Eplontersen is a subcutaneous, transthyretin-directed antisense oligonucleotide indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis. In a randomized, open-label trial, eplontersen-treated subjects with hATTR with polyneuropathy experienced statistically significant improvements in the modified Neuropathy Impairment Scale+7 (mNIS+7) composite score and the Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) total score from baseline to week 35 compared to subjects who received placebo. Eplontersen treatment leads to a decrease in serum vitamin A concentrations; supplementation at the recommended daily allowance of vitamin A is advised for persons receiving eplontersen.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Eplontersen is a clear and colorless to yellow solution; do not use if cloudiness, particulate matter, or discoloration are observed prior to administration.
-Missed dose: Administer eplontersen as soon as possible after a missed dose. Resume dosing at monthly intervals from the date of the most recently administered dose.
Subcutaneous Administration
-Remove the single-dose autoinjector from the refrigerator. Keep the autoinjector in the original carton and allow the autoinjector to warm to room temperature for 30 minutes before the injection. Do not try to speed up the warming process using other heat sources, such as a microwave or hot water.
-Check the expiration date. Do not use the autoinjector if the clear cap is missing, expiration date has passed, medication looks cloudy, discolored, or has particles, or the autoinjector appears damaged.
-Choose an injection site on the abdomen or front of the thigh. The back of the upper arm can also be used as an injection site if a health care provider or caregiver administers the injection.
-Clean injection site with an alcohol wipe in a circular motion and let the skin air dry. Do not inject within 2 inches (5 cm) of the belly button, into skin that is bruised, tender, red, or hard, or into scars or damaged skin.
-Remove the clear cap from the autoinjector by pulling it straight off. Do not twist it off. The needle is inside the orange needle shield. Throw away the clear cap in the trash or sharps container. Do not remove the clear cap until right before the injection. Do not recap the autoinjector. Do not push the orange needle shield against the hand or finger.
-Hold the autoinjector in 1 hand. Place the orange needle shield at a 90-degree angle against the skin. Make sure the viewing window is visible. Push firmly and hold the autoinjector straight against the skin. An audible click will be heard as the injection starts; a second click may be heard. Hold the autoinjector against the skin for 10 seconds to make sure the full dose has been given. Do not move, turn, or change the angle of the autoinjector during the injection.
-Check to ensure that the orange plunger rod has moved down to fill the entire viewing window. If the orange plunger rod does not fill the viewing window, the full dose may not have been administered.
-Remove the autoinjector by lifting it straight up. If needed, press a cotton ball or gauze on the injection site and apply a small bandage.
-Do not reuse the autoinjector. Discard the autoinjector in a sharps container. Do not discard in household trash.
-Storage: After removing from refrigerator, the autoinjector may be stored in the original carton at room temperature up to 30 degrees C (86 degrees F) for up to 6 weeks. If not used within 6 weeks stored at room temperature, discard. Do not freeze. Do not expose to heat. Protect from light.
During clinical trials, 3 serious adverse reactions of atrioventricular (AV) heart block (2%) occurred in eplontersen-treated subjects, including a single case of complete AV block.
During clinical trials, vomiting was reported in 9% of eplontersen-treated subjects.
During clinical trials, proteinuria was reported in 8% of eplontersen-treated subjects.
During clinical trials, blurred vision (6%) and cataracts (6%) were reported in eplontersen-treated subjects.
During clinical trials, injection site reaction, including erythema, pain, and pruritus, was reported in 7% of eplontersen-treated subjects.
During clinical trials, all subjects treated with eplontersen had normal vitamin A concentrations at baseline and 95% of eplontersen-treated subjects developed low vitamin A concentrations during treatment; all subjects were instructed to take the recommended daily allowance of vitamin A. Decreased vitamin A concentration, including vitamin A deficiency, was reported as an adverse reaction in 15% of eplontersen-treated subjects. Eplontersen reduced the mean steady-state serum vitamin A concentration by 71% by week 37. Supplementation with the recommended daily allowance of vitamin A is advised for persons receiving eplontersen. Do not give higher doses than the recommended daily allowance of vitamin A to try to achieve normal serum vitamin A concentrations during eplontersen treatment, as serum vitamin A concentrations do not reflect the total amount of vitamin A in the body. Refer persons to an ophthalmologist for evaluation if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness, dry eyes).
There are no data available on eplontersen use during human pregnancy to inform a drug-associated risk of adverse developmental outcomes. Vitamin A supplementation is recommended for persons taking eplontersen due to a decrease in serum vitamin A concentrations with treatment. Vitamin A is essential for normal embryofetal development; however, excessive vitamin A concentrations are associated with adverse developmental effects. The effect of vitamin A supplementation on the fetus in the setting of a reduction in maternal serum transthyretin (TTR) caused by eplontersen are unknown. No adverse developmental effects were observed when eplontersen or a mouse-specific surrogate was administered to mice prior to mating and continuing throughout organogenesis.
Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for eplontersen and any potential adverse effects on the breast-fed infant from eplontersen or the underlying maternal condition. There is no information regarding the presence of eplontersen in human milk, the effects on the breast-fed infant, or the effects on milk production.
For the treatment of hereditary transthyretin amyloidosis-associated polyneuropathy:
Subcutaneous dosage:
Adults: 45 mg subcutaneously once monthly.
Maximum Dosage Limits:
-Adults
45 mg/month subcutaneously.
-Geriatric
45 mg/month subcutaneously.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dose adjustment is necessary in persons with mild hepatic impairment [total bilirubin 1 times the upper limit of normal (ULN) or less and AST more than 1 times ULN, or total bilirubin more than 1 to 1.5 times the ULN and any AST]. Eplontersen has not been studied in persons with moderate or severe hepatic impairment.
Patients with Renal Impairment Dosing
No dose adjustment is necessary in persons with mild to moderate renal impairment (estimated GFR 30 to 89 mL/minute/1.73 m2). Eplontersen has not been studied in persons with severe renal impairment or end-stage renal disease.
*non-FDA-approved indication
There are no drug interactions associated with Eplontersen products.
Eplontersen is an antisense oligonucleotide-GalNAc conjugate that causes degradation of mutant and wild-type transthyretin (TTR) messenger RNA (mRNA) through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues.
Eplontersen is administered subcutaneously. Eplontersen is bound to human plasma proteins (more than 98%) in vitro. The population estimate for the apparent central Vd is 12 L and the apparent peripheral Vd is 11,100 L. Eplontersen is metabolized by endo- and exonucleases to short oligonucleotide fragments of varying sizes within the liver. Less than 1% of the administered eplontersen dose is excreted unchanged in urine within 24 hours. The terminal elimination half-life of eplontersen is approximately 3 weeks.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Subcutaneous Route
After subcutaneous administration, eplontersen is absorbed with the time to maximum plasma concentrations of approximately 2 hours, based on population estimates. Eplontersen is expected to distribute primarily to the liver and kidney cortex after subcutaneous dosing. Eplontersen Cmax and AUC showed a slightly greater than dose-proportional increase after single subcutaneous doses ranging from 45 to 120 mg (i.e., 1 to 2.7-times the recommended dose) in healthy volunteers. Population estimates (mean +/- SD) of steady-state maximum concentrations (Cmax), and area under the curve (AUC) were 283 +/- 152 ng/mL, and 2,190 +/- 689 ng/mL, respectively, after 45 mg monthly dosing in subjects with hereditary transthyretin-mediated (hATTR) amyloidosis. No accumulation of eplontersen Cmax and AUC was observed in repeated dosing (once every 4 weeks). During clinical trials, after administration of the recommended eplontersen dose every 4 weeks to subjects with hATTR amyloidosis, a decrease in serum transthyretin (TTR) concentrations was observed at the first assessment and the least square mean serum TTR at week 35 decreased by 81% from baseline.
-Special Populations
Hepatic Impairment
Population pharmacokinetic analysis showed no clinically meaningful differences in the pharmacokinetics of eplontersen based on mild hepatic impairment [total bilirubin of 1 times the upper limit of normal (ULN) or less and AST more than 1 times the ULN, or total bilirubin more than 1 to 1.5 times the ULN and any AST]. Eplontersen has not been studied in persons with moderate to severe hepatic impairment or in persons with prior liver transplant.
Renal Impairment
Population pharmacokinetic analysis showed no clinically meaningful differences in the pharmacokinetics of eplontersen based on mild and moderate renal impairment (estimated GFR 30 to 89 mL/minute). Eplontersen has not been studied in persons with severe renal impairment or end-stage renal disease.
Geriatric
Population pharmacokinetic analysis showed no clinically meaningful differences in the pharmacokinetics of eplontersen based on age.
Gender Differences
Population pharmacokinetic analysis showed no clinically meaningful differences in the pharmacokinetics of eplontersen based on sex.
Ethnic Differences
Population pharmacokinetic analysis showed no clinically meaningful differences in the pharmacokinetics of eplontersen based on race.
Obesity
Population pharmacokinetic analysis showed no clinically meaningful differences in the pharmacokinetics of eplontersen based on body weight.
Other
Transthyretin Gene Variant
Population pharmacokinetic analysis showed no clinically meaningful differences in the pharmacokinetics of eplontersen based on Val30Met variant status.