Wainua (Solution) Instructions for Use

Marketing Authorization Holder

AstraZeneca AB (Sweden)

Manufactured By

Vetter Pharma-Fertigung, GmbH & Co. KG (Germany)

Labeled By

RESILIENCE US, Inc. (USA)

Or

ASTRAZENECA, AB (Sweden)

Quality Control Release

ASTRAZENECA, AB (Sweden)

Contact Information

AstraZeneca Pharmaceuticals LLC (Russia)

ATC Code

N07XX21 (Eplontersen)

Active Substance

Eplontersen (Rec.INN registered by WHO)

Dosage Form

Wainua

Solution for subcutaneous administration 45 mg: 0.8 mL pen-injector

Dosage Form, Packaging, and Composition

Solution for subcutaneous administration clear, colorless to yellow.

Excipients: sodium dihydrogen phosphate dihydrate, disodium phosphate, sodium chloride, concentrated hydrochloric acid¹, sodium hydroxide¹, water for injections.

¹ Added as a diluted solution to water for injections to adjust pH to 7.4.

0.8 mL – pen-injectors* (1) – cardboard packs with first opening control.

* primary packaging: 0.8 mL in a type I glass syringe with a needle, needle protective cap, and plunger travel limiter; the syringe is built into a pen-injector consisting of a drive unit and a syringe unit.

Clinical-Pharmacological Group

A drug used for the treatment of hereditary transthyretin-mediated amyloid polyneuropathy

Pharmacotherapeutic Group

Other preparations for the treatment of nervous system disorders

Pharmacological Action

* External placebo group from another randomized controlled trial (NEURO-TTR).

N – number of patients in the full analysis population at Week 66.

N – number of patients with missing data for baseline covariates and change from baseline at that time point.

The analysis was based on data collected during the period up to 28 days after the last dose of the investigational product. The time window for visits in the Week 65 analysis was from Day 419 to Day 479.

Based on a Mixed-effects Model for Repeated Measures (MMRM) adjusted using propensity scores with fixed categorical effects for treatment, time, treatment-by-time interaction, disease stage, Val30M mutation, prior treatment, and fixed covariates for baseline value and baseline-by-time interaction. The final analysis at Week 66 included data only up to Week 65.

CI – confidence interval; LS mean – least squares mean; mBMI – modified Body Mass Index; NSC – Neuropathy Symptoms and Change; PND – Polyneuropathy Disability; PCS – Physical Component Summary; SF-36 PCS = 36-Item Short Form Health Survey Physical Component Summary.

Figure 2. Percent Change from Baseline in Serum TTR Concentration up to Week 65, Wainua Compared to External Placebo* at Week 65 (NEURO-TTRansform Study) (Full Analysis Population)

* External placebo group from another randomized controlled trial (NEURO-TTR).

** The between-treatment difference represents the results of the formal interim analysis at Week 35. The interim analysis at Week 35 included data only up to Week 35.

Based on MMRM adjusted using propensity scores with fixed categorical effects for treatment, time, treatment-by-time interaction, disease stage, Val30Met mutation, prior treatment, and fixed covariates for baseline value and baseline-by-time interaction.

The analysis was based on data collected during the period up to 28 days after the last dose of the investigational product. Data up to Week 65 were included. Placebo was assessed at baseline, Weeks 5, 8, 13, 23, 35, 47, 57, and 65; Wainua was assessed at baseline, Weeks 5, 9, 13, 25, 35, 49, 59, and 65.

Presented is the between-treatment group difference in LS means at Week 35 and Week 65 (Wainua – placebo) with 95% CI (unadjusted).

CI – confidence interval; LS mean – least squares mean; SE – standard error, MMRM – mixed model for repeated measures; TTR – transthyretin.

Figure 3. Change from Baseline in LS Mean for the mNIS+7 Composite Score (NEURO-TTRansform Study) (Full Analysis Population)

* External placebo group from another randomized controlled trial (NEURO-TTR).

** The between-treatment difference represents the results of the formal interim analysis at Week 35. Based on MI ANCOVA adjusted using propensity scores with fixed categorical effects for treatment, disease stage, Val30Met mutation, prior treatment, and fixed covariates for baseline value. The interim analysis at Week 35 included data only up to Week 35.

The Week 66 analysis was based on MMRM adjusted using propensity scores with categorical effects for treatment, time, treatment-by-time interaction, disease stage, Val30Met mutation, prior treatment, and fixed covariates for baseline value and baseline-by-time interaction.

The analysis was based on data collected during the period up to 52 days after the last dose of the investigational product. Data up to Week 66 were included.

Presented is the between-treatment group difference in LS means at Week 35 and Week 65 (Wainua – placebo) with 95% CI (unadjusted).

CI – confidence interval; LS mean – least squares mean; SE – standard error, MI ANCOVA = Multiple Imputation Analysis of Covariance; MMRM – mixed model for repeated measures.

Figure 4. Histogram of Change from Baseline in mNIS+7 Composite Score (NEURO-TTRansform Study) (Full Analysis Population)

a) at Week 35

* External placebo group from another randomized controlled trial (NEURO-TTR).

b) at Week 66

* External placebo group from another randomized controlled trial (NEURO-TTR).

Figure 5. Change from Baseline in LS Mean for the Norfolk QoL-DN Total Score (NEURO-TTRansform Study)

* External placebo group from another randomized controlled trial (NEURO-TTR).

** The between-treatment difference represents the results of the formal interim analysis at Week 35. Based on MI ANCOVA adjusted using propensity scores with fixed categorical effects for treatment, disease stage, Val30Met mutation, prior treatment, and fixed covariates for baseline value. The interim analysis at Week 35 included data only up to Week 35.

The Week 66 analysis was based on MMRM adjusted using propensity scores with categorical effects for treatment, time, treatment-by-time interaction, disease stage, Val30Met mutation, prior treatment, and fixed covariates for baseline value and baseline-by-time interaction.

The analysis was based on data collected during the period up to 52 days after the last dose of the investigational product. Data up to Week 66 were included.

Presented is the between-treatment group difference in LS means at Week 35 and Week 65 (Wainua – placebo) with 95% CI (unadjusted).

CI – confidence interval; LS mean – least squares mean; SE – standard error, MI ANCOVA – Multiple Imputation Analysis of Covariance; MMRM – mixed model for repeated measures.

Figure 6. Histogram of Change from Baseline in Norfolk QoL-DN Total Score (NEURO-TTRansform Study) (Full Analysis Population)

a) at Week 35

* External placebo group from another randomized controlled trial (NEURO-TTR).

b) at Week 66

* External placebo group from another randomized controlled trial (NEURO-TTR).

At Weeks 35 and 65/66, patients treated with Wainua showed similar reductions in serum TTR concentration, improvement in the mNIS+7 composite score, and Norfolk QoL-DN total score compared to placebo across all subgroups, including age, sex, race, region, baseline NIS score, Val30Met mutation status, cardiomyopathy status, baseline FAC diagnosis, and disease stage (Figures 1a and b, 7a and b, 8a and b).

Figure 7. Forest Plot of Between-Treatment Group Difference in LS Mean for Change from Baseline in mNIS+7 Composite Score in Key Subgroups (NEURO-TTRansform Study) (Full Analysis Population)

a) at Week 35

* External placebo group from another randomized controlled trial (NEURO-TTR).

[a] Previously treated with tafamidis or diflunisal.

The CM subgroup included patients diagnosed with FAC at study entry or with baseline interventricular septal thickness ≥13 mm in the absence of arterial hypertension (history of or diagnosed during the study).

LS mean differences, confidence intervals, and p-values are based on an ANCOVA model adjusted using propensity scores with effects for treatment, subgroup factors, disease stage, Val30Met mutation, prior treatment, treatment-by-subgroup interaction, and baseline value. The interim analysis at Week 35 included data up to Week 35.

b) at Week 66

* External placebo group from another randomized controlled trial (NEURO-TTR).

[a] Previously treated with tafamidis or diflunisal.

Based on MMRM adjusted using propensity scores with categorical effects for treatment, time, treatment-by-time interaction, disease stage, Val30Met mutation, prior treatment, and fixed covariates for baseline value and baseline-by-time interaction.

Subgroup models also included treatment-by-subgroup, time-by-subgroup, and treatment-by-time-by-subgroup interactions. Data up to Week 66 were included.

The CM subgroup included patients diagnosed with FAC at study entry or with baseline interventricular septal thickness ≥13 mm in the absence of arterial hypertension [history of or diagnosed during the study].

Presented is the between-treatment group difference in LS means at Week 66 (Wainua – placebo) with 95% CI (unadjusted). CI – confidence interval; LS mean – least squares mean; MMRM – mixed model for repeated measures; CM – cardiomyopathy, FAC – familial amyloid cardiomyopathy.

Figure 8. Forest Plot of Between-Treatment Group Difference in LS Mean for Change from Baseline in Norfolk QoL-DN Total Score in Key Subgroups (NEURO-TTRansform Study) (Full Analysis Population)

a) at Week 35

* External placebo group from another randomized controlled trial (NEURO-TTR).

[a] Previously treated with tafamidis or diflunisal.

The CM subgroup included patients diagnosed with FAC at study entry or with baseline interventricular septal thickness ≥13 mm in the absence of arterial hypertension (history of or diagnosed during the study).

LS mean differences, confidence intervals, and p-values are based on an ANCOVA model adjusted using propensity scores with effects for treatment, subgroup factors, disease stage, Val30Met mutation, prior treatment, treatment-by-subgroup interaction, and baseline value. The interim analysis at Week 35 included data only up to Week 35.

b) at Week 66

* External placebo group from another randomized controlled trial (NEURO-TTR).

[a] Previously treated with tafamidis or diflunisal.

Based on MMRM adjusted using propensity scores with categorical effects for treatment, time, treatment-by-time interaction, disease stage, Val30Met mutation, prior treatment, and fixed covariates for baseline value and baseline-by-time interaction.

Subgroup models also included treatment-by-subgroup, time-by-subgroup, and treatment-by-time-by-subgroup interactions. Data up to Week 66 were included.

The CM subgroup included patients diagnosed with FAC at study entry or with baseline interventricular septal thickness ≥13 mm in the absence of arterial hypertension [history of or diagnosed during the study].

Presented is the between-treatment group difference in LS means at Week 66 (Wainua – placebo) with 95% CI (unadjusted). CI – confidence interval; LS mean – least squares mean; MMRM – mixed model for repeated measures; CM – cardiomyopathy, FAC – familial amyloid cardiomyopathy.

In an exploratory analysis of cardiac status using serial echocardiograms with Wainua, an improvement in the E/e’ ratio (a measure of left ventricular diastolic function) was observed after 65 weeks of treatment in the cardiomyopathy subgroup (placebo-adjusted LS mean difference: -3.94 [95% CI -6.46, -1.42]). Directional changes favoring Wainua over placebo at Week 66 were also noted for predefined exploratory cardiac endpoints of mean left ventricular wall thickness (LS mean difference -0.04 cm, [95% CI -0.12, 0.04]), interventricular septal wall thickness (difference -0.05 cm, [95% CI -0.16, 0.06]), and NT-proBNP, a prognostic biomarker of cardiac impairment (geometric LS mean 0.88, [95% CI 0.68, 1.14]). Despite these findings, clinical benefit in cardiomyopathy has not yet been established.

Analysis at Week 85 (End-of-Treatment Analysis)

Week 85 data for the external placebo group are not available because the treatment period in the NEURO-TTR study was only 66 weeks.

The observed effect in the Wainua treatment group on the mNIS+7 composite score was sustained and persisted until the end of treatment at Week 85. The mean (SD) change from baseline in the mNIS+7 composite score was -0.04% (16.2) at Week 35, -0.21% (17.6) at Week 66, and -2.9% (20.5) at Week 85. The mean Norfolk QoL-DN total score remained stable up to Week 85. In the eplontersen group, the mean (SD) change from baseline in the Norfolk QoL-DN total score was -4.8 (16.5) at Week 35, -7.2 (18.5) at Week 66, and -6.2 (18.0) at Week 85.

Results for NSC, PND, and mBMI remained stable up to Week 85, and the trend for improvement on the SF-36 scale was maintained.

Nonclinical Safety Data

Repeat-Dose Toxicity in Nonclinical Studies

Repeated administration of eplontersen or its rodent surrogate resulted in reduced liver TTR mRNA levels (by ≈62% and 82% in monkeys and mice, respectively) followed by reduced plasma TTR protein levels (by up to 70% in monkeys). No toxicologically significant findings associated with pharmacological inhibition of TTR expression were identified.

Most changes observed after repeated administration for 6 months in mice and 9 months in monkeys were related to the uptake and accumulation of eplontersen and were not considered adverse. Microscopic changes associated with eplontersen uptake were noted in various cell types in various organs in all species examined, including monocytes/macrophages, renal proximal tubular epithelium, Kupffer cells in the liver, and histiocytic cell infiltrates in lymph nodes and injection sites.

In a subchronic toxicity study, one monkey at the maximum dose (24 mg/kg/week) exhibited a sharp decrease in platelet count accompanied by spontaneous hemorrhages. Similar changes were noted in monkeys receiving the drug at a mid-dose of 6 mg/kg/week, which is 73 times the human AUC at the recommended therapeutic dose of eplontersen.

Mutagenicity and Carcinogenicity

Eplontersen did not show genotoxic potential in vitro and in vivo and was not carcinogenic in ras.H2 transgenic mice.

Eplontersen did not demonstrate genotoxicity in in vitro assays (bacterial mutagenicity, chromosomal aberrations in Chinese hamster lung cells) and in an in vivo assay (mouse bone marrow micronucleus).

In a 26-week carcinogenicity study by subcutaneous administration in ras.H2 transgenic mice, Eplontersen was administered at doses of 250, 500, and 1500 mg/kg/month. After 26 weeks of treatment, no evidence of carcinogenicity of eplontersen was found.

Reproductive Toxicity

Embryofetal/Developmental Toxicity/Fertility

Administration of eplontersen had no effect on fertility and embryo-fetal development in mice at a dose up to 38 times the recommended human dose of 45 mg monthly. Eplontersen does not exhibit pharmacological activity in mice. However, administration in mice of an analogue of eplontersen, which caused >90% inhibition of TTR mRNA expression, also showed no effect on fertility and embryo-fetal development.

Pharmacokinetics

The pharmacokinetic (PK) properties of Wainua were evaluated after single and multiple subcutaneous doses (once every 4 weeks) in healthy volunteers and multiple doses (once every 4 weeks) in patients with ATTRv-PN.

Absorption

After subcutaneous administration, Eplontersen is rapidly absorbed into the systemic circulation, with the time to reach C_max in plasma being approximately 2 hours according to population estimates.

Distribution

Based on animal studies (mice, rats, and monkeys), after subcutaneous administration, Eplontersen is distributed primarily in the cortex of the liver and kidneys. Eplontersen has a high degree of binding to human plasma proteins (>98%). Population estimates for the apparent V_d in the central compartment are 12.9 L, and the apparent V_d in the peripheral compartment is 11100 L.

Metabolism

Eplontersen is metabolized by endo- and exonucleases into short oligonucleotide fragments of varying sizes in the liver. Large (long-chain) circulating metabolites have not been detected in the human body. Oligonucleotide drugs, including Eplontersen, are generally not metabolized by cytochrome P (CYP) enzymes.

Elimination

Eplontersen is eliminated primarily through metabolism followed by renal excretion of short oligonucleotide metabolites. The mean fraction of unchanged ASO excreted in urine was less than 1% of the administered dose within 24 hours. According to population estimates, the terminal T_1/2 is approximately 3 weeks.

Linearity/non-linearity

The steady-state C_max and AUC of eplontersen increased slightly more than dose-proportionally after a single subcutaneous administration of the drug at doses from 45 to 120 mg (i.e., 1-2.7 times the recommended dose) in healthy volunteers.

Population estimates for C_max, trough concentrations (C_trough), and AUC were 0.218 mcg/mL, 0.000200 mcg/mL, and 1.95 mcg×h/mL, respectively, after administration of the drug at a dose of 45 mg once every 4 weeks in patients with ATTRv-PN. No accumulation of eplontersen in plasma was observed for C_max and AUC with multiple administrations (once every 4 weeks). Accumulation was noted for C_trough, and steady-state concentration is reached at approximately 17 weeks.

Pharmacokinetics in special patient groups

Sex, race, body weight

Based on population pharmacokinetic and pharmacodynamic analyses, body weight, sex, race, and Val30Met mutation status do not have a clinically significant effect on eplontersen exposure and the reduction of serum TTR levels at steady state. In some cases, the final estimates were limited because the covariates were limited by the overall low number.

Elderly patients

Overall, no differences in pharmacokinetics were noted between adult patients and elderly individuals (≥65 years).

Renal impairment

No formal clinical studies have been conducted to investigate the effect of renal failure on the PK of eplontersen. Population pharmacokinetic and pharmacodynamic analyses did not reveal clinically significant differences in the pharmacokinetics and pharmacodynamics of eplontersen in mild and moderate renal impairment (eGFR from ≥30 to <90 mL/min.). The use of eplontersen has not been studied in patients with severe renal impairment or in patients with end-stage renal disease.

Hepatic impairment

No formal clinical studies have been conducted to investigate the effect of hepatic impairment on Eplontersen. Population pharmacokinetic and pharmacodynamic analyses did not reveal clinically significant differences in the pharmacokinetics and pharmacodynamics of eplontersen in mild hepatic impairment (total bilirubin ≤1×ULN and AST >1×ULN or total bilirubin >1.0-1.5×ULN and any AST). The use of eplontersen has not been studied in patients with moderate or severe hepatic impairment, or in patients with prior liver transplantation.

Drug interactions

Drug interaction studies have not been conducted. In vitro studies have established that Eplontersen is not a substrate or inhibitor of transporters, does not interact with drugs that actively bind to plasma proteins, and is not an inhibitor or inducer of CYP enzymes. Oligonucleotide drugs, including Eplontersen, are generally not substrates of CYP enzymes. Thus, eplontersen is not expected to cause or influence drug interactions mediated through drug transporters, plasma protein binding, or CYP enzymes.

Immunogenicity

The presence of antibodies to eplontersen did not affect the C_max and AUC of eplontersen in plasma but increased C_trough. In patients with antibodies to eplontersen, no clinically significant effect on the efficacy, safety, pharmacokinetics, or pharmacodynamics of Wainua was identified.

Indications

• Treatment of adult patients aged 18 years and older with polyneuropathy associated with hereditary transthyretin-mediated amyloidosis (ATTRv).

ICD codes

Dosage Regimen

Adults

The recommended dose of Wainua is 45 mg. The drug must be administered as a subcutaneous injection once a month.

Missed dose

If a dose of the drug is missed, it should be administered as soon as possible. After that, the use of the drug should be resumed at intervals of 1 month, starting from the date of the last dose administered.

Special patient groups

Elderly patients

No dose adjustment is required for elderly patients aged 65 years and older (see section “Pharmacokinetics”).

Patients with renal impairment

In patients with mild and moderate renal impairment (eGFR from ≥30 to <90 mL/min/1.73 m²), no dose adjustment is required (see section “Pharmacokinetics”). The use of Wainua has not been studied in patients with severe renal impairment or with end-stage renal disease.

Patients with hepatic impairment

Patients with mild hepatic impairment do not require dose adjustment (total bilirubin ≤1×ULN and AST >1×ULN, or total bilirubin >1.0-1.5×ULN and any AST value) (see section “Pharmacokinetics”). The use of Wainua in patients with moderate or severe hepatic impairment has not been studied.

Children

The safety and efficacy of Wainua in children and adolescents under 18 years of age have not been established. No data are available.

Method of administration

Wainua is administered as a subcutaneous injection.

The first injection, performed by the patient or a caregiver, should be conducted under the guidance of a qualified healthcare professional. Patients and/or their caregivers should be trained in the subcutaneous administration of Wainua.

The pen should be removed from the refrigerator at least 30 minutes before administration and allowed to warm to room temperature before injection. Other heating methods should not be used.

The solution should be visually inspected before use. The solution should be clear, colorless to yellow. Do not use if cloudiness, visible particles, or discoloration of the solution is observed before administration.

For self-administration, Wainua is injected into the abdomen or upper thigh. When the injection is performed by a caregiver, the drug can also be administered into the back of the upper arm.

Instructions for using Wainua

The patient should read these instructions before starting to use the pen and each time a new pack is used, as the information may be updated.

Important information

The Wainua pen should be stored in a refrigerator at a temperature of 2°C (35.6°F) to 8°C (46.4°F) in the original carton until use. If necessary, the unopened Wainua pack can be stored at room temperature below 30°C (86°F) for no more than 6 weeks.

Each pen contains one dose and is for single use only.

Do not use the pen if

• The drug has been frozen;
• The pen has been dropped, or is damaged, or the first-opening control on the carton is broken;
• The drug’s expiration date has passed.

Do not use the pen for other persons.

Keep the pen out of the reach of children.

The injection starts automatically when the orange needle guard is pressed against the skin.

To receive the full dose of the medication, the pen must be pressed firmly against the skin.

The injection is considered complete only if the viewing window is completely orange (not shown in the picture).

Before removing the protective cap and administering the drug, read the instructions completely.

Wainua pen

Do not remove the pen cap until the moment of injection.

Do not touch the orange needle guard.

Preparing for injection with the pen

Step 1 – Prepare injection supplies

Step 2 – Inspect the package and wait 30 minutes

Before administration, the carton with the Wainua pen must be kept at room temperature for 30 minutes.

Do not warm the pen by other methods. For example, do not warm it in a microwave or hot water, do not place it near heat sources.

Keep the pen away from light and direct sunlight.

Step 3 – Remove the pen from the package and inspect it

Check the pen for damage.

Check the expiration date.

Inspect the solution through the viewing window.

The presence of small air bubbles in the solution is acceptable.

The solution should be clear, colorless to yellow.

Do not inject if the solution is cloudy, discolored, or contains visible particles.

Administering the drug with the pen

Step 4 – Choose the injection site

The recommended injection site is the front of the thigh or the lower part of the abdomen (anterior abdominal wall).

When the injection is performed by a caregiver, the drug can also be administered into the back of the upper arm. If the patient is self-administering, do not inject into the shoulder area.

For each subsequent injection, choose a new site at least 3 cm away from the previous injection site.

Do not inject

• Within a 5 cm radius around the navel;
• Into areas where the skin is red, warm; into areas of sensitive skin; into bruised, scaly, or hardened skin;
• Into areas with scars, into damaged, discolored, or tattooed skin;
• Through clothing.

Step 5 – Wash hands and clean the injection site

Wash hands thoroughly with soap and water.

Clean the injection site with an alcohol wipe or with soap and water. Let it air dry.

Do not touch the cleaned area before the injection.

Step 6 – Remove the cap

Holding the pen body with one hand, use the other hand to gently remove the transparent needle cap. The orange needle guard is now visible, and the needle is hidden behind it.

• Discard the transparent cap.
• Do not touch the needle, do not press the orange needle guard with your finger.
• Do not attempt to put the cap back on the pen. This may cause premature release of the drug or damage the pen.

Step 7 – Administering the drug with the pen

Administer the drug with the pen by following the instructions in figures a, b, c, and d. When administering the drug, press and hold the pen for 10 seconds until the orange plunger fills the viewing window. The patient may hear a first “click” at the start of the injection and a second “click” at the end of the injection. This is normal. Do not move or change the position of the pen after the injection has started.

Pen position

Place the needle guard at a right angle (90°) to the skin surface.

The patient should ensure they can see the viewing window.

Press the pen firmly until the orange needle guard is hidden.

A first “click” will be heard. The click means the drug administration has started.

The downward movement of the orange plunger will be visible in the viewing window as the drug is administered.

While pressing firmly, hold for approximately 10 seconds.

The viewing window is occupied by the orange plunger.

A second “click” will be heard. The second click means the drug administration is complete.

After the injection is complete, lift the pen straight up

This will cause the orange needle guard to extend and cover the needle.

Step 8 – Check the viewing window

Check the viewing window to ensure the solution was administered completely.

If the orange plunger does not completely fill the viewing window, the patient may not have received the full dose of the drug. In this case, or if other questions arise, contact the treating physician.

Step 9 – Check the injection site

There may be a small amount of blood or fluid at the injection site. This is normal.

If necessary, gently press a cotton ball or gauze pad to the injection site and apply a small bandage.

Step 10 – Disposal of the used pen

Immediately after use, place the used pen in a puncture-resistant sharps disposal container.

Do not dispose of the pen with household waste.

Disposal recommendations

Dispose of the full container according to the instructions of the pharmacy worker.

Do not recycle the puncture-resistant container.

Adverse Reactions

Summary of the safety profile

The safety data presented below were obtained from a clinical study of Wainua in 144 patients with ATTRv polyneuropathy (ATTRv-PN) who were randomized to receive Wainua and received at least one dose of this drug. Of these, 141 patients received treatment for at least six months, and 137 patients for at least 12 months. The mean duration of treatment was 541 days (range from 57 to 582 days).

The most frequent adverse reactions during treatment with Wainua, observed in ≥5% of patients, were vomiting and decreased vitamin A concentration.

Summary of adverse reactions

Adverse reactions are listed according to system organ classes of the Medical Dictionary for Regulatory Activities (MedDRA). Within each system organ class, preferred terms are listed in order of decreasing frequency, and then in order of decreasing severity. The frequency of adverse reactions is defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from the available data).

Table 4. Summary of adverse reactions by frequency category

Description of selected adverse reactions

Decreased vitamin A concentration

In the clinical study involving patients with ATTRv-PN, all patients were instructed to take the recommended daily allowance of vitamin A. All patients receiving Wainua therapy had normal baseline vitamin A concentrations; in 96.5% of them, the vitamin A concentration fell below the lower limit of normal during the study (see section “Pharmacodynamics”).

Injection site reactions

In patients with ATTRv-PN receiving Wainua therapy, injection site erythema, injection site pain, and injection site pruritus were reported in 3.5%, 3.5%, and 2.1% of cases, respectively.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to eplontersen or to any of the excipients included in the drug.

Use in Pregnancy and Lactation

Women of childbearing potential

The use of Wainua reduces the concentration of vitamin A in plasma, which is necessary for normal fetal development. It is unknown whether vitamin A supplementation will be sufficient to reduce the risk to the fetus. Therefore, before starting therapy with Wainua, pregnancy must be excluded, and women of childbearing potential should use effective methods of contraception.

If a woman is planning a pregnancy, the use of Wainua and vitamin A supplementation should be discontinued, and the serum vitamin A level should be monitored before attempting conception to ensure it has normalized. Due to the long half-life of eplontersen (see section “Pharmacokinetics”), vitamin A deficiency may develop even after treatment is discontinued.

Contraception

Women of childbearing potential should use effective methods of contraception.

Pregnancy

There are no data on the use of Wainua in pregnant women.

Administration of eplontersen or a pharmacologically active surrogate to rodents at doses 38 times the recommended human dose in a combined fertility and embryofetal development toxicity study did not result in effects on fertility in male or female mice or on embryofetal development in mice (see the “Nonclinical Safety Data” subsection).

Due to the potential teratogenic risk associated with unbalanced vitamin A concentration, Wainua should not be used during pregnancy. In case of pregnancy, careful monitoring of fetal condition and vitamin A concentration should be performed, especially during the first trimester.

The background risk of major birth defects and miscarriage in the target population is unknown.

Lactation

No studies on lactation in humans or animals have been conducted to assess the presence of eplontersen or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. A risk to breastfed children cannot be excluded. A decision should be made either to discontinue breastfeeding or to discontinue/withhold Wainua therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

There is no information on the effects of eplontersen on human fertility.

Administration of eplontersen or a pharmacologically active surrogate to rodents at doses providing up to 38 times higher exposure than the recommended human dose did not reveal any effects of eplontersen on fertility in male or female mice.

Use in Hepatic Impairment

No dose adjustment is required for patients with mild hepatic impairment (total bilirubin ≤1 × ULN and AST >1 × ULN, or total bilirubin >1.0-1.5 × ULN and any AST). The use of Wainua in patients with moderate or severe hepatic impairment has not been studied.

Use in Renal Impairment

No dose adjustment is required for patients with mild and moderate renal impairment (eGFR from ≥30 to <90 mL/min/1.73 m²). The use of Wainua has not been studied in patients with severe renal impairment or end-stage renal disease.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age (safety and efficacy have not been established).

Geriatric Use

No dose adjustment is required for elderly patients aged 65 years and older.

Special Precautions

Reduction of Serum Vitamin A Levels and Vitamin A Supplementation

Based on the mechanism of action, Wainua is expected to reduce serum vitamin A (retinol) concentrations below normal values (see the “Pharmacodynamics” section).

Any symptoms or signs associated with vitamin A deficiency should be assessed before starting treatment with Wainua.

Patients receiving Wainua should take vitamin A at the recommended daily allowance to reduce the potential risk of ocular symptoms due to vitamin A deficiency. Higher doses of vitamin A above the recommended daily allowance should not be used to achieve normal serum vitamin A levels during treatment with Wainua, as serum vitamin A levels do not reflect total body vitamin A stores.

If ocular symptoms consistent with vitamin A deficiency occur, including worsening night vision or night blindness, as well as persistent dry eyes, an ophthalmological examination should be performed.

It is not known whether vitamin A supplementation during pregnancy will be sufficient to prevent vitamin A deficiency if a pregnant woman continues to receive Wainua (see the “Pregnancy and Lactation” section). Increasing the dose of vitamin A beyond the recommended amount during pregnancy is unlikely to correct serum retinol concentrations due to the mechanism of action of eplontersen and may be harmful to the mother and fetus.

Excipients

Sodium Content

This medicine contains less than 1 mmol (23 mg) of sodium per 0.8 ml, that is to say, it is essentially sodium-free.

Effects on Ability to Drive and Use Machines

Wainua has no or negligible influence on the ability to drive and use machines.

Overdose

Symptoms specific symptoms of eplontersen overdose are unknown.

Treatment there is no specific treatment for eplontersen overdose. In case of overdose, a doctor should be consulted and symptomatic treatment should be administered.

Drug Interactions

Formal drug interaction studies have not been conducted (see the “Pharmacokinetics” section).

Due to the lack of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Storage Conditions

Store at a temperature between 2°C (35.6°F) and 8°C (46.4°F) in the original package. Do not freeze.

Wainua can be stored in the original carton at room temperature below 30°C (86°F) for up to six weeks. If the medicine is not used within six weeks, it should be discarded.

Dispensing Status

The medicine is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.