4.1. Therapeutic indications

Wainzua is indicated for the treatment of hereditary transthyretin-mediated amyloidosis (ATTRv amyloidosis) in adult patients with Stage 1 and 2 polyneuropathy.

4.2. Posology and method of administration

Treatment should be prescribed and supervised by a treating physician knowledgeable in the management of patients with amyloidosis.

Posology

The recommended dose of Wainzua is 45 mg administered by subcutaneous injection. Doses should be administered monthly.

Vitamin A supplementation at approximately, but not exceeding, 2 500 U to 3 000 IU vitamin A per day is advised for patients treated with Wainzua (see section 4.4).

Missed dose

If a dose of Wainzua is missed, then the next dose should be administered as soon as possible. Resume dosing at monthly intervals from the date of the last dose.

Special populations

Elderly population

No dose adjustment is required in elderly patients (≥65 years of age) (see section 5.2).

Renal impairment

No dose adjustment is necessary in patients with mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] ≥ 45 to < 90 ml/min/1.73 m2). Eplontersen has not been studied in patients with eGFR <45 ml/min/1.73 m2 or end-stage renal disease and should only be used in these patients if the anticipated clinical benefit outweighs the potential risk (see section 5.2).

Hepatic impairment

No dose adjustment is necessary in patients with mild hepatic impairment. Eplontersen has not been studied in patients with moderate or severe hepatic impairment and should only be used in these patients if the anticipated clinical benefit outweighs the potential risk (see section 5.2).

Patients undergoing liver transplant

Wainzua has not been studied in patients undergoing liver transplant.

Paediatric population

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

Method of administration

Wainzua is for subcutaneous use only. Wainzua is a pre-filled pen for self-administration, ready to use and for single-use only.

The first injection administered by the patient or caregiver should be performed under the guidance of an appropriately qualified health care professional. Patients and/or caregivers should be trained in the subcutaneous administration of Wainzua.

The pre-filled pen should be removed from refrigerated storage at least 30 minutes before use and allowed to reach room temperature prior to injection. Other warming methods should not be used.

Inspect solution visually before use. The solution should appear colourless to yellow. Do not use if cloudiness, particulate matter, or discolouration is observed prior to administration.

If self-administered, inject Wainzua in the abdomen or upper thigh region. If a caregiver administers the injection, the back of the upper arm can also be used.

Wainzua should not be injected into skin that is bruised, tender, red, or hard, into scars or damaged skin, the area around the navel should be avoided.

Comprehensive instructions for administration are provided in the 'Instructions for Use'.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Vitamin A deficiency

Based on the mechanism of action, Wainzua is expected to reduce serum vitamin A (retinol) below normal levels (see section 5.1). Serum vitamin A levels below the lower limit of normal should be corrected and any symptoms or signs related to vitamin A deficiency should be evaluated prior to initiation of treatment with Wainzua.

Patients receiving Wainzua should take oral supplementation of approximately, but not exceeding, 2 500 IU (female) to 3 000 IU (male) of vitamin A per day to reduce the potential risk of ocular symptoms due to vitamin A deficiency. Referral for ophthalmological assessment is recommended if patients develop ocular symptoms consistent with vitamin A deficiency, including reduced night vision or night blindness, persistent dry eyes, eye inflammation, corneal inflammation or ulceration, corneal thickening or corneal perforation.

During the first 60 days of pregnancy, both too high and too low vitamin A levels may be associated with an increased risk of foetal malformation. Therefore, pregnancy should be excluded before treatment initiation and women of childbearing potential should practise effective contraception (see section 4.6). If a woman intends to become pregnant, Wainzua and vitamin A supplementation should be discontinued and serum vitamin A levels should be monitored. Before conception is attempted, vitamin A should have returned to normal levels.

In the event of an unplanned pregnancy, Wainzua should be discontinued. Due to the long half-life of eplontersen (see section 5.2), a vitamin A deficit may even develop after cessation of treatment. No recommendation can be given whether to continue or discontinue vitamin A supplementation during the first trimester of an unplanned pregnancy. If vitamin A supplementation is continued, the daily dose should not exceed 3 000 IU per day, due to the lack of data supporting higher doses. Thereafter, vitamin A supplementation of 2 500 IU to 3 000 IU per day should be resumed in the second and third trimester if serum vitamin A levels have not yet returned to normal, because of the increased risk of vitamin A deficiency in the third trimester.

It is not known whether vitamin A supplementation in pregnancy will be sufficient to prevent vitamin A deficiency if the pregnant female continues to receive Wainzua. However, increasing vitamin A supplementation to above 3 000 IU per day during pregnancy is unlikely to correct serum retinol levels due to the mechanism of action of eplontersen and may be harmful to the mother and foetus.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose of 0.8 ml, that is to say essentially 'sodium‑free'.

4.5. Interaction with other medicinal products and other forms of interaction

No formal clinical drug-drug interaction studies have been performed. In vitro studies indicate that eplontersen is not a substrate or inhibitor of transporters, does not interact with highly plasma protein bound drugs, and is not an inhibitor or inducer of CYP enzymes. Oligonucleotide therapeutics, including eplontersen, are not typically substrates of CYP enzymes. Therefore, eplontersen is not expected to cause or be affected by drug-drug interactions mediated through drug transporters, plasma protein binding or CYP enzymes.

4.6. Fertility, pregnancy and lactation

Women of child-bearing potential

Wainzua will reduce the plasma levels of vitamin A, which is crucial for normal foetal development. It is not known whether vitamin A supplementation will be sufficient to reduce the risk to the foetus. For this reason, pregnancy should be excluded before initiation of Wainzua therapy and women of child-bearing potential should practice effective contraception.

If a woman intends to become pregnant, Wainzua and vitamin A supplementation should be discontinued, and serum vitamin A levels should be monitored and have returned to normal before conception is attempted (see section 4.4). Due to the long half-life of eplontersen (see section 5.2), a vitamin A deficit may develop even after cessation of treatment.

Pregnancy

There are no data regarding the use of Wainzua in pregnant women. Animal studies did not indicate reproductive toxicity (see section 5.3). Due to the potential teratogenic risk arising from unbalanced vitamin A levels, Wainzua should not be used during pregnancy. In case of pregnancy, close monitoring of the foetus and Vitamin A status should be carried out, especially during the first trimester.

Breast-feeding

Human or animal lactation studies have not been conducted to assess the presence of eplontersen or its metabolites in breast milk, the effects on the breastfed infant, or the effects on milk production for the mother. A risk to the breastfed child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Wainzua therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

There is no information available on the effects of eplontersen on human fertility. No impact on male or female fertility was detected in animal studies (see section 5.3).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

The safety data described below reflects exposure to Wainzua in 144 patients with polyneuropathy caused by ATTRv (ATTRv-PN) randomised to eplontersen and who received at least one dose of eplontersen. Of these, 141 patients received at least 6 months of treatment and 137 patients received at least 12 months of treatment. The mean duration of treatment was 541 days (range: 57 to 582 days).

The most frequent adverse reactions during treatment with eplontersen observed in ≥5% of patients were vitamin A decreased, injection site reactions, vomiting and proteinuria.

Tabulated list of adverse reactions

Adverse reactions are organised by MedDRA System Organ Class (SOC). Within each SOC, preferred terms are arranged by decreasing frequency and then by decreasing seriousness. Frequencies of occurrence of adverse reactions are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000) and not known (cannot be estimated from available data).

Table 1: Summary of adverse reactions reported for Wainzua

System organ class

Adverse reaction

Frequency

Gastrointestinal disorders

Vomiting

Common

General disorders and administration site conditions

Injection site reactions a

Common

Investigations

Vitamin A decreased

Very Common

Renal and urinary disorders

Proteinuria

Common

Eye disorders

Cataracts

Common

a. Injection site erythema, injection site pain, injection site pruritus

Description of selected adverse reaction

Vitamin A decreased

In clinical study in patients with ATTRv-PN, all patients were instructed to take the recommended daily allowance of vitamin A. All patients treated with eplontersen had normal vitamin A levels at baseline, 96.5% of those developed vitamin A levels below the lower limit of normal during the study (see section 5.1).

Injection site reactions

In patients with ATTRv-PN treated with eplontersen, injection site erythema, injection site pain and injection site pruritus were reported in 3.5%, 3.5%, and 2.1% respectively.

Immunogenicity

In the clinical study in patients with ATTRv-PN, after an 84‑week treatment period (median treatment duration of 561 days (80 weeks), range: 57 to 582 days), 58 patients (40.3%) developed treatment‑emergent anti-drug antibodies (ADAs). The presence of ADAs did not affect eplontersen plasma Cmax or AUC, but increased Ctrough. In the patients who tested positive for anti-eplontersen antibodies, there was no clinically meaningful impact on the efficacy, safety, pharmacokinetics, or pharmacodynamics of eplontersen.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

4.9. Overdose

There is no specific treatment for an overdose with eplontersen. In the event of an overdose, supportive medical care should be provided including consulting with a healthcare professional.