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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Have been reported in patients treated with TRYNGOLZA. Advise patients on the signs and symptoms of hypersensitivity reactions and instruct patients to promptly seek medical attention and discontinue use of TRYNGOLZA if hypersensitivity reactions occur. ( 5.1 ) Liver Enzyme Abnormalities: Increases in liver enzymes and hepatic fat have occurred in adults. Consider liver enzyme testing before TRYNGOLZA initiation or an increase in dosage and when clinically indicated thereafter. If persistent elevations in liver enzymes occur, consider dose interruption and/or dose reduction. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue TRYNGOLZA. ( 5.2 ) 5.1 Hypersensitivity Reactions Hypersensitivity reactions (including symptoms of bronchospasm, diffuse erythema, facial swelling, urticaria, chills, and myalgias) have been reported in patients treated with TRYNGOLZA [see Adverse Reactions (6.1) ] . Advise patients on the signs and symptoms of hypersensitivity reactions and instruct patients to promptly seek medical attention and discontinue use of TRYNGOLZA if hypersensitivity reactions occur. TRYNGOLZA is contraindicated in patients with a history of serious hypersensitivity to olezarsen or any of the excipients in TRYNGOLZA. 5.2 Liver Enzyme Abnormalities TRYNGOLZA can cause increases in liver enzymes and hepatic fat in adults [see Adverse Reactions (6.1) ] . Increases in liver enzymes were more frequently reported with the 80 mg dose as compared to the 50 mg dose. In patients with sHTG, increases in liver enzymes greater than or equal to three times the upper limit of normal were reported more frequently with TRYNGOLZA 80 mg (7%) compared to TRYNGOLZA 50 mg (3%) and placebo (3%). Consider liver enzyme testing before TRYNGOLZA initiation or an increase in dosage and when clinically indicated thereafter. If persistent elevations in liver enzymes occur (such as three times the upper limit of normal or greater), consider dose interruption and/or dose reduction. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue TRYNGOLZA.
6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling: Hypersensitivity Reactions [ see Warnings and Precautions (5.1) ] Liver Enzyme Abnormalities [see Warnings and Precautions (5.2) ] Most common adverse reactions in patients with FCS (incidence >5% of TRYNGOLZA-treated patients and >3% higher frequency than placebo) were injection site reactions, decreased platelet count, and arthralgia. ( 6.1 ) Most common adverse reactions in patients with sHTG (incidence ≥2% higher than placebo) were injection site reactions and liver enzyme increases. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ionis Pharmaceuticals, Inc. at toll free number 1-833-644-6647 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 TRYNGOLZA cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trial in Patients with FCS The safety of TRYNGOLZA was evaluated in 66 patients with FCS enrolled in Trial 1 (NCT #04568434) [see Clinical Studies (14.1) ] . In this trial, 43 patients received at least one dose of TRYNGOLZA, 50 mg (N=21) or 80 mg (N=22) and 23 patients received placebo. TRYNGOLZA 50 mg is not an approved dosing regimen for FCS [see Dosage and Administration (2.1) ]. Across treatment groups, the mean age was 45 years and 42% of patients were male. Eighty-five percent (85%) of patients were White, 9% were Asian and 6% were reported as other races; 11% identified as Hispanic or Latino ethnicity. Forty-three (43) patients were exposed to TRYNGOLZA for a median of 52 weeks; 22 patients were treated with TRYNGOLZA 80 mg every 4 weeks for a median of 52 weeks. Adverse reactions led to discontinuation of treatment in 7% of TRYNGOLZA-treated patients and 0% of placebo-treated patients. The most common reason for TRYNGOLZA treatment discontinuation was hypersensitivity reactions. Adverse reactions (>5% of patients treated with TRYNGOLZA and at >3% higher frequency than placebo) are presented in Table 1. Table 1. Adverse Reactions That Occurred in >5% of Patients with FCS Treated with TRYNGOLZA and at >3% Higher Frequency than with Placebo (Trial 1) Adverse Reaction Grouped terms composed of several similar terms Total TRYNGOLZA (N=43) Placebo (N=23) Injection site reactions 8 (19%) 2 (9%) Decreased platelet count 5 (12%) 1 (4%) Arthralgia 4 (9%) 0 Clinical Trials in Patients with sHTG The safety of TRYNGOLZA was evaluated in two randomized, double-blind, placebo-controlled trials [Trial 2 (NCT #05079919) and Trial 3 (NCT #05552326)] that included a total of 1,061 adult patients with sHTG [see Clinical Studies (14.2) ] . In these trials, 705 patients received at least one dose of TRYNGOLZA, 50 mg (N=354) or 80 mg (N=351), and 356 patients received placebo. Across treatment groups, the mean age was 54 years and 76% of patients were male. Eighty-eight percent (88%) of patients were White, 5% Asian, 2% Black or African American, 2% American Indian or Alaskan Native, less than 1% Native Hawaiian or Pacific Islander, and 2% other or multiple races; 12% identified as Hispanic or Latino ethnicity. The median exposure to TRYNGOLZA was 364 days (N=705). Adverse reactions led to discontinuation of treatment in 5% of TRYNGOLZA-treated patients and 2% of placebo-treated patients. The most common adverse reaction for TRYNGOLZA treatment discontinuation was injection site reactions. Adverse reactions (in patients treated with TRYNGOLZA at ≥2% higher frequency than placebo) are presented in Table 2. Table 2. Adverse Reactions Occurring in ≥2% of Patients with sHTG Treated with TRYNGOLZA than with Placebo (Trial 2 and Trial 3) Adverse Reaction Grouped terms composed of several similar terms TRYNGOLZA 50 mg (N=354) TRYNGOLZA 80 mg (N=351) Placebo (N=356) Injection site reactions 43 (12%) 64 (18%) 8 (2%) Transaminases increased 11 (3%) 14 (4%) 2 (1%) Laboratory Tests Decrease in Platelet Count: TRYNGOLZA can cause reductions in platelet count. Across all trials (Trials 1, 2, and 3), mean decreases from baseline through Week 53 ranging from 6% (50 mg, Trial 2 and Trial 3) to 10% (80 mg across all trials), were observed in TRYNGOLZA-treated patients, whereas placebo-treated patients showed an increase of 22% in Trial 1 or no change in Trial 2 and Trial 3. The proportion of patients experiencing a bleeding adverse event was similar between the TRYNGOLZA and placebo groups. There were no major bleeding events associated with low platelet counts. Increase in Glucose: Increases in average values in fasting glucose (≤17 mg/dL) and HbA1c (<0.2 percentage points) were observed over time with TRYNGOLZA treatment in the FCS population in Trial 1. The incidence of hyperglycemia (defined as adverse events, new antidiabetic medication, or laboratory values) was higher in patients with FCS treated with TRYNGOLZA without a medical history of diabetes at baseline (52%) compared to placebo-treated patients (35%). In Trials 2 and 3, increases in average values in fasting glucose (≤9 mg/dL) and HbA1c (<0.3 percentage points) were observed over time in the sHTG population treated with TRYNGOLZA. These increases were more pronounced in patients with a history of diabetes at baseline; however, increases in fasting glucose and HbA1c were also observed more frequently with TRYNGOLZA compared to placebo in patients without a history of diabetes at baseline. Increase in Liver Enzymes: Mean liver enzyme values increased from baseline with TRYNGOLZA treatment but remained within the normal range. These increases occurred within the first 6 months of treatment and stabilized. However, when evaluating any liver enzyme increase in patients with sHTG, increases in liver enzymes greater than or equal to three times the upper limit of normal were reported more frequently with TRYNGOLZA 80 mg (7%) compared to TRYNGOLZA 50 mg (3%) and placebo (3%). Liver enzymes returned toward baseline with discontinuation of TRYNGOLZA. Increase in Hepatic Fat Fraction: Hepatic fat fraction (HFF) was assessed in patients with sHTG in a substudy within Trial 2 and Trial 3. Mean HFFs were elevated at baseline (17% TRYNGOLZA 50 mg, 14% TRYNGOLZA 80 mg, 14% placebo). Dose-dependent changes in HFF at 12 months of treatment were a mean increase of 2 percentage points in the TRYNGOLZA 50 mg group and 4 percentage points in the TRYNGOLZA 80 mg group versus 0 percentage points in the placebo group. The clinical meaningfulness of these findings remains uncertain. Increase in LDL-cholesterol: In all trials, increases were observed in LDL-C in TRYNGOLZA-treated patients compared with placebo. These increases were accompanied by decreases in non–high-density lipoprotein cholesterol (non-HDL-C). Among patients with FCS, total apolipoprotein B (apoB) increased, whereas among patients with sHTG, apoB decreased [see Clinical Studies (14) ] .