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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

ADUHELM can cause amyloid related imaging abnormalities-edema (ARIA-E), which can be observed on MRI as brain edema or sulcal effusions, and amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis. The safety of ADUHELM in patients with 10 or more brain microhemorrhages, any pre-treatment localized superficial siderosis, and/or with a brain hemorrhage greater than 1 cm within one year of treatment initiation has not been established
In clinical studies of ADUHELM, the severity of ARIA 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
In Studies 1 and 2, ARIA (-E and/or -H) was observed in 41% of patients treated with ADUHELM with a planned dose of 10 mg/kg (454 out of 1105), compared to 10% of patients on placebo (111 out of 1087)
ARIA-E was observed in 35% of patients treated with ADUHELM 10 mg/kg, compared to 3% of patients on placebo
In Studies 1 and 2, 16% of patients in the ADUHELM 10 mg/kg group were apolipoprotein E ε4 (ApoE ε4) homozygotes, 51% were heterozygotes, and 32% were noncarriers. In these studies, randomization was stratified by ApoE ε4 carrier status (i.e., carrier or noncarrier); therefore, interpretation of analyses by ApoE ε4 homozygous and heterozygous carrier status should consider the limitations of the unbalanced subgroups and the small number of homozygotes enrolled in the study. The incidence of ARIA-E was higher in ApoE ε4 carriers than in ApoE ε4 noncarriers (64% in homozygotes, 35% in heterozygotes, and 20% in noncarriers). Severe radiographic ARIA-E occurred in 11% of homozygotes, 4% of heterozygotes, and 2% of noncarriers. 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. Testing for ApoE ε4 carrier status may be considered when initiating treatment with ADUHELM to inform the risk of developing ARIA
The majority of ARIA-E radiographic events occurred early in treatment (within the first 8 doses), although ARIA can occur at any time. Among patients treated with a planned dose of ADUHELM 10 mg/kg who had ARIA-E, the maximum radiographic severity was mild in 30%, moderate in 58%, and severe in 13% of patients. Resolution occurred in 68% of ARIA-E patients by 12 weeks, 91% by 20 weeks, and 98% overall after detection. 10% of all patients who received ADUHELM 10 mg/kg had more than one episode of ARIA-E, and 1% had three or more episodes of ARIA-E
ARIA-H in the setting of ARIA-E associated with the use of ADUHELM 10 mg/kg was observed in 21% of patients treated with ADUHELM 10 mg/kg, compared to 1% of patients on placebo. There was no imbalance in isolated ARIA-H (i.e., ARIA-H in patients who did not also experience ARIA-E) between ADUHELM and placebo. Intracerebral hemorrhage greater than 1 cm in diameter was reported in 0.5% of patients after treatment with ADUHELM 10 mg/kg compared to 0.4% of patients on placebo
Clinical symptoms were present in 24% of patients treated with ADUHELM 10 mg/kg who had an observation of ARIA (-E and/or -H), compared to 5% of patients on placebo. The most common symptom in patients treated with ADUHELM 10 mg/kg with ARIA was headache (13%). Other frequent symptoms were confusion/delirium/altered mental status/disorientation (5%), dizziness/vertigo (4%), visual disturbance (2%), and nausea (2%). Serious symptoms associated with ARIA were reported in 0.3% of patients treated with ADUHELM 10 mg/kg. Overall, recurrent episodes of ARIA-E were less frequently symptomatic (12%) compared with initial episodes of ARIA-E (25%). Clinical symptoms associated with ARIA resolved in the majority of patients (88%) during the period of observation
Seizure, including status epilepticus, which can be serious and life-threatening, has been associated with ARIA. 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

Monitoring and Management

Monitoring for ARIA-E and ARIA-H
- Obtain recent (within one year) baseline brain magnetic resonance imaging (MRI) prior to initiating treatment
- Enhanced clinical vigilance for ARIA is recommended during the first 8 doses of treatment with ADUHELM, particularly during titration, as this is the time the majority of ARIA was observed in Studies 1 and 2. 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
- Obtain brain MRIs prior to the 5th infusion (first dose of 6 mg/kg), 7th infusion (first dose of 10 mg/kg), 9th infusion (third dose of 10 mg/kg), and 12th infusion (sixth dose of 10 mg/kg) of ADUHELM to evaluate for the presence of asymptomatic ARIA. For patients with radiographic findings of ARIA, enhanced clinical vigilance is recommended. Additional MRIs may be considered if clinically indicated
ARIA-E Management
- In Studies 1 and 2, dosing was suspended for symptomatic patients with ARIA-E of any severity and for asymptomatic patients with moderate or severe ARIA-E. There is limited experience in patients who continued dosing through symptomatic ARIA-E or through asymptomatic moderate or severe ARIA-E
- Recommendations for dosing in patients with ARIA-E are dependent on clinical symptoms and radiographic severity. There is limited data in dosing patients who experienced three or more episodes of ARIA-E. Use clinical judgment in considering whether to continue dosing in patients with recurrent ARIA-E (more than two episodes)
ARIA-H Management
- In Studies 1 and 2, dosing was suspended for symptomatic patients with ARIA-H of any severity and for asymptomatic patients with moderate or severe ARIA-H. Dosing was permanently discontinued for any severe ARIA-H
- Recommendations for dosing in patients with ARIA-H are dependent on the type of ARIA-H and radiographic severity

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
Immunogenicity: The immunogenicity of ADUHELM has been evaluated using an in vitro assay for the detection of binding anti-aducanumab avwa antibodies. In up to 41 months of treatment in the combined placebo-controlled and long-term extension periods of Studies 1 and 2, up to 0.6% (15/2689) of patients receiving ADUHELM once monthly developed anti-aducanumab-avwa antibodies. Based on the limited number of patients who tested positive for anti-aducanumab-avwa antibodies, no observations were made concerning a potential effect of neutralizing activity of anti-aducanumab-avwa antibodies on exposure or efficacy; however, the available data are too limited to make definitive conclusions regarding an effect on pharmacokinetics, safety, or efficacy of ADUHELM. Quantification of neutralizing anti-aducanumab-avwa antibodies has not been assessed

Please see full Prescribing Information.

INDICATION AND IMPORTANT
SAFETY INFORMATION

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

ADUHELM can cause amyloid related imaging abnormalities-edema (ARIA-E), which can be observed on MRI as brain edema or sulcal effusions, and amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis
Obtain recent (within one year) brain magnetic resonance imaging (MRI) prior to initiating treatment. The safety of ADUHELM in patients with any pre-treatment localized superficial siderosis, 10 or more brain microhemorrhages, and/or with a brain hemorrhage greater than 1 cm within one year of treatment initiation has not been established

INDICATION AND IMPORTANT
SAFETY INFORMATION

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

ADUHELM can cause amyloid related imaging abnormalities-edema (ARIA-E), which can be observed on MRI as brain edema or sulcal effusions, and amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis. The safety of ADUHELM in patients with 10 or more brain microhemorrhages, any pre-treatment localized superficial siderosis, and/or with a brain hemorrhage greater than 1 cm within one year of treatment initiation has not been established
In clinical studies of ADUHELM, the severity of ARIA 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
In Studies 1 and 2, ARIA (-E and/or -H) was observed in 41% of patients treated with ADUHELM with a planned dose of 10 mg/kg (454 out of 1105), compared to 10% of patients on placebo (111 out of 1087)
ARIA-E was observed in 35% of patients treated with ADUHELM 10 mg/kg, compared to 3% of patients on placebo
In Studies 1 and 2, 16% of patients in the ADUHELM 10 mg/kg group were apolipoprotein E ε4 (ApoE ε4) homozygotes, 51% were heterozygotes, and 32% were noncarriers. In these studies, randomization was stratified by ApoE ε4 carrier status (i.e., carrier or noncarrier); therefore, interpretation of analyses by ApoE ε4 homozygous and heterozygous carrier status should consider the limitations of the unbalanced subgroups and the small number of homozygotes enrolled in the study. The incidence of ARIA-E was higher in ApoE ε4 carriers than in ApoE ε4 noncarriers (64% in homozygotes, 35% in heterozygotes, and 20% in noncarriers). Severe radiographic ARIA-E occurred in 11% of homozygotes, 4% of heterozygotes, and 2% of noncarriers. 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. Testing for ApoE ε4 carrier status may be considered when initiating treatment with ADUHELM to inform the risk of developing ARIA
The majority of ARIA-E radiographic events occurred early in treatment (within the first 8 doses), although ARIA can occur at any time. Among patients treated with a planned dose of ADUHELM 10 mg/kg who had ARIA-E, the maximum radiographic severity was mild in 30%, moderate in 58%, and severe in 13% of patients. Resolution occurred in 68% of ARIA-E patients by 12 weeks, 91% by 20 weeks, and 98% overall after detection. 10% of all patients who received ADUHELM 10 mg/kg had more than one episode of ARIA-E, and 1% had three or more episodes of ARIA-E
ARIA-H in the setting of ARIA-E associated with the use of ADUHELM 10 mg/kg was observed in 21% of patients treated with ADUHELM 10 mg/kg, compared to 1% of patients on placebo. There was no imbalance in isolated ARIA-H (i.e., ARIA-H in patients who did not also experience ARIA-E) between ADUHELM and placebo. Intracerebral hemorrhage greater than 1 cm in diameter was reported in 0.5% of patients after treatment with ADUHELM 10 mg/kg compared to 0.4% of patients on placebo
Clinical symptoms were present in 24% of patients treated with ADUHELM 10 mg/kg who had an observation of ARIA (-E and/or -H), compared to 5% of patients on placebo. The most common symptom in patients treated with ADUHELM 10 mg/kg with ARIA was headache (13%). Other frequent symptoms were confusion/delirium/altered mental status/disorientation (5%), dizziness/vertigo (4%), visual disturbance (2%), and nausea (2%). Serious symptoms associated with ARIA were reported in 0.3% of patients treated with ADUHELM 10 mg/kg. Overall, recurrent episodes of ARIA-E were less frequently symptomatic (12%) compared with initial episodes of ARIA-E (25%). Clinical symptoms associated with ARIA resolved in the majority of patients (88%) during the period of observation
Seizure, including status epilepticus, which can be serious and life-threatening, has been associated with ARIA. 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

Monitoring and Management

Monitoring for ARIA-E and ARIA-H
- Obtain recent (within one year) baseline brain magnetic resonance imaging (MRI) prior to initiating treatment
- Enhanced clinical vigilance for ARIA is recommended during the first 8 doses of treatment with ADUHELM, particularly during titration, as this is the time the majority of ARIA was observed in Studies 1 and 2. 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
- Obtain brain MRIs prior to the 5th infusion (first dose of 6 mg/kg), 7th infusion (first dose of 10 mg/kg), 9th infusion (third dose of 10 mg/kg), and 12th infusion (sixth dose of 10 mg/kg) of ADUHELM to evaluate for the presence of asymptomatic ARIA. For patients with radiographic findings of ARIA, enhanced clinical vigilance is recommended. Additional MRIs may be considered if clinically indicated
ARIA-E Management
- In Studies 1 and 2, dosing was suspended for symptomatic patients with ARIA-E of any severity and for asymptomatic patients with moderate or severe ARIA-E. There is limited experience in patients who continued dosing through symptomatic ARIA-E or through asymptomatic moderate or severe ARIA-E
- Recommendations for dosing in patients with ARIA-E are dependent on clinical symptoms and radiographic severity. There is limited data in dosing patients who experienced three or more episodes of ARIA-E. Use clinical judgment in considering whether to continue dosing in patients with recurrent ARIA-E (more than two episodes)
ARIA-H Management
- In Studies 1 and 2, dosing was suspended for symptomatic patients with ARIA-H of any severity and for asymptomatic patients with moderate or severe ARIA-H. Dosing was permanently discontinued for any severe ARIA-H
- Recommendations for dosing in patients with ARIA-H are dependent on the type of ARIA-H and radiographic severity

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
Immunogenicity: The immunogenicity of ADUHELM has been evaluated using an in vitro assay for the detection of binding anti-aducanumab avwa antibodies. In up to 41 months of treatment in the combined placebo-controlled and long-term extension periods of Studies 1 and 2, up to 0.6% (15/2689) of patients receiving ADUHELM once monthly developed anti-aducanumab-avwa antibodies. Based on the limited number of patients who tested positive for anti-aducanumab-avwa antibodies, no observations were made concerning a potential effect of neutralizing activity of anti-aducanumab-avwa antibodies on exposure or efficacy; however, the available data are too limited to make definitive conclusions regarding an effect on pharmacokinetics, safety, or efficacy of ADUHELM. Quantification of neutralizing anti-aducanumab-avwa antibodies has not been assessed

Please see full Prescribing Information.

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