WAINUA

5 WARNINGS AND PRECAUTIONS 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. ( 5.1 ) 5.1 Reduced Serum Vitamin A Levels and Recommended Supplementation WAINUA treatment leads to a decrease in serum vitamin A levels [see Adverse Reactions (6.1) , Use in Specific Populations (8.1) , and Clinical Pharmacology (12.2) ] . Supplementation at the recommended daily allowance of vitamin A is advised for patients taking WAINUA. 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 WAINUA, 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, dry eyes).

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: • Reduced Serum Vitamin A Levels and Recommended Supplementation [see Warnings and Precautions (5.1) ]. Most common adverse reactions (that occurred in at least 9% of patients treated with WAINUA) were vitamin A decreased and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of WAINUA cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In Study 1 [see Clinical Studies (14) ] , a total of 144 patients with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) were randomized to WAINUA and received at least one dose of WAINUA. Of these, 141 patients received at least 6 months of treatment and 107 patients received at least 12 months of treatment. The mean duration of treatment was 15 months (range: 1.9 to 19.4 months). The median patient age at baseline was 52 years and 69% of the patients were male. Seventy-eight percent of patients treated with WAINUA were White, 15% were Asian, 4% were Black, 2% were reported as other races, and <1% were multiple races. Fifty-nine percent of patients had the Val30Met variant in the transthyretin gene; the remaining patients had one of 19 other variants. At baseline, 80% of patients were in Stage 1 of the disease and 20% were in Stage 2 with a mean duration from polyneuropathy diagnosis of 47 months. The mean duration from onset of polyneuropathy symptoms was 68 months. Table 1 lists the adverse reactions that occurred in at least 5% of patients treated with WAINUA in Study 1. Table 1: Adverse Reactions Reported in at least 5% of Patients Treated with WAINUA (Study 1) Adverse Reaction WAINUA N=144 % Vitamin A decreased Vitamin A decreased includes vitamin A deficiency and vitamin A decrease. 15 Vomiting 9 Proteinuria 8 Injection site reactions Injection site reactions includes erythema, pain, and pruritus. 7 Blurred vision 6 Cataract 6 Three serious adverse reactions of atrioventricular (AV) heart block (2%) occurred in WAINUA-treated patients, including 1 case of complete AV block. Laboratory Tests Vitamin A Decrease In Study 1, patients were instructed to take the recommended daily allowance of vitamin A [see Warnings and Precautions (5.1) ] . All patients treated with WAINUA had normal vitamin A levels at baseline, 95% of patients developed low vitamin A levels during the study. In some cases, the decreased vitamin A level was reported as an adverse reaction.

<table ID="_RefID0EBCAE" width="100.1%"><caption>Table 1: Adverse Reactions Reported in at least 5% of Patients Treated with WAINUA (Study 1)</caption><col width="46%"/><col width="54%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">WAINUA</content></paragraph><paragraph><content styleCode="bold">N=144</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Vitamin A decreased<footnote ID="_Ref178841792">Vitamin A decreased includes vitamin A deficiency and vitamin A decrease.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Proteinuria</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site reactions<footnote ID="_Ref178841811">Injection site reactions includes erythema, pain, and pruritus.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Blurred vision</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Cataract</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>6</paragraph></td></tr></tbody></table>