LEQEMBI

Treatment should be initiated and supervised by physicians experienced in the diagnosis and treatment of Alzheimer’s disease. 1). 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. 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. 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.

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. 4), if present, resolve, resumption of dosing should be guided by clinical judgement.

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 Symptomatic Suspend dosing Permanently discontinue treatment 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. 4), if present, resolve, resumption of dosing should be guided by clinical judgement.

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 Radiographic Severity1 ARIA Type 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 microhaemorrhag e ≤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.

1). Renal impairment No specific dose adjustment is necessary in patients […]

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.

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.

1% (1/764) on placebo. ARIA-H and ARIA-E can occur together. , 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.

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. 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.

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. 1% (1/764) of patients on placebo. 7% (3/450) of patients who did not. 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 […]

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. 8). 8). 2. ApoE ε4 Carrier Status and Risk of ARIA Approximately 15% of Alzheimer’s disease patients are ApoE ε4 homozygotes.

8). 1). 8). 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. 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.

, 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.

3). 1). 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. 8); the majority were mild or moderate and occurred with the first infusion. 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, […]

1. 4). 4).