Patisiran

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

Therapy should be initiated under the supervision of a physician knowledgeable in the management of amyloidosis. Posology The recommended dose of Onpattro is 300 micrograms 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. 1). 1). 4). 4). 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.

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. 8). 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.

2). 5 x ULN and any AST). 2). 73m2). 2). 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.

6). 2 micron polyethersulfone (PES) in-line 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.

4). • 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.

4). 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.

9%). 7%) discontinued treatment during clinical studies due to an infusion-related reaction. 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) Table 1: Adverse reactions reported for Onpattro 300 micrograms per kg System Organ Class Adverse Reaction Frequency Bronchitis Common Sinusitis Common Infections and infestations Rhinitis Common Immune system disorders Infusion-related reaction Very common Ear and labyrinth disorders Vertigo Common Respiratory, thoracic and mediastinal disorders Dyspnoea Common Gastrointestinal disorders Dyspepsia Common Skin and subcutaneous tissue disorders Erythema Common Arthralgia CommonMusculoskeletal and connective tissue disorders Muscle spasms Common Peripheral oedema Very commonGeneral disorders and administration site conditions Extravasation Uncommon 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. 1% of placebo-treated patients. 8%) in severity. 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.

4. 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. 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. 1). 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.

6%) patients with hATTR amyloidosis developed anti-drug 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 reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

1.

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

Therapy should be initiated under the supervision of a physician knowledgeable in the management of amyloidosis. Posology The recommended dose of Onpattro is 300 micrograms 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. 1). 1). 4). 4). 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.

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. 8). 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.

2). 5 x ULN and any AST). 2). 73m2). 2). 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.

6). 2 micron polyethersulfone (PES) in-line 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.

4). • 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.

4). 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.

9%). 7%) discontinued treatment during clinical studies due to an infusion-related reaction. 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) 7 Table 1: Adverse reactions reported for Onpattro 300 micrograms per kg System Organ Class Adverse Reaction Frequency Infections and infestations Bronchitis Common Sinusitis Common Rhinitis Common Immune system disorders Infusion-related reaction Very common Ear and labyrinth disorders Vertigo Common Respiratory, thoracic and mediastinal disorders Dyspnoea Common Gastrointestinal disorders Dyspepsia Common Skin and subcutaneous tissue disorders Erythema Common Musculoskeletal and connective tissue disorders Arthralgia Common Muscle spasms Common General disorders and administration site conditions Peripheral oedema Very common Extravasation Uncommon 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. 1% of placebo-treated patients. 8%) in severity. 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.

4. 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. 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. 1). 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.

6%) patients with hATTR amyloidosis developed anti-drug antibodies during treatment with Onpattro. One additional patient had pre-existing anti-drug 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 reactions Reporting suspected adverse reactions after authorisation 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 via the national reporting system listed in Appendix V.

1.

ONPATTRO (patisiran) is indicated for the treatment of polyneuropathy in adult patients with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis). 1 Pediatrics Pediatrics (< 18 years of age): No data are available to Health Canada.

Therefore, Health Canada has not authorized an indication for pediatric use. 3 Pharmacokinetics).

2 Recommended Dose and Dosage Adjustment 06/2023 TABLE OF CONTENTS Sections or subsections that are not applicable at the time of authorization are not listed. 7

1 Adverse Reaction Overview The most frequently occurring adverse reactions reported in ONPATTRO-treated patients (≥ 10% of patients and occurring ≥ 3 percentage points more frequently than in placebo-treated patients) were peripheral edema and infusion-related reactions (see 7 WARNINGS AND PRECAUTIONS).

7%). 2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials, therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use. 1 years. Of these 224 patients, 186 patients received ≥ 1 year of treatment, 137 patients received ≥ 2 years of treatment, and 52 patients received ≥ 3 years of treatment.

7 months. 2 Dosage and Dosage Adjustment). , having baseline left ventricular (LV) wall thickness ≥ 13 mm, with no history of hypertension or aortic valve disease. Adverse reactions for ONPATTRO are defined as those adverse events occurring at a ≥ 3 percentage point higher frequency in patients treated with ONPATTRO, compared with placebo, and other potentially relevant adverse events based on other studies with ONPATTRO.

0), sorted under the respective System Organ Class (SOCs) (Table 2). Page 13 of 32 Table 2 – Adverse Reactions That Occurred at a ≥ 3 Percentage Point Higher Frequency with ONPATTRO Compared to Placebo in the APOLLO Trial ONPATTRO N=148 (%) Placebo N=77 (%) General disorders and administration site conditions Peripheral edema 30 22 Immune system disorders Infusion-related reaction* 19 9 Gastrointestinal disorders Dyspepsia 8 4 Musculoskeletal and connective tissue disorders Muscle spasms Arthralgia 8 7 1 0 Respiratory, thoracic and mediastinal disorders Dyspnea 7 0 Skin and subcutaneous tissue disorders Erythema 7 3 Infections and infestations Bronchitis Rhinitis Sinusitis 6 4 4 3 0 0 Ear and labyrinth disorders Vertigo 5 1 *Infusion-related reaction symptoms 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, dyspnea or cough, chest discomfort or chest pain, headache, pruritus, rash, chills, dizziness, fatigue, increased heart rate or palpitations, hypotension (which may include syncope), hypertension, facial edema.

3 Pharmacokinetics). 3 Less Common Clinical Trial Adverse Reactions General disorders and administration site conditions: extravasation, including phlebitis or thrombophlebitis, infusion or injection site swelling, dermatitis, cellulitis, erythema or injection site redness, burning sensation, or injection site pain.

4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data 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.

6%) patients with hATTR amyloidosis developed anti-drug antibodies, as measured during treatment with ONPATTRO. One additional patient had pre-existing anti-drug antibodies. Anti-drug antibody titers were low and transient with no evidence of an effect on clinical efficacy, the safety profile, or the pharmacokinetic or pharmacodynamic profiles of ONPATTRO.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. In addition, the observed incidence of antibody positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease.

For these reasons, comparison of the incidence of antibodies to ONPATTRO with the incidence of antibodies to other products may be misleading. Vitamin A Levels 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 (see 7 WARNINGS AND PRECAUTIONS).

, anaphylaxis or anaphylactoid reactions) to patisiran or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.