2.1 Recommended Dosage

The recommended dosage of TRYNGOLZA is 80 mg administered subcutaneously once monthly [see Dosage and Administration (2.2)] .

2.2 Administration Instructions

Prior to initiation, train patients and/or caregivers on proper preparation and administration of TRYNGOLZA [see Instructions for Use] .

Remove the single-dose autoinjector from the refrigerator 30 minutes prior to the injection and allow to warm to room temperature. Do not use other warming methods.

Inspect TRYNGOLZA visually for particulate matter prior to administration. The solution should be clear and colorless to yellow. Do notuse if cloudiness, particulate matter, or discoloration is observed prior to administration.

Maintain a low-fat diet (≤20g fat per day) in conjunction with TRYNGOLZA.

Inject TRYNGOLZA subcutaneously into the abdomen or front of the thigh. The back of the upper arm can also be used as an injection site if a healthcare provider or caregiver administers the injection.

Administer TRYNGOLZA as soon as possible after a missed dose. Resume dosing at monthly intervals from the date of the most recently administered dose.

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.

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.

The safety of TRYNGOLZA was evaluated in 66 patients with FCS enrolled in Trial 1 (NCT #04568434) [see Clinical Studies (14)] . 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 reasons for TRYNGOLZA treatment discontinuation were 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 Treated with TRYNGOLZA and at >3% Higher Frequency than Placebo (Trial 1)

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness of TRYNGOLZA in pediatric patients have not been established.

8.5 Geriatric Use

No dose adjustment is recommended in patients aged 65 years and older [see Clinical Pharmacology (12.3)] . In clinical studies, 111 (38%) patients treated with TRYNGOLZA were ≥65 years of age. No overall differences in safety or effectiveness of TRYNGOLZA have been observed between patients 65 years of age and older and younger adult patients.

8.6 Renal Impairment

No dose adjustment is necessary in patients with mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] ≥30 to <90 mL/min) [see Clinical Pharmacology (12.3)] . TRYNGOLZA has not been studied in patients with severe renal impairment or end-stage renal disease.

8.7 Hepatic Impairment

No dose adjustment is recommended in patients with mild hepatic impairment [see Clinical Pharmacology (12.3)] . TRYNGOLZA has not been studied in patients with moderate or severe hepatic impairment.

12.1 Mechanism of Action

Olezarsen is an ASO-GalNAc 3conjugate that binds to apoC-III mRNA leading to mRNA degradation and resulting in a reduction of serum apoC-III protein. Reduction of apoC-III protein leads to increased clearance of plasma TG and VLDL.

12.2 Pharmacodynamics

Fasting apoC-III
Olezarsen decreased fasting apoC-III following administration of TRYNGOLZA 80 mg dosage every 4 weeks to patients with FCS [See Clinical Studies (14)] . The placebo-corrected percent change in fasting apoC-III from baseline was -57% at 1 month, -69% at 3 months, -72% at 6 months, and -80% at 12 months.

12.3 Pharmacokinetics

Olezarsen steady state mean (SD) maximum concentrations (C max) is 883 (662) ng/mL and area under the curve (AUC τ) is 7440 (3880) ng*h/mL at the approved recommended dosage in patients with FCS. Olezarsen C maxand AUC increase dose-proportionally following single subcutaneous doses ranging from 10 to 120 mg (i.e., 0.13- to 1.5-times the approved recommended dose) in healthy volunteers. No olezarsen accumulation occurs with repeat dosing.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies (ADAs) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADAs in the study described below with the incidence of anti-drug antibodies in other studies, including those of olezarsen.

In Trial 1, with duration of treatment up to 53 weeks, 18 out of 43 (42%) patients treated with TRYNGOLZA developed treatment-emergent ADAs. The presence of ADAs did not affect olezarsen plasma C max, but increased C trough. Although ADA development was not found to affect the pharmacodynamics, safety, or efficacy of TRYNGOLZA in these patients, the available data are limited to make definitive conclusions.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

16.1 How Supplied

TRYNGOLZA injection is a sterile, preservative-free, clear, colorless to yellow solution supplied in a single-dose autoinjector. Each autoinjector of TRYNGOLZA is filled to deliver 0.8 mL of solution containing 80 mg of olezarsen.

TRYNGOLZA is available in cartons containing one 80 mg single-dose autoinjector each.
(NDC 71860-101-01).

16.2 Storage and Handling

Store the TRYNGOLZA autoinjector in the refrigerator between 2°C and 8°C (36°F and 46°F) in the original carton.

Once taken out of the refrigerator, the TRYNGOLZA autoinjector can be stored at room temperature between 15°C and 30°C (59°F and 86°F) in the original carton for up to 6 weeks. If not used within the 6 weeks stored at room temperature, discard TRYNGOLZA.

Do notfreeze. Do notexpose to heat .Protect from light.

Hypersensitivity

Inform patients that serious hypersensitivity reactions, including bronchospasm, diffuse erythema, facial swelling, urticaria, chills, and myalgia, have been reported in patients treated with TRYNGOLZA. Advise patients on the signs and symptoms of hypersensitivity reactions and instruct them to stop taking TRYNGOLZA and seek medical advice promptly if such symptoms occur. [see Warnings and Precautions (5.1)] .

Adherence to Diet

Advise patients with FCS that use of lipid-regulating agents does not reduce the importance of adhering to a low-fat diet [see Dosage and Administration (2)] .

Missed Dose

Instruct patients to take TRYNGOLZA as prescribed. If a dose is missed, instruct patients to take it as soon as they remember. Resume dosing at monthly intervals from the date of the most recently administered dose  [see Dosage and Administration (2.1)] .