Olezarsen (Monograph)

Brand name: Tryngolza
Drug class: Antilipemic Agents, Miscellaneous

Introduction

Antisense oligonucleotide that binds to apolipoprotein C-III (apoC-III) mRNA.

Uses for Olezarsen

Familial Chylomicronemia Syndrome

Adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS).

Designated an orphan drug by FDA for treatment of FCS.

FCS is a rare autosomal recessive disorder characterized by extremely high serum triglyceride concentrations caused by an inherited inability to hydrolyze circulating triglycerides. Nonpharmacologic management includes medical nutrition therapy with an extremely low-fat diet (e.g., restricting fat intake to <10 to 15% of daily calories or <20 g). Olezarsen is currently the only FDA-approved treatment for adults with FCS in the US.

Olezarsen Dosage and Administration

Administration

Sub-Q Administration

Administer by sub-Q injection.

Commercially available as prefilled single-dose autoinjector in concentration of 80 mg/0.8 mL.

Prior to initiation of therapy, train patients and/or caregivers on proper preparation and administration.

Remove autoinjector from refrigerator 30 minutes prior to administration and allow to warm to room temperature.

Administer sub-Q to abdomen or front of thigh. May be administered in the back of upper arm if healthcare provider or caregiver administers the injection.

If a dose is missed, administer as soon as possible. Resume dosing at monthly intervals from the date of most recently administered dose.

Dosage

Available as olezarsen sodium; dosage expressed in terms of olezarsen.

Adults

Familial Chylomicronemia Syndrome

Sub-Q

80 mg sub-Q once monthly.

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

Special Populations

Hepatic Impairment

No dosage adjustment required in mild hepatic impairment. Not studied in moderate to severe hepatic impairment.

Renal Impairment

No dosage adjustment necessary in mild to moderate renal impairment. No specific dosage recommendations in severe renal impairment or end stage renal disease (ESRD).

Geriatric Patients

No dosage adjustment recommended in patients ≥65 years of age.

Cautions for Olezarsen

Contraindications

History of serious hypersensitivity reactions to olezarsen or any of the excipients in the formulation.

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions, including bronchospasm, diffuse erythema, facial swelling, urticaria, chills, and myalgias reported.

Advise patients on signs and symptoms of hypersensitivity reactions and instruct them to promptly seek medical attention and discontinue use if hypersensitivity reactions occur.

Immunogenicity

Treatment-emergent anti-drug antibodies (ADAs) reported. Antibodies do not appear to affect pharmacodynamics, safety, or efficacy of olezarsen; however, data are limited.

Specific Populations

Pregnancy

Insufficient data in pregnant women to determine whether there is a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Patients with FCS are at risk for pancreatitis during pregnancy because of defects in lipid metabolism and increased triglyceride levels.

Lactation

Unknown whether olezarsen is distributed into human milk, or if drug has any effects on breastfed infant or on milk production. The unconjugated antisense oligonucleotide is present in the milk of lactating mice at low levels; however, not likely to have clinically relevant effects in breastfed infants.

Consider benefits of breastfeeding along with mother's clinical need for olezarsen and any potential adverse effects on the breastfed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in safety or efficacy observed between patients ≥65 years of age and younger adult patients.

Hepatic Impairment

No clinically significant differences in pharmacokinetics observed in patients with mild hepatic impairment; not studied in patients with moderate to severe hepatic impairment.

Renal Impairment

No clinically significant differences in pharmacokinetics observed in patients with mild to moderate renal impairment; not studied in patients with severe renal impairment or end-stage renal disease.

Common Adverse Effects

Most common adverse reactions (>5%): injection site reactions, decreased platelet count, arthralgia.

Drug Interactions

Not metabolized by CYP enzymes.

Does not inhibit or induce CYP isoenzymes.

Does not inhibit and is not a substrate of organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)1, OCT2, organic anion transporter polypeptide (OATP)1B1, OATP1B3, multidrug and toxic extrusion protein (MATE)1, MATE2-K, breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), and bile salt export protein (BSEP).

Drugs that Affect Protein Binding

Does not displace warfarin or ibuprofen from plasma protein binding sites.

Olezarsen Pharmacokinetics

Absorption

Plasma Concentrations

Time to maximum concentration is approximately 2 hours.

Distribution

Extent

Distributed primarily to liver and kidneys.

Plasma Protein Binding

>99%.

Elimination

Metabolism

Antisense oligonucleotide moiety is metabolized by endo- and exonucleases within tissues to shorter oligonucleotide metabolites.

Elimination Route

<1% eliminated unchanged in urine within 24 hours.

Half-life

Terminal half-life is approximately 4 weeks.

Stability

Storage

Parenteral

Injection

Store prefilled autoinjector at 2-8ºC in original container to protect from light; do not freeze.

After removal from refrigerator, store at room temperature (15-30ºC) in original container for up to 6 weeks. If not used within 6 weeks stored at room temperature, discard the drug.

Actions

Antisense oligonucleotide directed against apolipoprotein C-III (apoC-III) mRNA and conjugated with N-acetyl galactosamine (GalNAc).
In patients with FCS, impaired clearance of chylomicrons from plasma occurs due to lack of functional lipoprotein lipase.
Olezarsen causes degradation of apoC-III mRNA through selective binding, which results in reduction of serum apoC-III protein. ApoC-III appears to regulate both triglyceride metabolism and hepatic clearance of chylomicrons and other triglyceride-rich lipoproteins.

Advice to Patients

Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Inform patients that serious hypersensitivity reactions, including bronchospasm, diffuse erythema, facial swelling, urticaria, chills, and myalgia, have been reported in patients treated with olezarsen. Advise patients on the signs and symptoms of hypersensitivity reactions and instruct them to stop taking olezarsen and seek medical advice promptly if such symptoms occur.
Advise patients with familial chylomicronemia syndrome that use of lipid-regulating agents does not reduce the importance of adhering to a low-fat diet.
Instruct patients to take olezarsen 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.
Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Olezarsen is obtained through designated specialty pharmacies. Contact the manufacturer or consult the olezarsen website ([Web]) for specific availability information.