PATISIRAN: 2,708 Adverse Event Reports & Safety Profile

ONPATTRO contains patisiran, a double-stranded small interfering ribonucleic acid (siRNA), formulated as a lipid complex for delivery to hepatocytes. Patisiran specifically binds to a genetically conserved sequence in the 3' untranslated region (3'UTR) of mutant and wild-type transthyretin (TTR) messenger RNA (mRNA). The structural formula is: A, adenosine; C, cytidine; G, guanosine; U, uridine; Cm, 2'- O- methylcytidine; Um, 2'- O- methyluridine; dT, thymidine ONPATTRO is supplied as a sterile, preservative-free, white to off-white, opalescent, homogeneous solution for intravenous infusion in a single-dose glass vial.

Each

1 mL of solution contains 2 mg of patisiran (equivalent to 2.1 mg of patisiran sodium).

Each

1 mL also contains 6.2 mg cholesterol USP, 13.0 mg (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl-4-(dimethylamino) butanoate (DLin-MC3-DMA), 3.3 mg 1,2-distearoyl- sn -glycero-3-phosphocholine (DSPC), 1.6 mg α-(3'-{[1,2-di(myristyloxy)propanoxy] carbonylamino}propyl)-ω-methoxy, polyoxyethylene (PEG 2000 -C-DMG), 0.2 mg potassium phosphate monobasic anhydrous NF, 8.8 mg sodium chloride USP, 2.3 mg sodium phosphate dibasic heptahydrate USP, and Water for Injection USP. The pH is ~7.0. The molecular formula of patisiran sodium is C 412 H 480 N 148 Na 40 O 290 P 40 and the molecular weight is 14304 Da.

Chemical

Structure

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.

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) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> .

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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span>. 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>. 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>. After completion of the infusion, flush the intravenous administration set with 0.9% Sodium Chloride Injection, USP to ensure that all ONPATTRO has been administered.

None. None

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> . 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 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 in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. Anti-drug antibodies to ONPATTRO were evaluated by measuring antibodies specific to PEG 2000 -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 anti-drug antibodies during treatment with ONPATTRO. One additional patient had pre-existing anti-drug antibodies. There was no evidence of an effect of anti-drug antibodies on clinical efficacy, safety, or the pharmacokinetic or pharmacodynamic profiles of ONPATTRO. Although these data do not demonstrate an impact of anti-drug antibody development on the efficacy or safety of ONPATTRO in these patients, the available data are too limited to make definitive conclusions.

6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ONPATTRO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Symptoms of infusion-related reactions have included syncope <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> and pruritus.

AND PRECAUTIONS Infusion-related reactions: Monitor for signs and symptoms during infusion. Slow or interrupt the infusion if clinically indicated. Discontinue the infusion if a serious or life-threatening infusion-related reaction occurs ( 5.1 ) Reduced serum vitamin A levels and recommended supplementation: Supplement with the recommended daily allowance of vitamin A. Refer to an ophthalmologist if ocular symptoms suggestive of vitamin A deficiency occur ( 5.2 )

5.1 Infusion-Related Reactions Infusion-related reactions (IRRs) have been observed in patients treated with ONPATTRO. In clinical studies, all patients received premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) to reduce the risk of IRRs. In a controlled clinical study, 19% of ONPATTRO-treated patients experienced IRRs, compared to 9% of placebo-treated patients. Among ONPATTRO-treated patients who experienced an IRR, 79% experienced the first IRR within the first 2 infusions. The frequency of IRRs decreased over time. IRRs led to infusion interruption in 5% of patients. IRRs resulted in permanent discontinuation of ONPATTRO in less than 1% of patients in clinical studies. Across clinical studies, the most common symptoms (reported in greater than 2% of patients) of IRRs with ONPATTRO were flushing, back pain, nausea, abdominal pain, dyspnea, and headache <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Severe hypotension and syncope have been reported as symptoms of IRRs in the expanded access program and postmarketing setting. Patients should receive premedications on the day of ONPATTRO infusion, at least 60 minutes prior to the start of infusion <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> . Monitor patients during the infusion for signs and symptoms of IRRs. If an IRR occurs, consider slowing or interrupting the ONPATTRO infusion and instituting medical management (e.g., corticosteroids or other symptomatic treatment), as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. In the case of a serious or life-threatening IRR, the infusion should be discontinued and not resumed. 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> .

5.2 Reduced Serum Vitamin A Levels and Recommended Supplementation ONPATTRO treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking ONPATTRO. Higher doses than the recommended daily allowance of vitamin A should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as serum vitamin A levels do not reflect the total vitamin A in the body. Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness).