Version May 2024
Monoclonal antibodies directed against aggregated forms of beta amyloid, including aducanumab, can cause amyloid related imaging abnormalities (ARIA), characterized as ARIA with edema (ARIA-E) and ARIA with hemosiderin deposition (ARIA-H). Incidence and timing of ARIA vary among treatments. ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events rarely can occur. Serious intracerebral hemorrhages, some of which have been fatal, have been observed in patients treated with this class of medications.
Patients who are apolipoprotein E ε4 (ApoE ε4) homozygotes (~15% of Alzheimer disease patients) treated with this class of medications, including aducanumab, have a higher incidence of ARIA, including symptomatic, serious, and severe radiographic ARIA, compared to heterozygotes and noncarriers. 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 aducanumab; however, it cannot be determined if they are ApoE ε4 homozygotes and at higher risk for ARIA.
Consider the benefit of aducanumab for the treatment of Alzheimer disease and potential risk of serious adverse events associated with ARIA when deciding to initiate treatment with aducanumab.
Note: Confirm the presence of amyloid beta pathology prior to treatment initiation.
Alzheimer disease: IV: Initial: Dosing based on actual body weight: 1 mg/kg once every 4 weeks for infusions 1 and 2; 3 mg/kg once every 4 weeks for infusions 3 and 4; 6 mg/kg once every 4 weeks for infusions 5 and 6; maintenance dose: 10 mg/kg once every 4 weeks starting with infusion 7. Administer infusions at least 21 days apart.
Missed dose: Administer as soon as possible and at least 21 days apart.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, aducanumab is not expected to undergo renal elimination.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, aducanumab is not expected to undergo hepatic metabolism.
|
Severity of clinical symptoms |
ARIA-E severity on MRI | ||
|---|---|---|---|
|
Mild |
Moderate |
Severe | |
|
Asymptomatic |
Continue current aducanumab dose and schedule. |
Withhold aducanumab until MRI shows radiographic resolution and symptoms (if present) resolve; consider follow-up MRI to assess for resolution 2 to 4 months after initial identification. May resume at same dose and titration prior to withholding therapy, as guided by clinical judgement. |
Withhold aducanumab until MRI shows radiographic resolution and symptoms (if present) resolve; consider follow-up MRI to assess for resolution 2 to 4 months after initial identification. May resume at same dose and titration prior to withholding therapy, as guided by clinical judgement. |
|
Mild |
Continue aducanumab dosing based on clinical judgement. |
Withhold aducanumab until MRI shows radiographic resolution and symptoms (if present) resolve; consider follow-up MRI to assess for resolution 2 to 4 months after initial identification. May resume at same dose and titration prior to withholding therapy, as guided by clinical judgement. |
Withhold aducanumab until MRI shows radiographic resolution and symptoms (if present) resolve; consider follow-up MRI to assess for resolution 2 to 4 months after initial identification. May resume at same dose and titration prior to withholding therapy, as guided by clinical judgement. |
|
Moderate or severe |
Withhold aducanumab until MRI shows radiographic resolution and symptoms (if present) resolve; consider follow-up MRI to assess for resolution 2 to 4 months after initial identification. May resume at same dose and titration prior to withholding therapy, as guided by clinical judgement. |
Withhold aducanumab until MRI shows radiographic resolution and symptoms (if present) resolve; consider follow-up MRI to assess for resolution 2 to 4 months after initial identification. May resume at same dose and titration prior to withholding therapy, as guided by clinical judgement. |
Withhold aducanumab until MRI shows radiographic resolution and symptoms (if present) resolve; consider follow-up MRI to assess for resolution 2 to 4 months after initial identification. May resume at same dose and titration prior to withholding therapy, as guided by clinical judgement. |
|
Clinical symptom severity |
ARIA-H severity on MRI | ||
|---|---|---|---|
|
Mild |
Moderate |
Severe | |
|
Asymptomatic |
Continue current aducanumab dose and schedule. |
Withhold aducanumab until MRI shows radiographic stabilization and symptoms (if present) resolve; consider follow-up MRI to assess for resolution 2 to 4 months after initial identification. May resume at same dose and titration prior to withholding therapy, as guided by clinical judgement. |
Withhold aducanumab until MRI shows radiographic stabilization and symptoms (if present) resolve. Use clinical judgement to determine whether to continue treatment or permanently discontinue aducanumab. |
|
Symptomatic |
Withhold aducanumab until MRI shows radiographic stabilization and symptoms (if present) resolve; consider follow-up MRI to assess for resolution 2 to 4 months after initial identification. May resume at same dose and titration prior to withholding therapy, as guided by clinical judgement. |
Withhold aducanumab until MRI shows radiographic stabilization and symptoms (if present) resolve; consider follow-up MRI to assess for resolution 2 to 4 months after initial identification. May resume dose at same and titration prior to withholding therapy, as guided by clinical judgement. |
Withhold aducanumab until MRI shows radiographic stabilization and symptoms (if present) resolve. Use clinical judgement to determine whether to continue treatment or permanently discontinue aducanumab. |
Intracerebral hemorrhage >1 cm in diameter: Withhold aducanumab until MRI shows radiographic stabilization and symptoms (if present) resolve. Use clinical judgement to determine whether to continue treatment or permanently discontinue aducanumab; in some studies, aducanumab was permanently discontinued in patients who developed intracerebral hemorrhage >1 cm in diameter (Ref).
Refer to adult dosing.
Amyloid-related imaging abnormalities (ARIA), including ARIA consistent with vasogenic edema and/or sulcal effusions (ARIA-E) (Ref) and ARIA with hemosiderin deposition (ARIA-H) characterized by superficial siderosis and microhemorrhages (Ref) have been reported with aducanumab therapy. Patients may develop ARIA-H with concomitant ARIA-E. In patients who developed ARIA (-E and/or -H) during aducanumab clinical trials, most cases were asymptomatic with mild to moderate radiographic severity; however, serious and/or fatal symptoms have been reported. Recurrent episodes have also been described and were less symptomatic than initial episodes. Clinical symptoms suggesting ARIA (-E and/or -H) may include altered mental status, abnormal gait, confusion, delirium, disorientation, dizziness, focal neurologic deficits, headache, nausea, seizure, and visual disturbance. Resolution of ARIA (-E and/or -H) occurred within 12 to 20 weeks in the majority of cases in clinical trials.
Mechanism: Not clearly established; speculated that increased clearance of amyloid from parenchymal plaques into perivascular space may result in excess fluid shifts. This movement of amyloid into cerebral vessel walls may also increase vascular friability and permeability, thus impairing vessel wall integrity to permit small amounts of blood passage. Increased vascular permeability at which both fluid and red blood cells cross the vessel wall may suggest a common pathophysiologic mechanism for both ARIA-E and ARIA-H (Ref).
ARIA-E: Dose-related; related to the pharmacologic action. Increased cerebrovascular permeability due to antibody binding to deposited amyloid-beta results in an increase in extracellular fluid volume and vasogenic edema (Ref).
ARIA-H: Dose-related; related to the pharmacologic action. Leakage of blood from a vessel into adjacent tissue parenchyma or subarachnoid space/periadvential compartments leaves residual deposits of iron in the form of hemosiderin, resulting in superficial siderosis and/or radiographic evidence of hemorrhage (Ref).
Onset: Varied; ARIA may occur at any time during treatment, but most events occur within the first 8 doses.
Risk factors:
ARIA-E:
• Apolipoprotein E ε4 carriers; specifically ApoE ε4 homozygotes (Ref)
• Dose; risk increases with higher doses (Ref) and during dose titration (Ref)
ARIA-H: Microhemorrhages:
• Apolipoprotein E ε4 carriers; specifically ApoE ε4 homozygotes (Ref)
• Increasing age (Ref)
• Greater number of microhemorrhages at baseline (Ref)
• Older adults with cardiovascular risk factors and/or evidence of prior cerebrovascular event (Ref)
• Concomitant risk factors for intracerebral hemorrhages (prior cerebral hemorrhage >1 cm, >4 microhemorrhages, superficial siderosis, vasogenic edema, aneurysm, vascular malformation)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults. ARIA-E: amyloid related imaging abnormalities-edema; ARIA-H: amyloid related imaging abnormalities-hemosiderin deposition.
>10%:
Hematologic & oncologic: Hemosiderosis (ARIA-H, including microhemorrhages and superficial siderosis: 15% to 19%) (table 1)
|
Drug (Aducanumab) |
Placebo |
Number of Patients (Aducanumab) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|
|
19% |
7% |
1,105 |
1,087 |
ARIA-H microhemorrhage |
|
15% |
2% |
1,105 |
1,087 |
ARIA-H superficial siderosis |
Nervous system: Brain edema (ARIA-E, including sulcal effusion: 20% to 64%; higher in apolipoprotein E ε4 carriers) (table 2), falling (15%), headache (21%) (table 3)
|
Drug (Aducanumab) |
Placebo |
Number of Patients (Aducanumab) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|
|
64% |
N/A |
N/A |
N/A |
ARIA-E; apolipoprotein E ε4 carriers; homozygotes |
|
35% |
3% |
1,105 |
1,087 |
ARIA-E; apolipoprotein E ε4 carriers; heterozygotes |
|
20% |
N/A |
N/A |
N/A |
ARIA-E; apolipoprotein E ε4 non-carriers |
|
Drug (Aducanumab) |
Placebo |
Number of Patients (Aducanumab) |
Number of Patients (Placebo) |
|---|---|---|---|
|
21% |
16% |
1,105 |
1,087 |
1% to 10%:
Gastrointestinal: Diarrhea (9%)
Nervous system: Altered mental status (≤8%) (table 4), confusion (≤8%) (table 5), delirium (≤8%) (table 6), disorientation (≤8%) (table 7)
|
Drug (Aducanumab) |
Placebo |
Number of Patients (Aducanumab) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|
|
≤8% |
≤4% |
1,105 |
1,087 |
Defined as "confusion, delirium, altered mental status, disorientation" |
|
Drug (Aducanumab) |
Placebo |
Number of Patients (Aducanumab) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|
|
≤8% |
≤4% |
1,105 |
1,087 |
Defined as "confusion, delirium, altered mental status, disorientation" |
|
Drug (Aducanumab) |
Placebo |
Number of Patients (Aducanumab) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|
|
≤8% |
≤4% |
1,105 |
1,087 |
Defined as "confusion, delirium, altered mental status, disorientation" |
|
Drug (Aducanumab) |
Placebo |
Number of Patients (Aducanumab) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|
|
≤8% |
≤4% |
1,105 |
1,087 |
Defined as "confusion, delirium, altered mental status, disorientation" |
<1%:
Dermatologic: Urticaria
Hypersensitivity: Angioedema
Immunologic: Antibody development
Nervous system: Seizure (associated with ARIA)
Postmarketing: Nervous system: Status epilepticus
There are no contraindications listed in the manufacturer's labeling.
Dosage form specific issues:
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
Other warning/precautions:
• Appropriate use: Confirm the presence of amyloid beta pathology prior to treatment initiation.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous [preservative free]:
Aduhelm: Aducanumab-avwa 300 mg/3 mL (3 mL); Aducanumab-avwa 170 mg/1.7 mL (1.7 mL) [contains polysorbate 80]
No
Solution (Aduhelm Intravenous)
170 mg/1.7 mL (per mL): $338.40
300 mg/3 mL (per mL): $338.40
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
IV: Dilution required prior to administration. Allow refrigerated infusion bags to warm to room temperature prior to administering. Administer by IV infusion over ~60 minutes through an IV line containing a sterile, low-protein binding, 0.2 or 0.22 micron in-line filter. Discard unused portion.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761178s011lbl.pdf#page=26, must be dispensed with this medication.
Alzheimer disease: Treatment of Alzheimer disease in patients with mild cognitive impairment or mild dementia stage of disease, with confirmed presence of amyloid beta pathology prior to treatment initiation.
Aducanumab may be confused with adalimumab.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Rozanolixizumab: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Adverse events were not observed in animal reproduction studies. The pharmacologic target of aducanumab (amyloid beta) is not present in rats, which may limit the relevance of animal data.
Aducanumab is a humanized monoclonal antibody (IgG1). Human IgG is known to cross the placenta; exposure is dependent upon the IgG subclass, maternal serum concentrations, newborn birth weight, and GA, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009).
It is not known if aducanumab is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
PET or lumbar puncture to confirm presence of amyloid beta pathology (prior to initiation); brain MRI (prior to initiation [within 1 year], prior to infusion 5 [first dose of 6 mg/kg], infusion 7 [first dose of 10 mg/kg], infusion 9 [third dose of 10 mg/kg], and infusion 12 [sixth dose of 10 mg/kg]); monitor closely for clinical and MRI changes; monitor for symptoms suggestive of amyloid-related imaging abnormalities (ARIA) (eg, headache, altered mental status, dizziness, visual disturbance, seizure, nausea); MRI as indicated if ARIA symptoms present or asymptomatic ARIA observed (Hameed 2020; manufacturer’s labeling).
Aducanumab is a monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. Aducanumab reduces amyloid beta plaques, the accumulation of which is a defining pathophysiological feature of Alzheimer disease.
Distribution: Vd: 9.63 L.
Metabolism: Degraded via catabolic pathways into small peptides and amino acids.
Half-life elimination: 24.8 days.
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