Patisiran

12.1 Mechanism of Action Patisiran is a double-stranded siRNA that causes degradation of mutant and wild-type TTR mRNA through RNA interference, which results in a reduction of serum TTR protein and TTR protein deposits in tissues.

1 INDICATIONS AND USAGE ONPATTRO is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. ONPATTRO contains a transthyretin-directed small interfering RNA and is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

2 DOSAGE AND ADMINISTRATION For patients weighing less than 100 kg, the recommended dosage is 0.3 mg/kg every 3 weeks by intravenous infusion. For patients weighing 100 kg or more, the recommended dosage is 30 mg ( 2.1 ) Premedicate with a corticosteroid, acetaminophen, and antihistamines ( 2.2 ) Filter and dilute prior to administration ( 2.3 ) Infuse over approximately 80 minutes ( 2.4 ) 2.1 Dosing Information ONPATTRO should be administered by a healthcare professional. ONPATTRO is administered via intravenous (IV) infusion. Dosing is based on actual body weight. For patients weighing less than 100 kg, the recommended dosage is 0.3 mg/kg once every 3 weeks. For patients weighing 100 kg or more, the recommended dosage is 30 mg once every 3 weeks. Missed Dose If a dose is missed, administer ONPATTRO as soon as possible. If ONPATTRO is administered within 3 days of the missed dose, continue dosing according to the patient's original schedule. If ONPATTRO is administered more than 3 days after the missed dose, continue dosing every 3 weeks thereafter. 2.2 Required Premedication All patients should receive premedication prior to ONPATTRO administration to reduce the risk of infusion-related reactions (IRRs) [see Warnings and Precautions (5.1) ] . Each of the following premedications should be given on the day of ONPATTRO infusion at least 60 minutes prior to the start of infusion: Intravenous corticosteroid (e.g., dexamethasone 10 mg, or equivalent) Oral acetaminophen (500 mg) Intravenous H1 blocker (e.g., diphenhydramine 50 mg, or equivalent) Intravenous H2 blocker (e.g., famotidine 20 mg, or equivalent) For premedications not available or not tolerated intravenously, equivalents may be administered orally. For patients who are tolerating their ONPATTRO infusions but experiencing adverse reactions related to the corticosteroid premedication, the corticosteroid may be reduced by 2.5 mg increments to a minimum dose of 5 mg of dexamethasone (intravenous), or equivalent. Some patients may require additional or higher doses of one or more of the premedications to reduce the risk of IRRs [see Warnings and Precautions (5.1) ] . 2.3 Preparation Instructions ONPATTRO must be filtered and diluted 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 and allow to warm to room temperature. Do not shake or vortex. Inspect visually for particulate matter and discoloration. Do not use if discoloration 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 dose of ONPATTRO based on the recommended weight-based dosage [see Dosage and Administration (2.1) ]. 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 0.9% Sodium Chloride Injection, USP for a total volume of 200 mL. Use infusion bags that are di(2-ethylhexyl)phthalate-free (DEHP-free). Gently invert the bag to mix the solution. Do not shake. Do not mix or dilute with other drugs. Discard any unused portion of ONPATTRO. ONPATTRO does not contain preservatives. The diluted solution should be administered immediately after preparation. If not used immediately, store in the infusion bag at room temperature (up to 30°C [86°F]) for up to 16 hours (including infusion time). Do not freeze. 2.4 Infusion Instructions Use a dedicated line with an infusion set containing a 1.2 micron polyethersulfone (PES) in-line infusion filter. Use infusion sets and lines that are DEHP-free. Infuse the diluted solution of ONPATTRO intravenously, via an ambulatory infusion pump, over approximately 80 minutes, at an initial infusion rate of approximately 1 mL/min for the first 15 minutes, then 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 Warnings and Precautions (5.1) ]. Administer only through a free-flowing venous access line. Monitor the infusion site for possible infiltration during drug administration. Suspected extravasation should be managed according to local standard practice for non-vesicants. Observe the patient during the infusion and, if clinically indicated, following the infusion [see Warnings and Precautions (5.1) ]. After completion of the infusion, flush the intravenous administration set with 0.9% Sodium Chloride Injection, USP to ensure that all ONPATTRO has been adminis

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Infusion-Related Reactions [see Warnings and Precautions (5.1) ] The most frequently reported adverse reactions (that occurred in at least 10% of ONPATTRO-treated patients and at least 3% more frequently than on placebo) were upper respiratory tract infections and infusion-related reactions ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alnylam Pharmaceuticals at 1-877-256-9526 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of ONPATTRO cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. A total of 224 patients with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) received ONPATTRO in the placebo-controlled and open-label clinical studies, including 186 patients exposed for at least 1 year, 137 patients exposed for at least 2 years, and 52 patients exposed for at least 3 years. In the placebo-controlled study, 148 patients received ONPATTRO for up to 18 months (mean exposure 17.7 months). Baseline demographic and disease characteristics were generally similar between treatment groups. The median age of study patients was 62 years and 74% were male. Seventy-two percent of study patients were Caucasian, 23% were Asian, 2% were Black, and 2% were reported as other. At baseline, 46% of patients were in Stage 1 of the disease and 53% were in Stage 2. Forty-three percent of patients had Val30Met mutations in the transthyretin gene; the remaining patients had 38 other point mutations. Sixty-two percent of ONPATTRO-treated patients had non-Val30Met mutations, compared to 48% of the placebo-treated patients. Upper respiratory tract infections and infusion-related reactions were the most common adverse reactions. One patient (0.7%) discontinued ONPATTRO because of an infusion-related reaction. Patients were instructed to take the recommended daily allowance of vitamin A [see Warnings and Precautions (5.2) ] . Sixty-four percent of patients treated with ONPATTRO had normal vitamin A levels at baseline, and 99% of those with a normal baseline developed low vitamin A levels. In one case, the decreased vitamin A level was reported as an adverse reaction. Table 1 lists the adverse reactions that occurred in at least 5% of patients in the ONPATTRO-treated group and that occurred at least 3% more frequently than in the placebo-treated group in the randomized controlled clinical trial. Table 1: Adverse Reactions from the Placebo-Controlled Trial that Occurred in at Least 5% of ONPATTRO-treated Patients and at Least 3% More Frequently than in Placebo-treated Patients Adverse Reaction ONPATTRO N=148 % Placebo N=77 % Upper respiratory tract infections Includes nasopharyngitis, upper respiratory tract infection, respiratory tract infection, pharyngitis, rhinitis, sinusitis, viral upper respiratory tract infection, upper respiratory tract congestion. 29 21 Infusion-related reaction 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, rash, chills, dizziness, fatigue, increased heart rate or palpitations, hypotension, hypertension, facial edema. 19 9 Dyspepsia 8 4 Dyspnea Not part of an infusion-related reaction. , Includes dyspnea and exertional dyspnea. 8 0 Muscle spasms 8 1 Arthralgia 7 0 Erythema 7 3 Bronchitis Includes bronchitis, bronchiolitis, bronchitis viral, lower respiratory tract infection, lung infection. 7 3 Vertigo 5 1 Four serious adverse reactions of atrioventricular (AV) heart block (2.7%) occurred in ONPATTRO-treated patients, including 3 cases of complete AV block. No serious adverse reactions of AV block were reported in placebo-treated patients. Ocular adverse reactions that occurred in 5% or less of ONPATTRO-treated patients in the controlled clinical trial, but in at least 2% of ONPATTRO-treated patients, and more frequently than on placebo, include dry eye (5% vs. 3%), blurred vision (3% vs. 1%), and vitreous floaters (2% vs. 1%). Extravasation was observed in less than 0.5% of infusions in clinical studies, including cases that were reported as serious. 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. 6.2 Immunogenicity The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. In addition, the observed incidence of antibody (including neutralizing antibody) positivity in a