4.1. Therapeutic indications

Dawnzera is indicated for routine prevention of recurrent attacks of hereditary angioedema (HAE) in adults and adolescents aged 12 years and older.

4.2. Posology and method of administration

Treatment is to be initiated under the supervision of a physician experienced in the diagnosis and management of patients with HAE.

Posology

The recommended starting dose in adult and adolescent patients aged 12 years and older is 80 mg donidalorsen by subcutaneous injection once monthly.

A dosing interval of 80 mg once every 2 months may be considered if the patient is well controlled (e.g., attack free) for at least 3 months while receiving Dawnzera.

Based on the clinical data, a gradual reduction in attack rate is seen as early as Week 1 after the initial dose of donidalorsen with an expected maximum effect after 1 month.

Consideration should be given to discontinuing treatment in patients with normal C1-INH HAE (nC1- INH) who have shown insufficient reduction in attacks after 4 months of treatment (see section 4.4 and 5.1).

Dawnzera is not intended for the treatment of acute HAE attacks (see section 4.4).

Missed dose

If a dose is missed, the patient or caregiver should be instructed to administer the dose as soon as possible. Thereafter, dosing should be resumed at the prescribed dosing frequency (once monthly or once every 2 months) from the date of the most recently administered dose.

Special populations

Elderly

No dose adjustment is required for patients above 65 years of age (see section 5.2).

Hepatic impairment

No dose adjustment of donidalorsen is required for patients with mild hepatic impairment (see section 5.2).

Dawnzera has not been studied in patients with moderate or severe impairment. Donidalorsen should only be used in these patients if the anticipated clinical benefit outweighs the risk.

Renal impairment

No dose adjustment of donidalorsen is required for patients with mild renal impairment.

Dawnzera has not been studied in patients with moderate or severe impairment or end stage renal disease. Donidalorsen should only be used in these patients if the anticipated clinical benefit outweighs the risk.

Paediatric population

The safety and efficacy of donidalorsen in children aged < 12 years have not yet been established. No data are available.

See sections 4.8 and 5.1.

Changing from other HAE prophylactic medicinal products

The following treatment schedules (Table 1) are recommended for patients that are changing their HAE prophylactic therapy from berotralstat, a C1 esterase inhibitor, or lanadelumab to Dawnzera (see section 5.1).

Table 1: Treatment schedule for patients changing from other prophylactic therapy to Dawnzera.

Other prophylactic therapy

Recommended treatment schedule when changing to Dawnzera

Berotralstat

Continue taking the current dose of berotralstat for 14 days after initiating treatment with Dawnzera.

C1 esterase inhibitor

Continue taking the current dose of C1 esterase inhibitor for 14 days after initiating treatment with Dawnzera.

Lanadelumab

Administer last dose of lanadelumab 14 days prior to initiating treatment with Dawnzera.

Method of administration

Dawnzera is intended for subcutaneous use only.

Dawnzera is to be administered as a subcutaneous injection in the abdomen, upper thigh region, or for caregivers only, the back of the upper arm. Rotation of the injection site is recommended.

Dawnzera must not be injected into areas where the skin is tender, bruised, red, hard, infected or discoloured.

After proper training on correct subcutaneous injection technique, a patient or caregiver may inject Dawnzera if their physician determines it is appropriate. Comprehensive instructions for administration using the pre-filled pen are provided in the package leaflet and the instructions for use.

For further instructions on preparation and special precautions for handling, see section 6.6.

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

Hypersensitivity including anaphylaxis

Hypersensitivity reactions including anaphylaxis have been observed (see section 4.8). In case of a severe hypersensitivity reaction, administration of donidalorsen must be stopped immediately and appropriate treatment must be initiated.

Patients must be advised on the signs and symptoms of hypersensitivity reactions and instructed to promptly seek medical attention and to discontinue use of donidalorsen if serious hypersensitivity reactions occur.

General

Dawnzera is not intended for treatment of acute HAE attacks. In case of a breakthrough HAE attack, individualised treatment should be initiated with an approved rescue medicinal product.

There are limited data available on the use of donidalorsen in HAE patients with HAE-nC1INH (see section 5.1). Patients with HAE nC1-INH having mutations that are not associated with the kallikrein-kinin system (KKS) pathway are not expected to respond to Dawnzera.

It is recommended to perform genetic testing, if available, according to current HAE guidelines and to discontinue the treatment if clinical response is not observed (see sections 4.2 and 5.1).

Sodium

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

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

No clinical drug-drug interaction studies have been performed with donidalorsen. In vitro studies show that donidalorsen is not a substrate or inhibitor of transporters, does not interact with highly plasma protein bound active substances, and is not a substrate or inhibitor/inducer of cytochrome P450 (CYP) enzymes. Donidalorsen 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

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of donidalorsen in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of donidalorsen during pregnancy.

Breast-feeding

Available pharmacodynamic/toxicological data in animals have shown excretion of donidalorsen/metabolites in milk (see section 5.3).

A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from donidalorsen therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No clinical data on the effect of this medicinal product on human fertility are available. Donidalorsen had no effect on fertility and early embryonic development toxicity in murine models (see section 5.3).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

The most frequently observed adverse drug reactions (ADRs) in patients treated with 80 mg donidalorsen every 4 weeks were injection site reactions (24.4 %).

Tabulated list of adverse reactions

Adverse reactions associated with donidalorsen obtained from clinical trials are tabulated below.

All ADRs are listed by system organ class and frequency; very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2: Adverse drug reactions to donidalorsen

System organ class

Adverse drug reaction

Frequency

Immune system disorders

Hypersensitivity (including anaphylaxis)

Common

General disorders and administration site conditions

Injection site reactions a

Very common

Investigations

Hepatic enzyme increased b

Very common

a Injection site reactions include also: erythema, discolouration, pain, pruritus, induration, haematoma, bruising, exfoliation, hypersensitivity and swelling.

b mainly mild, and mostly in alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

Description of selected adverse reactions

Hypersensitivity including anaphylaxis

In clinical trials, a serious hypersensitivity reaction of anaphylaxis was reported in one patient. Symptoms included generalised rash, dyspnoea, chest pain and peri-oral swelling (see sections 4.3 and 4.4).

Injection site reactions

During double-blinded, placebo-controlled trials, injection site reactions were observed. All injection site reactions were non serious, mild to moderate in severity, and generally resolved over time. In some patients, the injection site reactions such as injection site erythema, injection site pruritus, and injection site discolouration persisted for 2 or more days. In one patient who received higher than labelled doses in accordance with the protocol, injection site discoloration led to permanent discontinuation of treatment.

Paediatric population

The safety of donidalorsen was evaluated in a double-blind placebo-controlled clinical trial in a subset of 7 adolescent patients aged 12 to 17 years. The safety profile in these adolescent patients was similar to the profile observed in adult patients.

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.

4.9. Overdose

There is no available information to identify potential signs and symptoms of overdose. If symptoms should occur, symptomatic treatment is recommended. There is no antidote available.