpaired ambulation; mostly mild sensory, motor and autonomic neuropathy in the lower limbs), and 53% had stage 2 disease (assistance with ambulation required; mostly moderate impairment progression to the lower limbs, upper limbs, and trunk). Approximately half (53%) of patients had prior treatment with tafamidis meglumine or diflunisal. Forty-nine percent (49%) and 50% of patients had a New York Heart Association (NYHA) Class of I or II, respectively. Approximately half of patients (56%) met pre-defined criteria for cardiac involvement (defined as baseline LV wall thickness ≥ 13 mm with no history of hypertension or aortic valve disease). Patient demographics and baseline characteristics were balanced between treatment groups, except that a higher proportion of patients in the Onpattro group had a non-V30M variant (62% vs. 48%). Ninety-three percent (93%) of Onpattro-treated and 62% of placebo-treated patients completed 18 months of the assigned treatment.
The primary efficacy endpoint was the change from baseline to 18 months in modified Neuropathy Impairment Score +7 (mNIS+7). This endpoint is a composite measure of motor, sensory, and autonomic polyneuropathy including assessments of motor strength and reflexes, quantitative sensory testing, nerve conduction studies, and postural blood pressure, with the score ranging from 0 to 304 points, where an increasing score indicates worsening impairment.
A statistically significant benefit in mNIS+7 with Onpattro relative to placebo was observed at 18 months (Table 2). Benefits relative to placebo were also observed across all mNIS+7 components. Changes were also seen at 9 months, the first post-baseline assessment in the study, where treatment with Onpattro led to a 16.0-point treatment difference, with a mean change from baseline of -2.0 points, compared to an increase of 14.0 points with placebo. In a threshold analysis of mNIS+7 (change from baseline of < 0 points), 56.1% of Onpattro-treated patients versus 3.9% of placebo-treated patients experienced improvement in mNIS+7 (p < 0.001).
Patients treated with Onpattro experienced statistically significant benefits in all secondary endpoints compared to patients who received placebo (all p < 0.001) (Table 2).
The key secondary endpoint was the change from baseline to 18 months in Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) total score. The Norfolk QoL-DN questionnaire (patient-reported) includes domains relating to small fibre, large fibre, and autonomic nerve function, symptoms, and activities of daily living, with the total score ranging from -4 to 136, where an increasing score indicates worsening quality of life. At 18 months, a benefit with Onpattro compared to placebo was observed across all domains of Norfolk QoL-DN, and 51.4% of Onpattro-treated patients experienced an improvement in quality of life (Norfolk QoL-DN change from baseline of < 0 points) compared to 10.4% of placebo-treated patients. Improvement was observed at 9 months, the first post-baseline assessment in the study.
Patients receiving Onpattro experienced similar benefits relative to placebo in mNIS+7 and Norfolk QoL-DN score across all subgroups including age, sex, race, region, NIS score, V30M variant status, prior tafamidis meglumine or diflunisal use, disease stage, and patients with pre-defined cardiac involvement. Patients experienced benefit across all TTR variants and the full range of disease severity studied.
In patients with pre-defined cardiac involvement, centrally assessed echocardiograms showed decreases in LV wall thickness (LS mean difference: -0.9 mm [95% CI -1.7, -0.2]) and longitudinal strain (LS mean difference: -1.37% [95% CI -2.48, -0.27]) with Onpattro treatment relative to placebo. N-terminal pro-B type natriuretic peptide (NT-proBNP) was 727 nanogram/L and 711 nanogram/L at baseline (geometric mean) in Onpattro-treated and placebo-treated patients, respectively. At 18 months, the adjusted geometric mean ratio to baseline was 0.89 with Onpattro and 1.97 with placebo (ratio, 0.45; p < 0.001), representing a 55% difference in favour of Onpattro.

Liver transplant recipients.

In an open-label study, 23 patients with hATTR amyloidosis and polyneuropathy progression after receiving a liver transplant were treated with patisiran at a dose of 300 microgram per kg via IV infusion once every 3 weeks. Median time from transplant to first patisiran dose was 9.4 years and median duration of patisiran treatment was 13.1 months. All patients received concomitant immunosuppressants. The study demonstrated a statistically significant median reduction in serum TTR levels from baseline of 91% (p < 0.001). Patients also showed stable or improved efficacy endpoints at Month 12 compared to baseline.

5.2 Pharmacokinetic Properties

The pharmacokinetic properties of Onpattro were characterised by measuring the plasma concentrations of patisiran and the lipid components DLin-MC3-DMA and PEG2000-C-DMG.

Absorption.

Greater than 95% of patisiran in the circulation is associated with lipid nanoparticles. At the dose regimen of 300 microgram per kg every 3 weeks, steady state was reached by 24 weeks of treatment. The estimated patisiran mean ± SD steady-state peak concentration (Cmax), trough concentration (Ctrough), and area under the curve (AUCτ) were 7.15 ± 2.14 microgram/mL, 0.021 ± 0.044 microgram/mL, and 184 ± 159 microgram.h/mL, respectively. The accumulation of AUCτ was 3.2-fold at steady-state compared to the first dose.
The estimated DLin-MC3-DMA mean ± SD steady-state Cmax, Ctrough and AUCτ were 40.2 ± 11.5 microgram/mL, 1.75 ± 0.698 microgram/mL, and 1403 ± 105 microgram.h/mL, respectively. The accumulation of AUCτ was 1.76-fold at steady-state compared to the first dose.
The estimated PEG2000-C-DMG mean ± SD steady-state Cmax, Ctrough and AUCτ were 4.22 ± 1.22 microgram/mL, 0.0236 ± 0.0093 microgram/mL, and 145 ± 64.7 microgram.h/mL, respectively. There was no accumulation of AUCτ at steady-state compared to the first dose.

Distribution.

Plasma protein binding of Onpattro is low, with ≤ 2.1% binding observed in vitro with human serum albumin and human α1-acid glycoprotein. At the dose regimen of 300 microgram per kg every 3 weeks, the mean ± SD steady-state volume of distribution (Vss) of patisiran, DLin-MC3-DMA and PEG2000-C-DMG was 0.26 ± 0.20 L/kg, 0.47 ± 0.24 L/kg and 0.13 ± 0.05 L/kg, respectively.

Metabolism.

Patisiran is metabolised by nucleases to nucleotides of various lengths. DLin-MC3-DMA is primarily metabolised to 4-dimethylaminobutyric acid (DMBA) by hydrolysis. There is little to no metabolism of PEG2000-C-DMG.

Excretion.

At the dose regimen of 300 microgram per kg every 3 weeks, mean ± SD steady state plasma clearance (CLss) of patisiran was 3.0 ± 2.5 mL/h/kg. The mean ± SD terminal elimination half-life (t1/2β) of patisiran was 3.2 ± 1.8 days. Less than 1% of patisiran in the administered dose was recovered intact in urine.
The estimated DLin-MC3-DMA mean ± SD steady-state CLss was 2.1 ± 0.8 mL/h/kg. Approximately 5.5% of DLin-MC3-DMA was recovered after 96 hours as its metabolite (DMBA) in urine.
The estimated PEG2000-C-DMG mean ± SD steady-state CLss was 2.1 ± 0.6 mL/h/kg. In rats and monkeys, PEG2000-C-DMG is eliminated unchanged in the bile. PEG2000-C-DMG excretion in humans was not measured.

Linearity/non-linearity.

Exposure to patisiran and the lipid components (DLin-MC3-DMA and PEG2000-C-DMG) increased proportionally with increase in dose over the range evaluated in clinical studies (10 to 500 microgram per kg). Patisiran and the lipid components exhibit linear and time independent pharmacokinetics with chronic dosing at the dose regimen of 300 microgram per kg every 3 weeks.

Pharmacokinetic/pharmacodynamic relationship(s).

Increasing the dose of patisiran resulted in greater TTR reduction, with maximal reductions plateauing at patisiran exposures obtained with 300 microgram per kg every 3 weeks dosing.

Interactions.

The components of Onpattro are not inhibitors or inducers of cytochrome P450 enzymes or transporters, except for CYP2B6 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Patisiran is not a substrate of cytochrome P450 enzymes.

Special populations.

Gender and race.

Clinical studies did not identify significant differences in steady state pharmacokinetic parameters or TTR reduction according to gender or race (non-Caucasian vs. Caucasian).

Weight.

No data are available for patients weighing ≥ 110 kg.

Elderly patients.

In the placebo-controlled study, 62 (41.9%) patients treated with Onpattro were ≥ 65 years of age and 9 (6.1%) patients were ≥ 75 years of age. There were no significant differences in steady state pharmacokinetic parameters or TTR reduction between patients < 65 years of age and ≥ 65 years of age.

Hepatic impairment.

Population pharmacokinetic and pharmacodynamic analyses indicated no impact of mild hepatic impairment (bilirubin ≤ 1 x ULN and AST > 1 x ULN, or bilirubin > 1.0 to 1.5 x ULN and any AST) on patisiran exposure or TTR reduction compared to patients with normal hepatic function. Onpattro has not been studied in patients with moderate or severe hepatic impairment.

Liver transplant.

In a clinical study in hATTR amyloidosis patients who had undergone prior liver transplant, steady state pharmacokinetic parameters and TTR reduction were comparable to those observed in patients without a liver transplant.

Renal impairment.

Population pharmacokinetic and pharmacodynamic analyses indicated no impact of mild or moderate renal impairment (eGFR ≥ 30 to < 90 mL/min/1.73 m2) on patisiran exposure or TTR reduction compared to subjects with normal renal function. Onpattro has not been studied in patients with severe renal impairment or end-stage renal disease.

5.3 Preclinical Safety Data

Genotoxicity.

Onpattro was not mutagenic or clastogenic in the Ames bacterial mutagenicity assay, chromosomal aberration assay in human peripheral blood lymphocytes, or in the in vivo mouse micronucleus assay.

Carcinogenicity.

Onpattro was not carcinogenic in transgenic rasH2 mice at doses up to 6 mg/kg every 2 weeks when administered by intravenous bolus for 26 weeks (≤ 3-fold the human systemic exposure to Onpattro components at the clinically recommended dose).

6 Pharmaceutical Particulars

6.1 List of Excipients

DLin-MC3-DMA ((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl-4- (dimethylamino) butanoate); PEG2000-C-DMG (1,2-Dimyristoyl-sn-glycero-3-carboxaminopropylpolyethylene glycol 2000 methyl ether); distearoylphosphatidylcholine [DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine)]; cholesterol; dibasic sodium phosphate heptahydrate; monobasic potassium phosphate; sodium chloride; water for injections.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned, see Section 6.6 Special Precautions for Disposal.

6.3 Shelf Life

Unopened vials.

36 months.

After dilution.

To reduce microbiological hazard, use as soon as practicable after reconstitution/preparation. If not used immediately and if storage is necessary, hold at room temperature (15°C up to 30°C) for up to 16 hours (including infusion time). Do not freeze.

6.4 Special Precautions for Storage

Store at 2°C to 8°C. (Refrigerate. Do not freeze).
If refrigeration is not available, Onpattro vials can be stored at room temperature up to 25°C for up to 14 days. Onpattro must be discarded if not used within the 14-day period.
For storage conditions after dilution of the medicinal product, see Section 6.3 Shelf Life.

6.5 Nature and Contents of Container

5 mL concentrate in a Type I glass vial with a chlorobutyl stopper and an aluminium flip-off cap. Pack size of 1 vial.

6.6 Special Precautions for Disposal

Product is for single use in one patient only. Discard any residue.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

1386913-72-9 (patisiran sodium).

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes