Onpattro

5 WARNINGS 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 [see Adverse Reactions (6.1) ] . 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 [see Dosage and Administration (2.2) ] . 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 [see Dosage and Administration (2.2) ] . 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).

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 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 [see Warnings and Precautions (5.1) ] and pruritus.

<table width="75%"><caption>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</caption><col width="50%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" align="center" valign="middle">Adverse Reaction</th><th styleCode="Rrule">ONPATTRO N=148 %</th><th styleCode="Rrule">Placebo N=77 %</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper respiratory tract infections <footnote ID="foot11">Includes nasopharyngitis, upper respiratory tract infection, respiratory tract infection, pharyngitis, rhinitis, sinusitis, viral upper respiratory tract infection, upper respiratory tract congestion.</footnote></td><td styleCode="Rrule">29</td><td styleCode="Rrule">21</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Infusion-related reaction <footnote ID="foot12">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.</footnote></td><td styleCode="Rrule">19</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspepsia</td><td styleCode="Rrule">8</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspnea <footnote ID="foot13">Not part of an infusion-related reaction.</footnote>^,<footnote ID="foot14">Includes dyspnea and exertional dyspnea.</footnote></td><td styleCode="Rrule">8</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Muscle spasms <footnoteRef IDREF="foot13"/></td><td styleCode="Rrule">8</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Arthralgia <footnoteRef IDREF="foot13"/></td><td styleCode="Rrule">7</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Erythema <footnoteRef IDREF="foot13"/></td><td styleCode="Rrule">7</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Bronchitis <footnote ID="foot15">Includes bronchitis, bronchiolitis, bronchitis viral, lower respiratory tract infection, lung infection.</footnote></td><td styleCode="Rrule">7</td><td styleCode="Rrule">3</td></tr><tr><td styleCode="Lrule Rrule">Vertigo</td><td styleCode="Rrule">5</td><td styleCode="Rrule">1</td></tr></tbody></table>