Leqembi

LEQEMBI is indicated for the treatment of Alzheimer’s disease. Treatment with LEQEMBI should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials.

• Confirm the presence of amyloid beta pathology prior to initiating treatment. (
  2.1

  Patient Selection

  Confirm the presence of amyloid beta pathology prior to initiating treatment

  [see Clinical Pharmacology (

  12.1

  )]

  .
  )
  
  
• Obtain a recent baseline brain MRI prior to initiating treatment. (
  2.4

  Monitoring and Dosing Interruption for Amyloid Related Imaging Abnormalities

  LEQEMBI can cause amyloid related imaging abnormalities -edema (ARIA-E) and -hemosiderin deposition (ARIA-H)

  [

  see

  Warnings and Precautions (

  5.1

  )]

  .

  Monitoring for ARIA

  Obtain a recent baseline brain magnetic resonance imaging (MRI) prior to initiating treatment with LEQEMBI. Obtain an MRI prior to the 3^rd, 5^th, 7^th, and 14^thinfusions. In general, the MRI should be performed within approximately one week before the scheduled infusion of LEQEMBI and reviewed prior to proceeding with the infusion. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including an MRI if indicated.

  Recommendations for Dosing Interruptions in Patients with ARIA

  ARIA-E

  The recommendations for dosing interruptions for patients with ARIA-E are provided in Table 2.

  Table 2: Dosing Recommendations for Patients with ARIA-E

  Clinical Symptom Severity 1	ARIA-E Severity on MRI 2
  	Mild	Moderate	Severe
  Asymptomatic	May continue dosing	Suspend dosing3	Suspend dosing3
  Mild	May continue dosing based on clinical judgment	Suspend dosing3
  Moderate or Severe	Suspend dosing3
  1Clinical SymptomSeverity Categories: Mild: discomfort noticed, but no disruption of normal daily activity. Moderate: discomfort sufficient to reduce or affect normal daily activity. Severe: incapacitating, with inability to work or to perform normal daily activity. 2See Table 4 for MRI radiographic severity [Warnings and Precautions ( 5.1 )] . 3Suspend until MRI demonstrates radiographic resolution and symptoms, if present, resolve; consider a follow-up MRI to assess for resolution 2 to 4 months after initial identification. Resumption of dosing should be guided by clinical judgment.

  ARIA-H

  The recommendations for dosing interruptions for patients with ARIA-H are provided in Table 3.

  Table 3: Dosing Recommendations for Patients with ARIA-H

  Clinical Symptom Severity		ARIA-H Severity on MRI 1
  		Mild	Moderate	Severe
  Asymptomatic		May continue dosing	Suspend dosing2	Suspend dosing3
  Symptomatic		Suspend dosing2	Suspend dosing2
  1	See Table 4 for MRI radiographic severity [Warnings and Precautions ( 5.1 )] .
  2	Suspend until MRI demonstrates radiographic stabilization and symptoms, if present, resolve; resumption of dosing should be guided by clinical judgment; consider a follow-up MRI to assess for stabilization 2 to 4 months after initial identification.
  3	Suspend until MRI demonstrates radiographic stabilization and symptoms, if present, resolve; use clinical judgment in considering whether to continue treatment or permanently discontinue LEQEMBI.

  In patients who develop intracerebral hemorrhage greater than 1 cm in diameter during treatment with LEQEMBI, suspend dosing until MRI demonstrates radiographic stabilization and symptoms, if present, resolve. Use clinical judgment in considering whether to continue treatment after radiographic stabilization and resolution of symptoms or permanently discontinue LEQEMBI.
  ,
  5.1

  Amyloid Related Imaging Abnormalities

  Monoclonal antibodies directed against aggregated forms of beta amyloid, including LEQEMBI, can cause amyloid related imaging abnormalities (ARIA), characterized as ARIA with edema (ARIA-E), which can be observed on MRI as brain edema or sulcal effusions, and ARIA with hemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis. ARIA can occur spontaneously in patients with Alzheimer’s disease, particularly in patients with MRI findings suggestive of cerebral amyloid angiopathy, such as pretreatment microhemorrhage or superficial siderosis. ARIA-H associated with monoclonal antibodies directed against aggregated forms of beta amyloid generally occurs in association with an occurrence of ARIA-E. ARIA-H of any cause and ARIA-E can occur together.

  ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events, including seizure and status epilepticus, can occur. ARIA can be fatal. 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. In addition to ARIA, intracerebral hemorrhages greater than 1 cm in diameter have occurred in patients treated with LEQEMBI.

  Consider the benefit of LEQEMBI for the treatment of Alzheimer’s disease and potential risk of serious adverse events associated with ARIA when deciding to initiate treatment with LEQEMBI.

  Incidence of ARIA

  Symptomatic ARIA occurred in 3% (29/898) of patients treated with LEQEMBI in Study 2

  [see Clinical Studies (

  14

  )].

  Serious symptoms associated with ARIA were reported in 0.7% (6/898) of patients treated with LEQEMBI. Clinical symptoms associated with ARIA resolved in 79% (23/29) of patients during the period of observation. Similar findings were observed in Study 1.

  Including asymptomatic radiographic events, ARIA was observed in 21% (191/898) of patients treated with LEQEMBI, compared to 9% (84/897) of patients on placebo in Study 2.

  In Study 2, ARIA-E was observed in 13% (113/898) of patients treated with LEQEMBI, compared to 2% (15/897) of patients on placebo. ARIA-H was observed in 17% (152/898) of patients treated with LEQEMBI, compared to 9% (80/897) of patients on placebo. There was no increase in isolated ARIA-H (i.e., ARIA-H in patients who did not also experience ARIA-E) for LEQEMBI compared to placebo.

  Incidence of Intracerebral Hemorrhage

  Intracerebral hemorrhage greater than 1 cm in diameter was reported in 0.7% (6/898) of patients in Study 2 after treatment with LEQEMBI, compared to 0.1% (1/897) on placebo. Fatal events of intracerebral hemorrhage in patients taking LEQEMBI have been observed.

  Risk Factors for ARIA and Intracerebral Hemorrhage

  ApoE ε4 Carrier Status

  The risk of ARIA, including symptomatic and serious ARIA, is increased in apolipoprotein E ε4 (ApoE ε4) homozygotes.

  Approximately 15% of Alzheimer’s disease patients are ApoE ε4 homozygotes. In Study 2, 16% (141/898) of patients in the LEQEMBI arm were ApoE ε4 homozygotes, 53% (479/898) were heterozygotes, and 31% (278/898) were noncarriers. The incidence of ARIA was higher in ApoE ε4 homozygotes (45% on LEQEMBI vs. 22% on placebo) than in heterozygotes (19% on LEQEMBI vs 9% on placebo) and noncarriers (13% on LEQEMBI vs 4% on placebo). Among patients treated with LEQEMBI, symptomatic ARIA-E occurred in 9% of ApoE ε4 homozygotes compared to 2% of heterozygotes and 1% noncarriers. Serious events of ARIA occurred in 3% of ApoE ε4 homozygotes, and approximately 1% of heterozygotes and noncarriers. The recommendations on management of ARIA do not differ between ApoE ε4 carriers and noncarriers

  [see Dosage and Administration (

  2.4

  )].

  Testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, prescribers should discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results. Prescribers should inform patients that if genotype testing is not performed they can still be treated with LEQEMBI; however, it cannot be determined if they are ApoE ε4 homozygotes and at higher risk for ARIA. An FDA-authorized test for the detection of ApoE ε4 alleles to identify patients at risk of ARIA if treated with LEQEMBI is not currently available. Currently available tests used to identify ApoE ε4 alleles may vary in accuracy and design.

  Radiographic Findings of Cerebral Amyloid Angiopathy (CAA)

  Neuroimaging findings that may indicate CAA include evidence of prior intracerebral hemorrhage, cerebral microhemorrhage, and cortical superficial siderosis. CAA has an increased risk for intracerebral hemorrhage. The presence of an ApoE ε4 allele is also associated with cerebral amyloid angiopathy.

  The baseline presence of at least 2 microhemorrhages or the presence of at least 1 area of superficial siderosis on MRI, which may be suggestive of CAA, have been identified as risk factors for ARIA. Patients were excluded from enrollment in Study 2 for the presence of more than 4 microhemorrhages and additional findings suggestive of cerebral amyloid angiopathy (prior cerebral hemorrhage greater than 1 cm in greatest diameter, superficial siderosis, vasogenic edema) or other lesions (aneurysm, vascular malformation) that could potentially increase the risk of intracerebral hemorrhage.

  Concomitant Antithrombotic or Thrombolytic Medication

  In Study 2, baseline use of antithrombotic medication (aspirin, other antiplatelets, or anticoagulants) was allowed if the patient was on a stable dose. The majority of exposures to antithrombotic medications were to aspirin. Antithrombotic medications did not increase the risk of ARIA with LEQEMBI. The incidence of intracerebral hemorrhage was 0.9% (3/328 patients) in patients taking LEQEMBI with a concomitant antithrombotic medication at the time of the event, compared to 0.6% (3/545 patients) in those who did not receive an antithrombotic. Patients taking LEQEMBI with an anticoagulant alone or combined with an antiplatelet medication or aspirin had an incidence of intracerebral hemorrhage of 2.5% (2/79 patients), compared to none in patients who received placebo.

  Fatal cerebral hemorrhage has occurred in a patient taking an anti-amyloid monoclonal antibody in the setting of focal neurologic symptoms of ARIA and the use of a thrombolytic agent.

  Additional caution should be exercised when considering the administration of antithrombotics or a thrombolytic agent (e.g., tissue plasminogen activator) to a patient already being treated with LEQEMBI. 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 in a patient being treated with LEQEMBI.

  Caution should be exercised when considering the use of LEQEMBI in patients with factors that indicate an increased risk for intracerebral hemorrhage and in particular for patients who need to be on anticoagulant therapy, or patients with findings on MRI that are suggestive of cerebral amyloid angiopathy.

  Radiographic Severity

  The radiographic severity of ARIA associated with LEQEMBI was classified by the criteria shown in Table 4.

  Table 4: ARIA MRI Classification Criteria

  ARIA Type	Radiographic Severity
  	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 microhemorrhage	≤ 4 new incident microhemorrhages	5 to 9 new incident microhemorrhages	10 or more new incident microhemorrhages
  ARIA-H superficial siderosis	1 focal area of superficial siderosis	2 focal areas of superficial siderosis	> 2 areas of superficial siderosis

  In Study 2, the majority of ARIA-E radiographic events occurred early in treatment (within the first 7 doses), although ARIA can occur at any time and patients can have more than 1 episode. The maximum radiographic severity of ARIA-E in patients treated with LEQEMBI was mild in 4% (37/898) of patients, moderate in 7% (66/898) of patients, and severe in 1% (9/898) of patients. Resolution on MRI occurred in 52% of ARIA-E patients by 12 weeks, 81% by 17 weeks, and 100% overall after detection. The maximum radiographic severity of ARIA-H microhemorrhage in patients treated with LEQEMBI was mild in 9% (79/898), moderate in 2% (19/898), and severe in 3% (28/898) of patients; superficial siderosis was mild in 4% (38/898), moderate in 1% (8/898), and severe in 0.4% (4/898). Among patients treated with LEQEMBI, the rate of severe radiographic ARIA-E was highest in ApoE ε4 homozygotes 5% (7/141), compared to heterozygotes 0.4% (2/479) or noncarriers 0% (0/278). Among patients treated with LEQEMBI, the rate of severe radiographic ARIA-H was highest in ApoE ε4 homozygotes 13.5% (19/141), compared to heterozygotes 2.1% (10/479) or noncarriers 1.1% (3/278).

  Monitoring and Dose Management Guidelines

  Recommendations for dosing in patients with ARIA-E depend on clinical symptoms and radiographic severity

  [see Dosage and Administration (

  2.4

  )].

  Recommendations for dosing in patients with ARIA-H depend on the type of ARIA-H and radiographic severity

  [see Dosage and Administration (

  2.4

  )]

  . Use clinical judgment in considering whether to continue dosing in patients with recurrent ARIA-E.

  Baseline brain MRI and periodic monitoring with MRI are recommended

  [see Dosage and Administration (

  2.4

  )]

  . Enhanced clinical vigilance for ARIA is recommended during the first 14 weeks of treatment with LEQEMBI. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including MRI if indicated. If ARIA is observed on MRI, careful clinical evaluation should be performed prior to continuing treatment.

  There is no experience in patients who continued dosing through symptomatic ARIA-E, or through asymptomatic but radiographically severe ARIA-E. There is limited experience in patients who continued dosing through asymptomatic but radiographically mild to moderate ARIA-E. There are limited data in dosing patients who experienced recurrent ARIA-E. While experience is limited in these situations, dose management guidelines are provided

  [see Dosage and Administration (

  2.4

  )].

  Providers should encourage patients to participate in real world data collection (e.g., registries) to help further the understanding of Alzheimer’s disease and the impact of Alzheimer’s disease treatments. Providers and patients can contact Eisai at 888-274-2378 for a list of currently enrolling programs.
  )
  
  
• Obtain an MRI within approximately one week prior to the 3^rd, 5^th, 7^th, and 14^th infusions. If radiographically observed ARIA occurs, treatment recommendations are based on type, severity, and presence of symptoms. (
  2.4

  Monitoring and Dosing Interruption for Amyloid Related Imaging Abnormalities

  LEQEMBI can cause amyloid related imaging abnormalities -edema (ARIA-E) and -hemosiderin deposition (ARIA-H)

  [

  see

  Warnings and Precautions (

  5.1

  )]

  .

  Monitoring for ARIA

  Obtain a recent baseline brain magnetic resonance imaging (MRI) prior to initiating treatment with LEQEMBI. Obtain an MRI prior to the 3^rd, 5^th, 7^th, and 14^thinfusions. In general, the MRI should be performed within approximately one week before the scheduled infusion of LEQEMBI and reviewed prior to proceeding with the infusion. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including an MRI if indicated.

  Recommendations for Dosing Interruptions in Patients with ARIA

  ARIA-E

  The recommendations for dosing interruptions for patients with ARIA-E are provided in Table 2.

  Table 2: Dosing Recommendations for Patients with ARIA-E

  Clinical Symptom Severity 1	ARIA-E Severity on MRI 2
  	Mild	Moderate	Severe
  Asymptomatic	May continue dosing	Suspend dosing3	Suspend dosing3
  Mild	May continue dosing based on clinical judgment	Suspend dosing3
  Moderate or Severe	Suspend dosing3
  1Clinical SymptomSeverity Categories: Mild: discomfort noticed, but no disruption of normal daily activity. Moderate: discomfort sufficient to reduce or affect normal daily activity. Severe: incapacitating, with inability to work or to perform normal daily activity. 2See Table 4 for MRI radiographic severity [Warnings and Precautions ( 5.1 )] . 3Suspend until MRI demonstrates radiographic resolution and symptoms, if present, resolve; consider a follow-up MRI to assess for resolution 2 to 4 months after initial identification. Resumption of dosing should be guided by clinical judgment.

  ARIA-H

  The recommendations for dosing interruptions for patients with ARIA-H are provided in Table 3.

  Table 3: Dosing Recommendations for Patients with ARIA-H

  Clinical Symptom Severity		ARIA-H Severity on MRI 1
  		Mild	Moderate	Severe
  Asymptomatic		May continue dosing	Suspend dosing2	Suspend dosing3
  Symptomatic		Suspend dosing2	Suspend dosing2
  1	See Table 4 for MRI radiographic severity [Warnings and Precautions ( 5.1 )] .
  2	Suspend until MRI demonstrates radiographic stabilization and symptoms, if present, resolve; resumption of dosing should be guided by clinical judgment; consider a follow-up MRI to assess for stabilization 2 to 4 months after initial identification.
  3	Suspend until MRI demonstrates radiographic stabilization and symptoms, if present, resolve; use clinical judgment in considering whether to continue treatment or permanently discontinue LEQEMBI.

  In patients who develop intracerebral hemorrhage greater than 1 cm in diameter during treatment with LEQEMBI, suspend dosing until MRI demonstrates radiographic stabilization and symptoms, if present, resolve. Use clinical judgment in considering whether to continue treatment after radiographic stabilization and resolution of symptoms or permanently discontinue LEQEMBI.
  ,
  5.1

  Amyloid Related Imaging Abnormalities

  Monoclonal antibodies directed against aggregated forms of beta amyloid, including LEQEMBI, can cause amyloid related imaging abnormalities (ARIA), characterized as ARIA with edema (ARIA-E), which can be observed on MRI as brain edema or sulcal effusions, and ARIA with hemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis. ARIA can occur spontaneously in patients with Alzheimer’s disease, particularly in patients with MRI findings suggestive of cerebral amyloid angiopathy, such as pretreatment microhemorrhage or superficial siderosis. ARIA-H associated with monoclonal antibodies directed against aggregated forms of beta amyloid generally occurs in association with an occurrence of ARIA-E. ARIA-H of any cause and ARIA-E can occur together.

  ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events, including seizure and status epilepticus, can occur. ARIA can be fatal. 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. In addition to ARIA, intracerebral hemorrhages greater than 1 cm in diameter have occurred in patients treated with LEQEMBI.

  Consider the benefit of LEQEMBI for the treatment of Alzheimer’s disease and potential risk of serious adverse events associated with ARIA when deciding to initiate treatment with LEQEMBI.

  Incidence of ARIA

  Symptomatic ARIA occurred in 3% (29/898) of patients treated with LEQEMBI in Study 2

  [see Clinical Studies (

  14

  )].

  Serious symptoms associated with ARIA were reported in 0.7% (6/898) of patients treated with LEQEMBI. Clinical symptoms associated with ARIA resolved in 79% (23/29) of patients during the period of observation. Similar findings were observed in Study 1.

  Including asymptomatic radiographic events, ARIA was observed in 21% (191/898) of patients treated with LEQEMBI, compared to 9% (84/897) of patients on placebo in Study 2.

  In Study 2, ARIA-E was observed in 13% (113/898) of patients treated with LEQEMBI, compared to 2% (15/897) of patients on placebo. ARIA-H was observed in 17% (152/898) of patients treated with LEQEMBI, compared to 9% (80/897) of patients on placebo. There was no increase in isolated ARIA-H (i.e., ARIA-H in patients who did not also experience ARIA-E) for LEQEMBI compared to placebo.

  Incidence of Intracerebral Hemorrhage

  Intracerebral hemorrhage greater than 1 cm in diameter was reported in 0.7% (6/898) of patients in Study 2 after treatment with LEQEMBI, compared to 0.1% (1/897) on placebo. Fatal events of intracerebral hemorrhage in patients taking LEQEMBI have been observed.

  Risk Factors for ARIA and Intracerebral Hemorrhage

  ApoE ε4 Carrier Status

  The risk of ARIA, including symptomatic and serious ARIA, is increased in apolipoprotein E ε4 (ApoE ε4) homozygotes.

  Approximately 15% of Alzheimer’s disease patients are ApoE ε4 homozygotes. In Study 2, 16% (141/898) of patients in the LEQEMBI arm were ApoE ε4 homozygotes, 53% (479/898) were heterozygotes, and 31% (278/898) were noncarriers. The incidence of ARIA was higher in ApoE ε4 homozygotes (45% on LEQEMBI vs. 22% on placebo) than in heterozygotes (19% on LEQEMBI vs 9% on placebo) and noncarriers (13% on LEQEMBI vs 4% on placebo). Among patients treated with LEQEMBI, symptomatic ARIA-E occurred in 9% of ApoE ε4 homozygotes compared to 2% of heterozygotes and 1% noncarriers. Serious events of ARIA occurred in 3% of ApoE ε4 homozygotes, and approximately 1% of heterozygotes and noncarriers. The recommendations on management of ARIA do not differ between ApoE ε4 carriers and noncarriers

  [see Dosage and Administration (

  2.4

  )].

  Testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, prescribers should discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results. Prescribers should inform patients that if genotype testing is not performed they can still be treated with LEQEMBI; however, it cannot be determined if they are ApoE ε4 homozygotes and at higher risk for ARIA. An FDA-authorized test for the detection of ApoE ε4 alleles to identify patients at risk of ARIA if treated with LEQEMBI is not currently available. Currently available tests used to identify ApoE ε4 alleles may vary in accuracy and design.

  Radiographic Findings of Cerebral Amyloid Angiopathy (CAA)

  Neuroimaging findings that may indicate CAA include evidence of prior intracerebral hemorrhage, cerebral microhemorrhage, and cortical superficial siderosis. CAA has an increased risk for intracerebral hemorrhage. The presence of an ApoE ε4 allele is also associated with cerebral amyloid angiopathy.

  The baseline presence of at least 2 microhemorrhages or the presence of at least 1 area of superficial siderosis on MRI, which may be suggestive of CAA, have been identified as risk factors for ARIA. Patients were excluded from enrollment in Study 2 for the presence of more than 4 microhemorrhages and additional findings suggestive of cerebral amyloid angiopathy (prior cerebral hemorrhage greater than 1 cm in greatest diameter, superficial siderosis, vasogenic edema) or other lesions (aneurysm, vascular malformation) that could potentially increase the risk of intracerebral hemorrhage.

  Concomitant Antithrombotic or Thrombolytic Medication

  In Study 2, baseline use of antithrombotic medication (aspirin, other antiplatelets, or anticoagulants) was allowed if the patient was on a stable dose. The majority of exposures to antithrombotic medications were to aspirin. Antithrombotic medications did not increase the risk of ARIA with LEQEMBI. The incidence of intracerebral hemorrhage was 0.9% (3/328 patients) in patients taking LEQEMBI with a concomitant antithrombotic medication at the time of the event, compared to 0.6% (3/545 patients) in those who did not receive an antithrombotic. Patients taking LEQEMBI with an anticoagulant alone or combined with an antiplatelet medication or aspirin had an incidence of intracerebral hemorrhage of 2.5% (2/79 patients), compared to none in patients who received placebo.

  Fatal cerebral hemorrhage has occurred in a patient taking an anti-amyloid monoclonal antibody in the setting of focal neurologic symptoms of ARIA and the use of a thrombolytic agent.

  Additional caution should be exercised when considering the administration of antithrombotics or a thrombolytic agent (e.g., tissue plasminogen activator) to a patient already being treated with LEQEMBI. 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 in a patient being treated with LEQEMBI.

  Caution should be exercised when considering the use of LEQEMBI in patients with factors that indicate an increased risk for intracerebral hemorrhage and in particular for patients who need to be on anticoagulant therapy, or patients with findings on MRI that are suggestive of cerebral amyloid angiopathy.

  Radiographic Severity

  The radiographic severity of ARIA associated with LEQEMBI was classified by the criteria shown in Table 4.

  Table 4: ARIA MRI Classification Criteria

  ARIA Type	Radiographic Severity
  	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 microhemorrhage	≤ 4 new incident microhemorrhages	5 to 9 new incident microhemorrhages	10 or more new incident microhemorrhages
  ARIA-H superficial siderosis	1 focal area of superficial siderosis	2 focal areas of superficial siderosis	> 2 areas of superficial siderosis

  In Study 2, the majority of ARIA-E radiographic events occurred early in treatment (within the first 7 doses), although ARIA can occur at any time and patients can have more than 1 episode. The maximum radiographic severity of ARIA-E in patients treated with LEQEMBI was mild in 4% (37/898) of patients, moderate in 7% (66/898) of patients, and severe in 1% (9/898) of patients. Resolution on MRI occurred in 52% of ARIA-E patients by 12 weeks, 81% by 17 weeks, and 100% overall after detection. The maximum radiographic severity of ARIA-H microhemorrhage in patients treated with LEQEMBI was mild in 9% (79/898), moderate in 2% (19/898), and severe in 3% (28/898) of patients; superficial siderosis was mild in 4% (38/898), moderate in 1% (8/898), and severe in 0.4% (4/898). Among patients treated with LEQEMBI, the rate of severe radiographic ARIA-E was highest in ApoE ε4 homozygotes 5% (7/141), compared to heterozygotes 0.4% (2/479) or noncarriers 0% (0/278). Among patients treated with LEQEMBI, the rate of severe radiographic ARIA-H was highest in ApoE ε4 homozygotes 13.5% (19/141), compared to heterozygotes 2.1% (10/479) or noncarriers 1.1% (3/278).

  Monitoring and Dose Management Guidelines

  Recommendations for dosing in patients with ARIA-E depend on clinical symptoms and radiographic severity

  [see Dosage and Administration (

  2.4

  )].

  Recommendations for dosing in patients with ARIA-H depend on the type of ARIA-H and radiographic severity

  [see Dosage and Administration (

  2.4

  )]

  . Use clinical judgment in considering whether to continue dosing in patients with recurrent ARIA-E.

  Baseline brain MRI and periodic monitoring with MRI are recommended

  [see Dosage and Administration (

  2.4

  )]

  . Enhanced clinical vigilance for ARIA is recommended during the first 14 weeks of treatment with LEQEMBI. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including MRI if indicated. If ARIA is observed on MRI, careful clinical evaluation should be performed prior to continuing treatment.

  There is no experience in patients who continued dosing through symptomatic ARIA-E, or through asymptomatic but radiographically severe ARIA-E. There is limited experience in patients who continued dosing through asymptomatic but radiographically mild to moderate ARIA-E. There are limited data in dosing patients who experienced recurrent ARIA-E. While experience is limited in these situations, dose management guidelines are provided

  [see Dosage and Administration (

  2.4

  )].

  Providers should encourage patients to participate in real world data collection (e.g., registries) to help further the understanding of Alzheimer’s disease and the impact of Alzheimer’s disease treatments. Providers and patients can contact Eisai at 888-274-2378 for a list of currently enrolling programs.
  )
  
  
• Recommended starting dosage: 10 mg/kg once every 2 weeks administered after dilution as an intravenous infusion over approximately one hour. (
  2.2

  Recommended Dosage

  Initiate LEQEMBI as an intravenous infusion using the starting dosage (see Table 1). After 18 months, the starting dosage may be continued or a transition to maintenance dosage regimen may be considered, which can be administered by either intravenous infusion or subcutaneous injection (see Table 1). If transitioning from starting dosage to a maintenance dosage regimen, administer the first maintenance dose two weeks after the last starting dose.

  Table 1: Starting and Maintenance Dosage Regimens

  Route of Administration	Dose	Frequency	Infusion Rate (if Intravenous)
  Starting Dosage
  Intravenous Only (LEQEMBI)	10 mg/kg	Once every 2 weeks	Over approximately one hour
  Maintenance Dosage
  Intravenous (LEQEMBI)	10 mg/kg	Once every 4 weeks	Over approximately one hour
  Subcutaneous (LEQEMBI IQLIK)	360 mg	Once every week	------------------------

  For intravenous infusion, use LEQEMBI vials. LEQEMBI vials must be diluted before administration

  [see Dosage and Administration (

  2.5

  )].

  For subcutaneous administration, use LEQEMBI IQLIK

  [see Dosage and Administration (

  2.6

  )].
  )
  
  
• After 18 months, continue treatment once every 2 weeks or transition to an intravenous or subcutaneous maintenance dosage. (
  2.2

  Recommended Dosage

  Initiate LEQEMBI as an intravenous infusion using the starting dosage (see Table 1). After 18 months, the starting dosage may be continued or a transition to maintenance dosage regimen may be considered, which can be administered by either intravenous infusion or subcutaneous injection (see Table 1). If transitioning from starting dosage to a maintenance dosage regimen, administer the first maintenance dose two weeks after the last starting dose.

  Table 1: Starting and Maintenance Dosage Regimens

  Route of Administration	Dose	Frequency	Infusion Rate (if Intravenous)
  Starting Dosage
  Intravenous Only (LEQEMBI)	10 mg/kg	Once every 2 weeks	Over approximately one hour
  Maintenance Dosage
  Intravenous (LEQEMBI)	10 mg/kg	Once every 4 weeks	Over approximately one hour
  Subcutaneous (LEQEMBI IQLIK)	360 mg	Once every week	------------------------

  For intravenous infusion, use LEQEMBI vials. LEQEMBI vials must be diluted before administration

  [see Dosage and Administration (

  2.5

  )].

  For subcutaneous administration, use LEQEMBI IQLIK

  [see Dosage and Administration (

  2.6

  )].
  )
  
  
• Recommended maintenance dosage:
  • Intravenous infusion: 10 mg/kg once every 4 weeks (
    2.2

    Recommended Dosage

    Initiate LEQEMBI as an intravenous infusion using the starting dosage (see Table 1). After 18 months, the starting dosage may be continued or a transition to maintenance dosage regimen may be considered, which can be administered by either intravenous infusion or subcutaneous injection (see Table 1). If transitioning from starting dosage to a maintenance dosage regimen, administer the first maintenance dose two weeks after the last starting dose.

    Table 1: Starting and Maintenance Dosage Regimens

    Route of Administration	Dose	Frequency	Infusion Rate (if Intravenous)
    Starting Dosage
    Intravenous Only (LEQEMBI)	10 mg/kg	Once every 2 weeks	Over approximately one hour
    Maintenance Dosage
    Intravenous (LEQEMBI)	10 mg/kg	Once every 4 weeks	Over approximately one hour
    Subcutaneous (LEQEMBI IQLIK)	360 mg	Once every week	------------------------

    For intravenous infusion, use LEQEMBI vials. LEQEMBI vials must be diluted before administration

    [see Dosage and Administration (

    2.5

    )].

    For subcutaneous administration, use LEQEMBI IQLIK

    [see Dosage and Administration (

    2.6

    )].
    ,
    2.5

    Preparation and Administration of LEQEMBI for Intravenous Infusion

    Dilution

    • Prior to intravenous administration, LEQEMBI must be diluted in 250 mL of 0.9% Sodium Chloride Injection, USP.
      
      
    • Use aseptic technique when preparing the LEQEMBI diluted solution for intravenous infusion.
      
      
    • Calculate the dose (mg), the total volume (mL) of LEQEMBI solution required, and the number of vials needed based on the patient’s actual body weight and the recommended dose of 10 mg/kg. Each vial contains a LEQEMBI concentration of 100 mg/mL.
      
      
    • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Check that the LEQEMBI solution is clear to opalescent and colorless to pale yellow. Do not use if opaque particles, discoloration, or other foreign particles are present.
      
      
    • Remove the flip-off cap from the vial. Insert the sterile syringe needle into the vial through the center of the rubber stopper.
      
      
    • Withdraw the required volume of LEQEMBI from the vial(s) and add to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP.
      
      
    • Each vial is for one-time use only. Discard any unused portion.
      
      
    • Gently invert the infusion bag containing the LEQEMBI diluted solution to mix completely. Do not shake.
      
      
    • After dilution, immediate use is recommended
      [see Description (
      11
      )]
      . If not administered immediately, store LEQEMBI refrigerated at 2°C to 8°C (36°F to 46°F) for up to 4 hours, or at room temperature up to 30°C (86°F) for up to 4 hours. Do not freeze.

    Administration

    • Visually inspect the LEQEMBI diluted solution for particles or discoloration prior to administration. Do not use if it is discolored, opaque, or foreign particles are seen.

    • Prior to infusion, allow the LEQEMBI diluted solution to warm to room temperature.

    • Infuse the entire volume of the LEQEMBI diluted solution intravenously over approximately one hour through an intravenous line containing a terminal low-protein binding 0.2 micron in-line filter. Flush infusion line to ensure all LEQEMBI is administered.

    • Monitor for any signs or symptoms of an infusion-related reaction during the infusion and consider longer periods of observation if clinically indicated. 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, non-steroidal anti-inflammatory drugs, or corticosteroids

    [see Warnings and Precautions (

    5.3

    )].
    )
    
    
  • Subcutaneous injection: 360 mg administered once a week using the LEQEMBI IQLIK autoinjector (
    2.2

    Recommended Dosage

    Initiate LEQEMBI as an intravenous infusion using the starting dosage (see Table 1). After 18 months, the starting dosage may be continued or a transition to maintenance dosage regimen may be considered, which can be administered by either intravenous infusion or subcutaneous injection (see Table 1). If transitioning from starting dosage to a maintenance dosage regimen, administer the first maintenance dose two weeks after the last starting dose.

    Table 1: Starting and Maintenance Dosage Regimens

    Route of Administration	Dose	Frequency	Infusion Rate (if Intravenous)
    Starting Dosage
    Intravenous Only (LEQEMBI)	10 mg/kg	Once every 2 weeks	Over approximately one hour
    Maintenance Dosage
    Intravenous (LEQEMBI)	10 mg/kg	Once every 4 weeks	Over approximately one hour
    Subcutaneous (LEQEMBI IQLIK)	360 mg	Once every week	------------------------

    For intravenous infusion, use LEQEMBI vials. LEQEMBI vials must be diluted before administration

    [see Dosage and Administration (

    2.5

    )].

    For subcutaneous administration, use LEQEMBI IQLIK

    [see Dosage and Administration (

    2.6

    )].
    ,
    2.6

    Preparation and Administration of LEQEMBI IQLIK for Subcutaneous Injection

    Instruct patients and/or caregivers on the proper subcutaneous administration of LEQEMBI IQLIK. Direct patients and/or caregivers to follow the directions provided in the Instructions for Use for additional details on administration

    [see

    Instructions for Use

    ].

    Periodically reassess the ability of the patient or caregiver to safely and adequately administer LEQEMBI IQLIK.

    • Before injection, remove LEQEMBI IQLIK from the refrigerator and leave at room temperature for 20 minutes. Do not use an external heat source to heat LEQEMBI IQLIK because heat may damage the product.

    • Do not shake LEQEMBI IQLIK.

    • Visually inspect LEQEMBI IQLIK for particles or discoloration prior to administration. The solution should be a clear to opalescent, colorless to pale yellow solution, and free of visible particles. Do not use LEQEMBI IQLIK if it is cloudy or there are visible particles.

    • Do not use LEQEMBI IQLIK if it looks damaged or has been dropped.

    • Sites for injection include the abdomen, upper thigh, and back of the upper arm.

    • Do not inject into moles, scars, bruises, tattoos or into areas where the skin is red, hard, tender or injured.

    • Monitor for signs or symptoms of an injection reaction.
    ).
  
  
  
• See Full Prescribing Information for preparation and administration instructions. (
  2.5

  Preparation and Administration of LEQEMBI for Intravenous Infusion

  Dilution

  • Prior to intravenous administration, LEQEMBI must be diluted in 250 mL of 0.9% Sodium Chloride Injection, USP.
    
    
  • Use aseptic technique when preparing the LEQEMBI diluted solution for intravenous infusion.
    
    
  • Calculate the dose (mg), the total volume (mL) of LEQEMBI solution required, and the number of vials needed based on the patient’s actual body weight and the recommended dose of 10 mg/kg. Each vial contains a LEQEMBI concentration of 100 mg/mL.
    
    
  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Check that the LEQEMBI solution is clear to opalescent and colorless to pale yellow. Do not use if opaque particles, discoloration, or other foreign particles are present.
    
    
  • Remove the flip-off cap from the vial. Insert the sterile syringe needle into the vial through the center of the rubber stopper.
    
    
  • Withdraw the required volume of LEQEMBI from the vial(s) and add to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP.
    
    
  • Each vial is for one-time use only. Discard any unused portion.
    
    
  • Gently invert the infusion bag containing the LEQEMBI diluted solution to mix completely. Do not shake.
    
    
  • After dilution, immediate use is recommended
    [see Description (
    11
    )]
    . If not administered immediately, store LEQEMBI refrigerated at 2°C to 8°C (36°F to 46°F) for up to 4 hours, or at room temperature up to 30°C (86°F) for up to 4 hours. Do not freeze.

  Administration

  • Visually inspect the LEQEMBI diluted solution for particles or discoloration prior to administration. Do not use if it is discolored, opaque, or foreign particles are seen.

  • Prior to infusion, allow the LEQEMBI diluted solution to warm to room temperature.

  • Infuse the entire volume of the LEQEMBI diluted solution intravenously over approximately one hour through an intravenous line containing a terminal low-protein binding 0.2 micron in-line filter. Flush infusion line to ensure all LEQEMBI is administered.

  • Monitor for any signs or symptoms of an infusion-related reaction during the infusion and consider longer periods of observation if clinically indicated. 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, non-steroidal anti-inflammatory drugs, or corticosteroids

  [see Warnings and Precautions (

  5.3

  )].
  ,
  2.6

  Preparation and Administration of LEQEMBI IQLIK for Subcutaneous Injection

  Instruct patients and/or caregivers on the proper subcutaneous administration of LEQEMBI IQLIK. Direct patients and/or caregivers to follow the directions provided in the Instructions for Use for additional details on administration

  [see

  Instructions for Use

  ].

  Periodically reassess the ability of the patient or caregiver to safely and adequately administer LEQEMBI IQLIK.

  • Before injection, remove LEQEMBI IQLIK from the refrigerator and leave at room temperature for 20 minutes. Do not use an external heat source to heat LEQEMBI IQLIK because heat may damage the product.

  • Do not shake LEQEMBI IQLIK.

  • Visually inspect LEQEMBI IQLIK for particles or discoloration prior to administration. The solution should be a clear to opalescent, colorless to pale yellow solution, and free of visible particles. Do not use LEQEMBI IQLIK if it is cloudy or there are visible particles.

  • Do not use LEQEMBI IQLIK if it looks damaged or has been dropped.

  • Sites for injection include the abdomen, upper thigh, and back of the upper arm.

  • Do not inject into moles, scars, bruises, tattoos or into areas where the skin is red, hard, tender or injured.

  • Monitor for signs or symptoms of an injection reaction.
  )

Lecanemab-irmb is a clear to opalescent and colorless to pale yellow solution, available as:

• Injection: 500 mg/5 mL (100 mg/mL) in a single-dose vial
  
  
• Injection: 200 mg/2 mL (100 mg/mL) in a single-dose vial

• Injection: 360 mg/1.8 mL (200 mg/mL) in a single-dose prefilled autoinjector

There are no adequate data on LEQEMBI use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. No animal studies have been conducted to assess the potential reproductive or developmental toxicity of LEQEMBI.

In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.