Aducanumab is an intravenously-administered amyloid beta-directed antibody indicated for the treatment of adults with Alzheimer's disease. It is approved under the FDA's accelerated Approval Program which provides patients suffering from a serious disease earlier access to drugs when there is an expectation of clinical benefit as measured by a surrogate endpoint despite some uncertainty about the overall clinical benefit of the drug. In the case of aducanumab, the surrogate endpoint that allowed for accelerated approval in June 2021 was a reduction of amyloid beta plaque in treated patients. The efficacy of aducanumab was evaluated in two Phase 3 clinical trials (ENGAGE and EMERGE) and one dose-ranging Phase 1b study (PRIME). In these studies, aducanumab consistently showed a dose- and time-dependent effect on the lowering of amyloid beta plaques by 59% (p is less than 0.0001 in ENGAGE), 71% (p less than 0.0001 in EMERGE), and 61% (p less than 0.0001 in PRIME). Clinical trials were conducted primarily in patients with early-stage Alzheimer's disease. Continued approval for this indication is contingent upon verification of clinical benefit (e.g., slowed disease progression) in confirmatory trial(s). Treatment with aducanumab 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. Safety issues include a risk for serious hypersensitivity reactions and a warning for amyloid-related imaging abnormalities (ARIA), which most commonly present as temporary swelling in areas of the brain that usually resolves over time and does not cause symptoms, though some people may have symptoms such as headache, confusion, dizziness, vision changes, or nausea. The Alzheimer's Network for Treatment and Diagnostics (ALZ-NET) is a voluntary provider-enrolled patient registry that collects information on treatments for Alzheimer's disease, including aducanumab. Providers may obtain information about the registry at www.alz-net.org or contact [email protected].
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Prior to dilution, the injection is a clear to opalescent, and colorless to yellow solution.
-Missed dose: If an infusion is missed, resume administration at the same dose as soon as possible. Infusions are to be administered every 4 weeks and at least 21 days apart.
Intravenous Administration
Preparation of IV infusion
-Use aseptic technique when preparing. The injection solution must be further diluted in 100 mL of 0.9% sodium chloride injection to prepare the infusion prior to administration.
-Calculate the dose and total volume of aducanumab solution required, and the number of vials needed based on the patient's actual body weight. Each vial of injection solution contains an aducanumab concentration of 100 mg/mL.
-Withdraw the required volume of aducanumab from the vial(s) and add to an infusion bag of 100 mL of 0.9% Sodium Chloride Injection. Do not use any other intravenous diluents to prepare the aducanumab infusion.
-Each vial is for single-use only and is preservative-free. Discard any unused portion.
-Gently invert the infusion bag containing the aducanumab diluted solution to mix completely; do NOT shake.
-Storage: After dilution, immediate use is recommended. If not administered immediately, store the diluted solution in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F) for up to 3 days, or at room temperature up to 30 degrees C (86 degrees F) for up to 12 hours. Do not freeze.
IV infusion Administration
-Prior to infusion, allow the diluted infusion solution to warm to room temperature. Inspect the infusion prior to administration. Do not use the diluted infusion if it is discolored, or opaque or foreign particles are seen. Do NOT shake.
-Infuse diluted solution intravenously over approximately 1 hour through a dedicated IV line containing a sterile, low-protein binding, 0.2 or 0.22 micron in-line filter.
-Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity-type reaction.
Hypersensitivity reactions, including angioedema and urticaria were reported in 1 patient treated with aducanumab in the placebo-controlled clinical trial. Discontinue the infusion of aducanumab upon the initial observation of any signs or symptoms consistent with hypersensitivity reactions, and initiate the appropriate course of therapy.
In 2 placebo-controlled studies in patients with Alzheimer's disease, a total of 1,105 patients received aducanumab 10 mg/kg. Of the patients that received aducanumab, 21% reported headache (including migraine) vs. 16% of those receiving placebo.
Diarrhea and infectious diarrhea were reported in approximately 9% of patients receiving 10mg/kg of aducanumab vs. 7% of patients receiving placebo during the preapproval clinical trial.
Adverse reactions including states of confusion, delirium, altered mental status, and disorientation were reported in 8% of patients receiving 10 mg/kg of aducanumab vs. 4% of patients receiving placebo during the preapproval clinical trial. Fall was reported in 15% of patients receiving aducanumab vs. 12% of patients receiving placebo.
Aducanumab can cause amyloid-related imaging abnormalities-edema (ARIA-E), which can be observed on imaging studies as brain cerebral edema or sulcal effusions, and amyloid-related imaging abnormalities-hemosiderin deposition (ARIA-H), which includes microhemorrhage (small areas of intracranial bleeding) (19% vs. 7% placebo) and superficial siderosis (hemosiderosis) (15% vs. 2% placebo). Including asymptomatic radiographic events, ARIA (-E and/or -H) was observed in 41% of patients treated with 10 mg/kg of aducanumab (454 out of 1,105) compared to 10% of patients on placebo (111 out of 1,087) in clinical trials. Symptomatic ARIA occurred in 10% (110 out of 1,105) of patients treated with aducanumab. ARIA-E was observed in 35% of patients treated with aducanumab 10 mg/kg, compared to 3% of patients on placebo. 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. Among patients treated with aducanumab who had ARIA-E, the maximum radiographic severity was mild in 10% (115 out of 1,105), moderate in 20% (223 out of 1,105), and severe in 4% of patients (49 out of 1,105). Resolution on MRI occurred in 68% of ARIA-E patients by 12 weeks, 91% by 20 weeks, and 98% overall after detection. ARIA-H was observed in 28% (312 out of 1,105) of patients treated with aducanumab compared to 9% (94 out of 1,087) of patients on placebo. There was no increase in isolated ARIA-H (ARIA-H in patients who did not also experience ARIA-E) for aducanumab compared to placebo. The maximum radiographic severity of ARIA-H microhemorrhage in patients treated with aducanumab was mild in 14% (154 out of 1,105), moderate in 3% (29 out of 1,105), and severe in 3% (29 out of 1,105) of patients. The maximum radiographic severity of ARIA-H superficial siderosis (hemosiderosis) in patients treated with aducanumab was mild in 7% (79 out of 1,105), moderate in 4% (47 out of 1,105), and severe in 3% (36 out of 1,105) of patients. The risk of severe radiographic ARIA-E or ARIA-H is also related to apolipoprotein Eepsilon4 (ApoEepsilon4) genetic status. Among patients treated with aducanumab, the incidence of severe radiographic ARIA-E was highest in ApoEepsilon4 homozygotes (11%; 20/182) compared to heterozygotes (4%; 21/564) or noncarriers (2%; 8/357). The incidence of severe radiographic ARIA-H (microhemorrhage or superficial siderosis) was also highest in ApoEepsilon4 homozygotes (20%; 36/182), compared to heterozygotes (4%; 21/564) or noncarriers (2%; 6/357). Intracerebral hemorrhage greater than 1 cm in diameter was reported in 0.5% (6 out of 1,105) of patients after treatment with aducanumab 10 mg/kg and 0.4% (4 out of 1,087) of patients on placebo. Events of intracerebral hemorrhage, including fatal events, have been reported in patients taking monoclonal antibodies directed at amyloid beta, including aducanumab. During clinical trials, the most common symptoms associated with ARIA included headache, confusion, visual impairment, dizziness, nausea, and gait disturbance. 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 aducanumab. Seizures (including status epilepticus) have also been associated with ARIA. The overall incidence of seizure (independent of ARIA) in studies 1 and 2 was 0.5% in the aducanumab 10 mg/kg group and 0.8% in the placebo group. In patients with ARIA in the aducanumab 10 mg/kg group, the incidence of seizure was 0.7%. Status epilepticus was reported in the placebo-controlled and long-term extension studies in patients receiving aducanumab.
Aducanumab should not be used in any patient with a known aducanumab hypersensitivity or hypersensitivity to any inactive ingredients of the product. Use with caution in patients with known hamster protein hypersensitivity, as the product is expressed in a Chinese hamster ovary cell line. Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity reaction, and initiate appropriate therapy. Hypersensitivity reactions, including angioedema and urticaria, have been reported in one patient during the aducanumab infusion during clinical trials.
Monoclonal antibodies directed against aggregated forms of beta amyloid, including aducanumab, can cause amyloid-related imaging abnormalities (ARIA). These abnormalities may appear as ARIA with edema (ARIA-E), which can be observed on a brain magnetic resonance imaging (MRI) as cerebral edema or sulcal effusions. ARIA with hemosiderin deposition (ARIA-H), which includes microhemorrhage (small areas of intracranial bleeding) and superficial siderosis (hemosiderosis), may also occur. ARIA can occur spontaneously in patients with Alzheimer's disease. When ARIA-H is associated with monoclonal antibodies directed against aggregated forms of beta amyloid, it generally occurs in association with an occurrence of ARIA-E. ARIA typically 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 typically resolve over time. The risk of ARIA, including symptomatic and serious ARIA, is increased in apolipoprotein Eepsilon4 (ApoEepsilon4) homozygotes. Approximately 15% of Alzheimer's disease patients are ApoEepsilon4 homozygotes. In clinical studies that included patients with a known ApoEepsilon4 genotype, 17% (182/1103) were homozygotes, 51% (182/1103) were heterozygotes, and 32% (357/1103) were non carriers. The incidence of symptomatic ARIA was higher in the ApoEepsilon4 homozygotes (16%) than heterozygotes (11%) and noncarriers (5%). Radiographic changes also varied by genotype, with the incidence of severe radiographic ARIA-E highest in ApoEepsilon4 homozygotes (11%; 20/182) compared to heterozygotes (4%; 21/564) or noncarriers (2%; 8/357). Severe radiographic ARIA-H was also noted to be increased with ApoEepsilon4 homozygotes (20%; 36/182) when compared to heterozygotes (4%; 21/564) or noncarriers (2%; 6/357). 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 ApoEepsilon4 carriers and noncarriers (2% in homozygotes, 1% in heterozygotes, and 2% in noncarriers). The recommendations for management of ARIA do not differ between ApoEepsilon4 carriers and noncarriers. Testing for ApoEepsilon4 status should be performed prior to initiation of treatment to determine the risk of developing ARIA. Prior to testing, prescribers should discuss the risk of ARIA across genotypes and the implications of genetic testing results with patients and caregivers. Prescribers should also inform patients that they can still be treated with aducanumab if genotype testing is not performed; however, it cannot be determined if they are ApoEepsilon4 homozygotes and at a higher risk for ARIA. An FDA-authorized test for detection of ApoEepsilon4 alleles to identify patients at risk of ARIA if treated with aducanumab is not currently available. Available tests used to identify ApoEepsilon4 alleles may vary in accuracy and design. In addition to ARIA, intracerebral hemorrhages greater than 1 cm in diameter have occurred in patients treated with aducanumab. Fatal events of intracerebral hemorrhage in patients taking aducanumab have been observed. Consider the benefit of aducanumab for treatment of Alzheimer's disease and the potential risk of serious adverse events associated with ARIA when deciding to initiate treatment with aducanumab. In order to determine baseline status and monitor for ARIA, a recent (within 1 year) brain MRI should be obtained before initiating treatment with aducanumab. Perform follow-up MRIs prior to the 5th (first dose of 6 mg/kg), 7th (first dose of 10 mg/kg), 9th (third dose of 10 mg/kg), and 12th infusions (sixth dose of 10 mg/kg). Enhanced clinical vigilance for ARIA is recommended during the first 8 doses of treatment with aducanumab, particularly during titration, but monitor treated individuals throughout therapy. If ARIA occur, the severity of symptoms (if present) or severity of ARIA-E or -H may affect decisions to continue or suspend treatment. For patients experiencing moderate or severe symptoms of ARIA-E or moderate or severe severity of ARIA-E, suspend treatment until MRI demonstrates radiographic stabilization and symptoms (if present) resolve. Consider a follow-up MRI 2 to 4 months after initial identification to assess for resolution and use clinical judgment to guide resumption of dosing. For moderate severity of ARIA-H, or mild severity of ARIA-H with symptoms, suspend treatment until the MRI demonstrates radiographic resolution and symptoms (if present) resolve. These findings should also receive a follow-up MRI 2 to 4 months following initial identification to assess for resolution of ARIA. Likewise, suspend treatment in those who develop severe ARIA-H as shown on MRI until radiographic stabilization and symptoms (if present) resolve; use clinical judgement to decide to resume treatment or permanently discontinue aducanumab. There are no systematic data on continued dosing with aducanumab following detection of radiographically moderate or severe ARIA. In studies 1 and 2, temporary dose suspension was required for radiographically moderate or severe ARIA-E and radiographically moderate ARIA-H. In studies 1 and 2, permanent discontinuation of dosing was required for radiographically severe ARIA-H. The benefits of reaching and maintaining the 10 mg/kg dose should be considered when evaluating a potential dose suspension.
Patients taking antiplatelet or anticoagulant therapy (other than 325 mg or less of aspirin daily) were excluded from enrollment in clinical studies of aducanumab. However, some patients received aspirin in doses greater than 325 mg daily, other antiplatelet medications, or anticoagulant therapy during clinical trials due to medical events that occurred after enrollment and required treatment. The majority of exposures to antithrombotic medications were to aspirin; few patients were exposed to other antiplatelet or anticoagulant therapy, limiting meaningful conclusions about the risk of ARIA or intracerebral hemorrhage in patients taking these medications. For the limited number of patient experiences in the study, those who received aducanumab and an antithrombotic medication (such as aspirin, other antiplatelets, or anticoagulant therapy) did not have an increased risk of ARIA-H or intracerebral hemorrhage compared to patients who received placebo and an antithrombotic medication. Because intracerebral hemorrhages greater than 1 cm in diameter have been observed in patients taking aducanumab, additional caution should be used when considering the administration of antithrombotics or thrombolytic therapy (e.g., tissue plasminogen activator) to treated patients. Individuals were also excluded from aducanumab clinical studies for the findings on neuroimaging that indicated an increased risk for intracerebral hemorrhage, including findings suggestive of cerebral amyloid angiopathy (prior intracerebral hemorrhage greater than 1 cm in diameter, more than 4 microhemorrhages, superficial siderosis, and a history of diffuse white matter disease). Vasogenic edema could also be suggestive of cerebral amyloid angiopathy. These and other lesions (aneurysm, vascular malformation) could potentially increase the risk of intracerebral hemorrhage. The presence of an apolipoprotein Eepsilon4 allele is also associated with cerebral amyloid angiopathy which has an increased risk for intracerebral hemorrhage. Caution is advised when considering the use of aducanumab for patients with these risk factors and in particular for patients who need to be on anticoagulant therapy.
There are no adequate data on aducanumab use during pregnancy to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes; therefore, aducanumab should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. Intravenous administration of aducanumab to female rats through organogenesis, and throughout pregnancy and lactation had no adverse effects on embryofetal, and pre- or postnatal development, respectively. The relevance of these data to humans is limited because aggregated amyloid beta, the pharmacological target of aducanumab, is not present in the rat.
There are no data on the presence of aducanumab in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Data from other monoclonal antibodies indicate low passage of these medications into human milk and limited systemic exposure in the breastfed infant. The effects of this exposure are unknown, so the developmental and health benefits of breast-feeding should be considered along with the clinical need for aducanumab and any potential adverse effects on the breastfed infant or from the underlying condition of the lactating individual.
For the treatment of Alzheimer's disease:
NOTE: Initiate treatment in persons 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.
Intravenous dosage:
Adults: 1 mg/kg IV infusion every 4 weeks for 2 doses, then 3 mg/kg IV infusion every 4 weeks for 2 doses, then 6 mg/kg IV infusion every 4 weeks for 2 doses. At the 7th infusion and beyond: 10 mg/kg IV infusion every 4 weeks.
Therapeutic Drug Monitoring:
The presence of amyloid beta pathology should be confirmed prior to initiating treatment. Obtain recent (within 1 year) brain magnetic resonance imaging (MRI) prior to starting aducanumab. Obtain MRIs prior to the 5th, 7th, 9th, and 12th infusions to monitor for development of amyloid related imaging abnormalities -edema (ARIA-E) and -hemosiderin deposition (ARIA-H).
Dosing interruptions for patients with ARIA-E (based on clinical symptom severity and ARIA-E severity on MRI):
-Asymptomatic and mild ARIA-E on MRI: May continue dosing at current dose and schedule.
-Asymptomatic and moderate or severe ARIA-E on MRI: Suspend dosing until MRI demonstrates radiographic resolution and consider a follow-up MRI to assess for resolution 2 to 4 months after initial identification. Use clinical judgment to determine whether to resume aducanumab.
-Mild symptom severity and mild ARIA-E on MRI: May continue dosing based on clinical judgment.
-Moderate or severe symptoms (regardless of ARIA-E severity seen on MRI) or moderate or severe ARIA-E on MRI (regardless of symptoms): Suspend dosing 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. Use clinical judgment to determine whether to resume aducanumab.
Clinical symptom severity:
-Mild: noticeable discomfort, but no disruption in normal daily activity
-Moderate: discomfort is sufficient to reduce or affect normal daily activity
-Severe: incapacitating; inability to work or perform normal daily activity.
Dosing interruptions for patients with ARIA-H (based on clinical symptom severity and ARIA-H severity on MRI):
-Asymptomatic and mild ARIA-H on MRI: May continue dosing at current dose and schedule.
-Asymptomatic and moderate ARIA-H on MRI: Suspend dosing until MRI demonstrates radiographic stabilization; consider a follow-up MRI to assess for stabilization 2 to 4 months after initial identification. Use clinical judgment to determine whether to resume aducanumab.
-Symptomatic and mild or moderate ARIA-H on MRI: Suspend dosing until MRI demonstrates radiographic stabilization and symptoms, if present, resolve. Consider a follow-up MRI to assess for stabilization 2 to 4 months after initial identification. Use clinical judgment to determine whether to resume aducanumab.
-Severe ARIA-H on MRI (regardless of symptoms): Suspend dosing until MRI demonstrates radiographic stabilization and symptoms, if present, resolve. Use clinical judgment to determine whether to continue treatment or permanently discontinue aducanumab. During clinical studies, dosing was permanently discontinued in patients who developed intracerebral hemorrhage greater than 1 cm in diameter.
Maximum Dosage Limits:
-Adults
10 mg/kg/dose IV infusion for maintenance therapy.
-Geriatric
10 mg/kg/dose IV infusion for maintenance therapy.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No studies have been conducted in these patients; however, aducanumab is not expected to undergo metabolism by hepatic enzymes.
Patients with Renal Impairment Dosing
No studies have been conducted in these patients; however, aducanumab is not expected to undergo renal elimination.
*non-FDA-approved indication
There are no drug interactions associated with Aducanumab products.
The accumulation of amyloid beta plaques in the brain is a defining pathophysiological feature of Alzheimer's disease. Aducanumab is a human, immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. The drug reduces amyloid beta plaques by selectively binding to aggregated forms of beta amyloid protein such as amyloid beta fibrils and soluble oligomers. Aducanumab targets these aggregated forms of amyloid beta with high affinity and specificity and recognizes amyloid plaques in brain tissue.
Aducanumab is administered intravenously. The mean volume of distribution at steady-state is 9.63 L (95% CI, 9.48 to 9.79 L). Aducanumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. Aducanumab clearance is 0.0159 L/hour (95% CI, 0.0156 to 0.0161 L/hour). The terminal half-life is 24.8 days (95% CI, 14.8 to 37.9 days).
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: None
-Route-Specific Pharmacokinetics
Intravenous Route
Steady-state concentrations of aducanumab were reached by 16 weeks of repeated IV infusion dosing with an every 4-week regimen, and the systemic accumulation was 1.7-fold. The peak concentration (Cmax), trough concentration (Cmin), and area under the plasma concentration versus time curve at steady state (AUCss) of aducanumab increased dose proportionally in the dose range of 1 to 10 mg/kg IV infusion every 4 weeks.
-Special Populations
Hepatic Impairment
No studies were conducted to evaluate the pharmacokinetics of aducanumab in patients with hepatic impairment. Aducanumab is not expected to undergo metabolism by hepatic enzymes.
Renal Impairment
No studies were conducted to evaluate the pharmacokinetics of aducanumab in patients with renal impairment. Aducanumab is not expected to undergo renal elimination.
Geriatric
Age was found to impact exposure to aducanumab; however, it was not found to be clinically significant.
Gender Differences
Sex was found to impact exposure to aducanumab; however, it was not found to be clinically significant.
Ethnic Differences
Race was found to impact exposure to aducanumab; however, it was not found to be clinically significant.
Obesity
Body weight was found to impact exposure to aducanumab; however, it was not found to be clinically significant.