4.1. Therapeutic indications

Lecanemab is indicated for the treatment of mild cognitive impairment and mild dementia due to Alzheimer's disease in adult patients that are apolipoprotein E ε4 (ApoE ε4) heterozygotes or non-carriers (see section 5.1).

4.2. Posology and method of administration

Treatment should be initiated and supervised by physicians experienced in the diagnosis and treatment of Alzheimer's disease.

The presence of amyloid beta (Aβ) pathology must be confirmed using approved methods such as amyloid Positron Emission Tomography (PET) scan or cerebrospinal fluid (CSF) analysis or equivalent validated methods, prior to initiating treatment (see section 5.1).

Testing for apolipoprotein E ε4 (ApoE ε4) status should be performed prior to initiation of treatment using a validated test (see section 4.1). Prior to testing patients should be appropriately counselled and consented according to national or local guidelines, as applicable.

Posology

The recommended initial dosing regimen is 10 mg/kg administered as an intravenous (IV) infusion over approximately one hour, once every 2 weeks. After 18 months, the regimen of 10 mg/kg once every two weeks may be continued, or a transition to the maintenance dosing regimen of 10 mg/kg once every 4 weeks may be considered.

Treatment with lecanemab should be discontinued once the patient progresses to moderate Alzheimer's disease. The efficacy of continued treatment in patients with moderate Alzheimer's disease has not been established.

The duration of placebo-controlled efficacy data for lecanemab was 18 months (see section 5.1).

Dose Adjustments

No dose reductions are recommended. If a patient develops amyloid related imaging abnormalities (ARIA), see detailed Magnetic Resonance Imaging (MRI) monitoring and dosing interruption guidelines below.

Monitoring for Amyloid Related Imaging Abnormalities (ARIA)

Lecanemab can cause amyloid related imaging abnormalities-oedema (ARIA-E) and -haemosiderin deposition (ARIA-H) (see section 4.4).

Access to MRI should be available during the treatment period of lecanemab.

Obtain a recent brain MRI prior to initiating treatment with lecanemab. Obtain an MRI prior to the 5th, 7th and 14th infusions. Enhanced clinical vigilance for ARIA is recommended during the first 14 weeks of treatment with lecanemab. If a patient experiences symptoms suggestive of ARIA (see section 4.4), clinical evaluation should be performed, including an MRI if indicated.

Recommendations for Dosing Interruptions or Treatment Discontinuation in Patients with ARIA

ARIA-E

Table 1: Dosing Recommendations for Patients with ARIA-E

Clinical symptoms

ARIA-E Severity on MRI1

Mild

Moderate

Severe

Asymptomatic

May continue dosing based on clinical judgement

Suspend dosing

Suspend dosing

Symptomatic

Suspend dosing

1See Table 3 for MRI radiographic severity.

Dosing may continue in asymptomatic, mild radiographic ARIA-E cases based on clinical judgement with enhanced clinical monitoring and follow-up MRI scans starting 2 months after occurrence and every 1 or 2 months thereafter until ARIA-E has resolved.

Suspend dosing for any symptomatic or radiographically moderate or severe ARIA-E. A follow-up MRI should be performed to assess for resolution 2 to 4 months after initial identification. Once the MRI demonstrates radiographic resolution and symptoms (see section 4.4), if present, resolve, resumption of dosing should be guided by clinical judgement.

Following an initial event of ARIA-E, the rate of recurrence on resumption of treatment with lecanemab is common in ApoE ε4 non-carriers and very common in heterozygotes (see section 4.8).

ARIA-H

Table 2: Dosing Recommendations for Patients with ARIA-H

Clinical symptoms

ARIA-H Severity on MRI1

Mild

Moderate

Severe

Asymptomatic

May continue dosing based on clinical judgement

Suspend dosing

Permanently discontinue treatment

Symptomatic

Suspend dosing

1See Table 3 for MRI radiographic severity.

Dosing may continue in asymptomatic, mild radiographic ARIA-H cases based on clinical judgement with enhanced clinical monitoring and follow-up MRI scans starting 2 months after occurrence and every 1 or 2 months thereafter until ARIA-H has stabilised.

Suspend dosing for any symptomatic or radiographically moderate ARIA-H. A follow-up MRI should be performed to assess for stabilisation 2 to 4 months after initial identification. Once the MRI demonstrates radiographic stabilisation and symptoms (see section 4.4), if present, resolve, resumption of dosing should be guided by clinical judgement.

Following an initial event of ARIA-H, the rate of recurrence on resumption of treatment with lecanemab is very common in both ApoE ε4 non-carriers and in heterozygotes (see section 4.8).

In the event of radiographically severe ARIA-H, treatment with lecanemab should be permanently discontinued.

Radiographic Findings

The radiographic severity of ARIA associated with lecanemab was classified by the criteria shown in Table 3.

Table 3: ARIA MRI Severity Classification Criteria

ARIA Type

Radiographic Severity1

Mild

Moderate

Severe

ARIA-E

FLAIR hyperintensity confined to sulcus and/or cortex/subcortex white matter in one location <5 cm

FLAIR hyperintensity 5 to 10 cm in single greatest dimension, or more than 1 site of involvement, each measuring <10 cm

FLAIR hyperintensity >10 cm with associated gyral swelling and sulcal effacement. One or more separate/ independent sites of involvement may be noted.

ARIA-H microhaemorrhage

≤4 new incident microhaemorrhages

5 to 9 new incident microhaemorrhages

10 or more new incident microhaemorrhages

ARIA-H superficial siderosis

1 focal area of superficial siderosis

2 focal areas of superficial siderosis

>2 areas of superficial siderosis

1Radiographical severity is defined by the total number of new microhaemorrhages from baseline or total number of areas for superficial siderosis.

Intracerebral Haemorrhage

Lecanemab should be permanently discontinued if intracerebral haemorrhage greater than 1 cm in diameter occurs.

Delayed or missed doses

If an infusion is missed, administer the next dose as soon as possible.

Special populations

Elderly

No dose adjustment is necessary in patients ≥ 65 years (see section 5.1).

Renal impairment

No specific dose adjustment is necessary in patients with mild to moderate renal impairment (see section 5.2).

Hepatic impairment

No specific dose adjustment is needed for patients with mild to moderate hepatic impairment (see section 5.2).

Down syndrome

The safety and efficacy of lecanemab in adults with Down syndrome has not been established (see section 4.4).

Paediatric population

There is no relevant use of lecanemab in the paediatric population.

Method of administration

This medicinal product is for IV use only.

Lecanemab is administered as an IV infusion over approximately 1 hour once every 2 weeks during the first 18 months of treatment, and after 18 months of treatment, the regimen of 10 mg/kg once every two weeks may be continued, or a transition to the maintenance dosing regimen of 10 mg/kg once every 4 weeks may be considered. It must not be administered as an IV push or bolus injection.

Lecanemab is diluted prior to IV infusion. Infuse the entire volume of diluted solution intravenously over approximately 1 hour through an IV line containing a terminal 0.2 micron in-line filter. Flush infusion line to ensure all lecanemab is administered.

Patients should be monitored for any signs or symptoms of an infusion-related reaction (see section 4.4). The infusion rate may be reduced, or the infusion may be discontinued, and appropriate therapy administered as clinically indicated. Consider pre-medication at subsequent dosing with antihistamines, paracetamol, non-steroidal anti-inflammatory drugs, or corticosteroids (see sections 4.4 and 4.8).

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

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

Pre-treatment MRI findings of prior intracerebral haemorrhage, more than 4 microhaemorrhages, superficial siderosis or vasogenic oedema, which are suggestive of cerebral amyloid angiopathy (CAA) (see section 4.4).

Treatment with lecanemab should not be initiated in patients receiving ongoing anticoagulant therapy (see section 4.4).

4.4. Special warnings and precautions for use

Controlled access programme

In order to promote the safe and effective use of lecanemab, initiation of treatment in all patients should be through a central registration system implemented as part of a controlled access programme.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Hypersensitivity reactions

Hypersensitivity reactions, including angioedema, bronchospasm, and anaphylaxis, have occurred in patients who were treated with lecanemab. Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity-type reaction and initiate appropriate therapy.

Amyloid Related Imaging Abnormalities (ARIA)

Lecanemab can cause ARIA, characterised as ARIA-E, which can be observed on MRI as brain oedema or sulcal effusions, and ARIA-H, which includes microhaemorrhage and superficial siderosis. ARIA can occur spontaneously in patients with Alzheimer's disease. ARIA-H associated with lecanemab generally occurs in association with an occurrence of ARIA-E.

ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events, including seizure and status epilepticus, rarely can occur. When present, reported symptoms associated with ARIA may include headache, confusion, visual changes, dizziness, nausea, and gait difficulty. Focal neurologic deficits may also occur. Symptoms associated with ARIA usually resolve over time (see section 4.8).

Consider the benefit of lecanemab for the treatment of Alzheimer's disease and potential risk of serious adverse events associated with ARIA when deciding to initiate treatment with lecanemab (see section 4.8).

Monitoring for ARIA and Dosing Interruption Guidelines

The recommendations for monitoring and management of ARIA-E, ARIA-H and intracerebral haemorrhage are provided in section 4.2.

ApoE ε4 Carrier Status and Risk of ARIA

Approximately 15% of Alzheimer's disease patients are ApoE ε4 homozygotes. Patients who are homozygotes and are treated with lecanemab have a higher incidence of ARIA, including symptomatic, serious, severe radiographic, and recurrent ARIA, compared to heterozygotes and non-carriers (see section 4.8). Lecanemab is not indicated for use in patients who are homozygotes (see section 4.1).

Intracerebral haemorrhage

Intracerebral haemorrhages greater than 1 cm in diameter have occurred in patients treated with lecanemab (see section 4.8). Fatal events of intracerebral haemorrhage in patients taking lecanemab have been observed (see section 4.8).

Concomitant Antithrombotic Medication

Baseline use of antithrombotic medication (aspirin, other antiplatelet agents, or anticoagulants) was allowed in Study 301 if the patient was on a stable dose. The majority of exposures to antithrombotic medications were to aspirin. Aspirin and other antiplatelet agents were used in the trial with no increase in the risk of ARIA-E, ARIA-H or intracerebral haemorrhage with lecanemab.

Because intracerebral haemorrhages have been observed in patients taking both lecanemab and anticoagulants (see section 4.8), and in patients receiving thrombolytic agents during lecanemab treatment, additional caution should be exercised when considering the administration of anticoagulants or a thrombolytic agent (e.g. tissue plasminogen activator) to a patient already being treated with lecanemab:

• If anticoagulation needs to be commenced during therapy with lecanemab (for example incident arterial thromboses, acute pulmonary embolism or other life-threatening indications) then lecanemab should be paused. Lecanemab can be reinstated if anticoagulation is no longer medically indicated. The use of concomitant aspirin and other antiplatelet therapy is permitted.

• There was only limited exposure to thrombolytic agents in the clinical trials however the risk of severe intracranial bleed resulting from concomitant use is plausible. Use of thrombolytic agents should be avoided except for immediately life-threatening indications with no alternative management (e.g., pulmonary embolism with haemodynamic compromise) when the benefits could outweigh the risks.

• Because ARIA-E can cause focal neurologic deficits that can mimic an ischemic stroke, treating clinicians should consider whether such symptoms could be due to ARIA-E before giving thrombolytic therapy to a patient being treated with lecanemab.

Treatment with lecanemab should not be initiated in patients receiving ongoing anticoagulant therapy (see section 4.3).

Other Risk Factors for Intracerebral Haemorrhage

Patients were excluded from enrolment in Study 301 for findings on neuroimaging (MRI) that indicated an increased risk for intracerebral haemorrhage (see section 5.1). Lecanemab should not be used in patients with pre-treatment MRI findings of prior intracerebral haemorrhage, more than 4 microhaemorrhages, superficial siderosis or vasogenic oedema which are suggestive of CAA (see section 4.3). Caution should be exercised when considering the use of lecanemab in patients with other factors that indicate an increased risk for intracerebral haemorrhage.

The presence of an ApoE ε4 allele is associated with CAA, which has an increased risk for intracerebral haemorrhage.

Down syndrome

There is a higher rate of CAA in patients with Down syndrome. The safety and efficacy of lecanemab in these patients are unknown.

Infusion-related reactions

Infusion-related reactions were observed in clinical trials with lecanemab (see section 4.8); the majority were mild or moderate and occurred with the first infusion. Most reactions including severe reactions occurred during the infusion or within approximately 2.5 hours after infusion completion. Symptoms of infusion-related reactions include fever and flu-like symptoms (chills, generalised aches, feeling shaky, and joint pain), nausea, vomiting, hypotension, hypertension, fatigue, dizziness, confusion and oxygen desaturation . In the event of an infusion-related reaction, the infusion rate may be reduced, or the infusion may be discontinued, and appropriate therapy initiated as clinically indicated. Prophylactic treatment with antihistamines, paracetamol, nonsteroidal anti-inflammatory drugs, or corticosteroids prior to future infusions may be considered (see section 4.2).

Patients excluded from clinical trials

Patients with a history of transient ischemic attacks (TIA), stroke or seizures within 12 months of screening, and patients with a bleeding disorder that was not under adequate control were excluded in the clinical trials with lecanemab. The safety and efficacy in these patients are unknown.

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

No pharmacokinetic (PK) drug interactions are expected with lecanemab.

The risk of intracerebral haemorrhage with lecanemab treatment may be increased in patients receiving anticoagulant therapy or thrombolytic agents (see sections 4.3 and 4.4).

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential must use effective contraception during and up to 3 months after treatment.

Pregnancy

There are no data on the use of lecanemab in pregnant women. Lecanemab should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

There are no data on the presence of lecanemab in human milk, the effects on the breastfed infant, or the effects of the drug on milk production.

A decision should be made whether to discontinue breast-feeding or to discontinue lecanemab, taking into account the benefit of breast-feeding for the child and the benefit of lecanemab therapy for the woman.

Fertility

There are no data on the effects of lecanemab on human fertility.

4.7. Effects on ability to drive and use machines

Lecanemab has no or negligible influence on the ability to drive and use machines. Patients should be advised to use caution when driving or operating machinery in case they experience dizziness or confusion during treatment with lecanemab.

4.8. Undesirable effects

Summary of the safety profile

The safety of lecanemab has been evaluated in 2203 patients who received at least one dose of lecanemab.

In the double-blind, placebo-controlled period of Study 301 in patients with mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia, a total of 898 patients received lecanemab at the recommended dose of 10 mg/kg every 2 weeks, of which 757 patients were non-carriers or heterozygotes (the indicated population).

Of the patients treated with lecanemab 31% (278/898) were non-carriers, 53% (479/898) were heterozygotes and 16% (141/898) were homozygotes. With the exception of events of ARIA, the safety profile was the same across genotypes.

In the indicated population, the most common adverse reactions were infusion-related reaction (26%), ARIA-H (13%), fall (11%), headache (11%) and ARIA-E (9%).

Tabulated list of adverse reactions

Adverse reactions reported in clinical trials are listed below in Table 4. The adverse reactions are listed by MedDRA System Organ Class and categories of frequency. Frequencies 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 <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each System Organ Class and frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 4: Adverse reactions

System Organ Class (SOC)

Very common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Immune system disorders

Hypersensitivity reactions

Anaphylaxis

Nervous system disorders

ARIA-H1

Headache

ARIA-E2

Intracerebral haemorrhage

Cardiac disorders

Atrial fibrillation

Skin and subcutaneous tissue disorders

Rash3

General disorders and administration site conditions

Infusion-related reactions

1ARIA-H: Amyloid related imaging abnormality-microhaemorrhage and haemosiderin deposit; Superficial siderosis of central nervous system, and Cerebellar microhaemorrhage.

2ARIA-E is common in the indicated population and very common in the homozygote population.

3Rash: acne, erythema, infusion-site rash, injection-site rash, rash, rash erythematous, rash pruritic, skin reactions, and urticaria.

Description of selected adverse reactions

Incidence of ARIA in the Indicated Population Symptomatic ARIA occurred in 2% (16/757) of patients on lecanemab who are non-carriers and heterozygotes in Study 301. Serious symptoms associated with ARIA that required hospitilisation were reported in 0.4% (3/757) of patients on lecanemab. Clinical symptoms associated with ARIA resolved in 75% (12/16) of patients during the 18-month study period; clinical symptoms in 50% of these patients resolved within 3 days.

Including asymptomatic radiographic events, ARIA was observed in 17% (128/757) of patients on lecanemab compared to 7% (55/764) of patients on placebo.

ARIA-E was observed in 9% (67/757) of patients on lecanemab compared with 1% (10/764) of patients on placebo. The majority of ARIA-E was asymptomatic, with symptomatic ARIA-E reported in 2% (12/757) patients on lecanemab and no patients on placebo

ARIA-H was observed in 13% (98/757) of patients on lecanemab compared with 7% (52/764) of patients on placebo. The majority of ARIA-H was asymptomatic, with symptomatic ARIA-H reported in 0.8% (6/757) of patients on lecanemab and 0.1% (1/764) on placebo. ARIA-H and ARIA-E can occur together. There was no increase in isolated ARIA-H (i.e., ARIA-H in patients who did not also experience ARIA-E) for lecanemab compared to placebo.

The majority of ARIA-E radiographic events occurred early in treatment (within the first 7 doses), although ARIA-E can occur at any time and patients can have more than 1 episode. The maximum radiographic severity of ARIA-E in patients on lecanemab was mild in 4% (31/757), moderate in 4% (33/757), and severe in 0.3% (2/757) of patients. Resolution on MRI occurred in 64% (43/67) of patients by 12 weeks, 87% (58/67) by 17 weeks, and 100% (67/67) overall after detection, compared with 80% (8/10) of patients on placebo.

The maximum radiographic severity of ARIA-H microhaemorrhage in patients on lecanemab was mild in 8% (60/757), moderate in 1% (8/757), and severe in 1% (10/757) of patients; ARIA-H superficial siderosis was mild in 3% (26/757), moderate in 0.5% (4/757), and severe in 0.3% (2/757) of patients. ARIA-H stabilised in 79% (77/97) of patients on lecanemab compared with 75% (39/52) of patients on placebo, either at the first follow-up MRI or within 20 weeks for most patients.

See Table 3 in section 4.2 for MRI radiographic severity.

Recurrence of ARIA in the Indicated Population

ARIA-E was observed in 9% (67/757) of patients on lecanemab, of which 88% (59/67) continued on lecanemab with or without dose interruption. Among those that continued lecanemab, 14% (8/59) experienced a recurrence of ARIA-E.

ARIA-H (with or without concurrent ARIA-E) was observed in 13% (98/757) of patients on lecanemab and 7% (52/764) of patients on placebo, of which 80% (78/98) and 77% (40/52) continued treatment with or without dose interruption, respectively. Among those that continued, 36% (28/78) of patients on lecanemab and 30% (12/40) of patients on placebo experienced a recurrence of ARIA-H.

Intracerebral Haemorrhage in the Indicated Population

Intracerebral haemorrhage was reported in 0.5% (4/757) of patients on lecanemab compared to 0.1% (1/764) of patients on placebo.

The incidence of intracerebral haemorrhage was 0.3% (1/286) of patients on lecanemab with a concomitant antithrombotic medication at the time of the event compared to 0.7% (3/450) of patients who did not. Patients taking lecanemab with an anticoagulant alone or combined with an antiplatelet medication or aspirin had an incidence of intracerebral haemorrhage of 1.5% (1/68 patients) compared to no patients on placebo.

Fatal events of intracerebral haemorrhage have been observed in patients taking lecanemab.

APOE ε4 Carrier Status and Risk of ARIA

In study 301, the incidence of ARIA was lower in non-carriers (13% lecanemab vs 4% placebo) and heterozygotes (19% lecanemab vs 9% placebo) than in homozygotes (45% lecanemab vs 22% placebo). Among patients treated with lecanemab, symptomatic ARIA-E occurred in 1% of non-carriers and 2% of heterozygotes compared with 9% of homozygotes. Serious events of ARIA occurred in approximately 1% of non-carriers and heterozygotes and 3% of homozygotes. Among patients treated with lecanemab, the rate of severe radiographic ARIA-E was lower in non-carriers 0% (0/278) and heterozygotes 0.4% (2/479) compared to homozygotes 5% (7/141). The rate of severe radiographic ARIA-H was lower in non-carriers 1% (3/278) and heterozygotes 2% (10/479) compared to homozygotes 14% (19/141).

Among the patients who experienced an event of ARIA-E and continued on lecanemab with or without dose interruption, the rates of recurrence were 9% (1/11) in non-carriers, 15% (7/48) in heterozygotes and 54% (20/37) in homozygotes.

Among the patients who experienced an event of ARIA-H and continued on lecanemab with or without dose interruption, the rates of recurrence were 22% (5/23) in non-carriers (compared with 14% [1/7] on placebo), 42% (23/55) in heterozygotes (compared with 33% [11/33] on placebo), and 62% (29/47) in homozygotes (compared with 50% [12/24] on placebo).

Infusion-related Reactions

Infusion-related reactions were observed in 26% (237/898) of patients treated with lecanemab compared to 7% of patients on placebo; and 75% (178/237) occurred with the first infusion. Infusion-related reactions were mostly mild (69%) or moderate (28%) in severity, severe infusion-related reactions were reported in less than 1% of patients. Infusion-related reactions resulted in discontinuations in 1% (12/898) of patients on lecanemab. The incidence of infusion-related reactions was similar regardless of ApoE ε4 genotype.

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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play and Apple App store.

4.9. Overdose

There is limited clinical experience with lecanemab overdose.

In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment initiated immediately.