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INDICATION

ADUHELM is indicated for the treatment of Alzheimer’s disease. Treatment with ADUHELM 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. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied. This indication is approved under accelerated approval based on reduction in amyloid beta plaques observed in patients treated with ADUHELM. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Amyloid Related Imaging Abnormalities

  • Monoclonal antibodies directed against aggregated forms of beta amyloid, including ADUHELM, 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-H can occur spontaneously in patients with Alzheimer’s disease. 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 is usually asymptomatic, although serious and life-threatening events, including seizure and status epilepticus, rarely can occur. Rarely, fatal events have occurred in the setting of ARIA. However, a causal relationship between ARIA and fatal outcomes has not been established. 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

Incidence of ARIA

  • Symptomatic ARIA occurred in 10% (110/1105) of patients treated with ADUHELM in Studies 1 and 2. Clinical symptoms associated with ARIA resolved in 88% of patients during the period of observation. Serious symptoms associated with ARIA were reported in 0.3% of patients treated with ADUHELM. Overall, recurrent episodes of ARIA-E were less frequently symptomatic (12%) compared with initial episodes of ARIA-E (25%)
  • Including asymptomatic radiographic events, ARIA was observed in 41% (454/1105) of patients treated with ADUHELM 10 mg/kg compared to 10% (111/1087) of patients on placebo in Studies 1 and 2. ARIA-E was observed in 35% (387/1105) of patients treated with ADUHELM 10 mg/kg compared with 3% (29/1087) of patients on placebo. ARIA-H was observed in 28% (312/1105) of patients treated with ADUHELM compared to 9% (94/1087) 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 ADUHELM compared to placebo
  • The overall incidence of seizure, independent of ARIA, was 0.5% in the 10 mg/kg ADUHELM group and 0.8% in the placebo group in Studies 1 and 2. In patients with ARIA in the 10 mg/kg ADUHELM group, the incidence of seizure was 0.7%. Status epilepticus was reported in the placebo-controlled and long-term extension studies in patients treated with ADUHELM
  • Intracerebral hemorrhage greater than 1 cm in diameter was reported in 0.5% (6/1105) of patients in Studies 1 and 2 after treatment with ADUHELM compared to 0.4% (4/1087) of patients on placebo. Events of intracerebral hemorrhage, including fatal events, have been reported in patients taking monoclonal antibodies directed at amyloid beta, including ADUHELM

ApoE ε4 Carrier Status and Risk of ARIA

  • In Studies 1 and 2, among patients with a known apolipoprotein E ε4 (ApoE ε4) genotype, 17% (182/1103) of patients in the ADUHELM group were ApoE ε4 homozygotes, 51% (564/1103) were heterozygotes, and 32% (357/1103) were noncarriers. The incidence of symptomatic ARIA was higher in ApoE ε4 homozygotes (16%) than in heterozygotes (11%) and noncarriers (5%) among patients treated with ADUHELM. However, the incidence of serious adverse reactions with ARIA-E, including risk of death, persistent or significant disability or incapacity, hospitalization, or other medically important event that may require intervention to prevent serious outcomes, was similar for ApoE ε4 carriers and noncarriers (2% in homozygotes, 1% in heterozygotes, 2% in noncarriers). The recommendations on management of ARIA do not differ between ApoE ε4 carriers and noncarriers. Consider testing for ApoE ε4 carrier status to inform the risk of developing ARIA when deciding to initiate treatment with ADUHELM

Radiographic Findings

  • The radiographic severity of ARIA associated with ADUHELM was classified by radiographic criteria. Mild ARIA-E: FLAIR hyperintensity confined to sulcus and or cortex/subcortical white matter in one location < 5 cm. Moderate ARIA-E: FLAIR hyperintensity 5 to 10 cm, or more than 1 site of involvement, each measuring < 10 cm. Severe ARIA-E: FLAIR hyperintensity measuring > 10 cm, often with significant subcortical white matter and/or sulcal involvement. One or more separate sites of involvement may be noted. Mild ARIA-H microhemorrhage: ≤ 4 new incident microhemorrhages. Moderate ARIA-H microhemorrhage: 5 to 9 new incident microhemorrhages. Severe ARIA-H microhemorrhage: 10 or more new incident microhemorrhages. Mild ARIA-H superficial siderosis: 1 focal area of superficial siderosis. Moderate ARIA-H superficial siderosis: 2 focal areas of superficial siderosis. Severe ARIA-H superficial siderosis: > 2 focal areas of superficial siderosis
  • The majority of ARIA-E radiographic events occurred early in treatment (within the first 8 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 ADUHELM was mild in 10% (115/1105) of patients, moderate in 20% (223/1105) of patients, and severe in 4% (49/1105) of patients. Resolution on MRI occurred in 68% of ARIA-E patients by 12 weeks, 91% by 20 weeks, and 98% overall after detection. The maximum radiographic severity of ARIA-H microhemorrhage in patients treated with ADUHELM was mild in 14% (154/1105) of patients, moderate in 3% (29/1105) of patients, and severe in 3% (29/1105) patients. The maximum radiographic severity of ARIA-H superficial siderosis in patients treated with ADUHELM was mild in 7% (79/1105) of patients, moderate in 4% (47/1105) of patients, and severe in 3% (36/1105) of patients

Concomitant Antithrombotic Medication and Other Risk Factors for Intracerebral Hemorrhage

  • Patients who received ADUHELM and an antithrombotic medication (aspirin, other antiplatelets, or anticoagulants) did not have an increased risk of ARIA-H or intracerebral hemorrhage compared to patients who received placebo and an antithrombotic medication. The majority of exposures to antithrombotic medications were to aspirin; few patients were exposed to other antiplatelet drugs or anticoagulants, limiting any meaningful conclusions about the risk of ARIA or intracerebral hemorrhage in patients taking other antiplatelet drugs or anticoagulants. Intracerebral hemorrhages greater than 1 cm in diameter have been observed in patients taking ADUHELM. 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 ADUHELM
  • Additionally, patients were excluded from enrollment in Studies 1 and 2 for the following risk factors for intracerebral hemorrhage: prior intracerebral hemorrhage greater than 1 cm in diameter, more than 4 microhemorrhages, superficial siderosis, and history of diffuse white matter disease. Caution should be exercised when considering the use of ADUHELM in patients with these risk factors

Monitoring and Dose Management Guidelines

  • Recommendations for dosing in patients with ARIA-E depend on clinical symptoms and radiographic severity. Recommendations for dosing in patients with ARIA-H depend on the type of ARIA-H and radiographic severity. 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. Enhanced clinical vigilance for ARIA is recommended during the first 8 doses of treatment with ADUHELM, particularly during titration. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including MRI testing if indicated. If ARIA is observed on MRI, careful clinical evaluation should be performed prior to continuing treatment
  • There is limited experience in patients who continued dosing through symptomatic ARIA-E or through asymptomatic moderate or severe ARIA-E. There are limited data in dosing patients who experienced recurrent ARIA-E

Hypersensitivity Reactions

  • Angioedema and urticaria were reported in one patient in the placebo-controlled period of Studies 1 and 2, and occurred during the ADUHELM infusion. Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity reaction, and initiate appropriate therapy

ADVERSE REACTIONS

  • In the combined placebo-controlled and long-term extension periods, 5% (66 out of 1386) of patients in the 10 mg/kg dose group withdrew from the study because of an adverse reaction. The most common adverse reaction resulting in study withdrawal in the combined placebo-controlled and long-term extension periods was ARIA-H superficial siderosis
  • The most common adverse reactions reported in at least 2% of patients treated with ADUHELM 10 mg/kg and at least 2% more frequently than in patients on placebo in Studies 1 and 2 were ARIA-E, headache, ARIA-H microhemorrhage, ARIA-H superficial siderosis, fall, diarrhea, and confusion/delirium/altered mental status/disorientation

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