WAINUA Solution for injection Ref.[107295] Active ingredients: Eplontersen

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).

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)]

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):

^* Vitamin A decreased includes vitamin A deficiency and vitamin A decrease.
^† Injection site reactions includes erythema, pain, and pruritis.

Three serious adverse reactions of atrioventricular (AV) heart block (2%) occurred in WAINUA-treated patients, including 1 case of complete AV block.

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.

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 eplontersen.

In Study 1, with duration of treatment up to 85 weeks (mean treatment duration of 445 days (63.2 weeks), range: 57 to 582 days), 53 out of 144 (37%) patients developed treatment-emergent ADAs during treatment with WAINUA. The presence of ADAs did not affect eplontersen plasma C_max or AUC, but increased C_trough. Although anti-drug antibody development was not found to affect the pharmacokinetics, pharmacodynamics, safety, or efficacy of WAINUA in these patients, the available data are too limited to make definitive conclusions.

Risk Summary

There are no available data on WAINUA use in pregnant women to inform drug-associated risk of adverse developmental outcomes. WAINUA treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking WAINUA. Vitamin A is essential for normal embryofetal development; however, excessive levels of vitamin A are associated with adverse developmental effects. The effect of vitamin A supplementation on the fetus in the setting of a reduction in maternal serum TTR caused by WAINUA administration is unknown [see Clinical Pharmacology (12.2) and Warnings and Precautions (5.1)].

No adverse developmental effects were observed when eplontersen or a mouse-specific surrogate was administered to mice prior to mating and continuing throughout organogenesis [see Animal Data].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Animal Data

Subcutaneous administration of eplontersen (0, 5, 25, or 75 mg/kg) or a mouse-specific surrogate (25 mg/kg) to male and female mice weekly prior to and during mating and administration continued every other day in females throughout the period of organogenesis resulted in no adverse effects on embryofetal development.

Risk Summary

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. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for WAINUA and any potential adverse effects on the breast-fed infant from WAINUA or from the underlying maternal condition.

Safety and effectiveness in pediatric patients have not been established.

No dose adjustment is required in patients ≥65 years of age [see Clinical Pharmacology (12.3)]. In Study 1 [see Clinical Studies (14)], 44 (31%) patients were 65 to 74 years of age, and 8 (5.6%) patients were ≥75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

No dose adjustment is necessary in patients with mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] ≥30 to <90 mL/min/1.73 m²) [see Clinical Pharmacology (12.3)].

WAINUA has not been studied in patients with severe renal impairment or end-stage renal disease.

No dose adjustment is necessary in patients with mild hepatic impairment (total bilirubin ≤1 x ULN and AST >1 x ULN, or total bilirubin >1.0 to 1.5 x ULN and any AST) [see Clinical Pharmacology (12.3)].

WAINUA has not been studied in patients with moderate or severe hepatic impairment.