Version July 2025
Monoclonal antibodies directed against aggregated forms of beta amyloid, including donanemab, 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 >1 cm, some of which have been fatal, have been observed in patients treated with this class of medications. 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 donanemab.
Patients who are apolipoprotein E ε4 (ApoE ε4) homozygotes (approximately 15% of Alzheimer's disease patients) treated with this class of medications, including donanemab, 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 donanemab; however, it cannot be determined if they are ApoE ε4 homozygotes and at higher risk for ARIA.
Consider the benefit of donanemab for the treatment of Alzheimer's disease and potential risk of serious adverse events associated with ARIA when deciding to initiate treatment with donanemab.
Dosage guidance:
Safety: Confirm the presence of amyloid beta pathology prior to treatment initiation. Consider testing for apolipoprotein E ε4 (ApoE ε4) status prior to treatment initiation.
Alzheimer disease:
Standard dosing: IV: Initial: 700 mg once every 4 weeks for 3 doses; then 1,400 mg once every 4 weeks until amyloid plaques are reduced to minimal levels on amyloid PET imaging (Ref).
Modified titration dosing: Based on preliminary data, a modified titration regimen may be associated with a reduced risk of amyloid-related imaging abnormalities (ARIA):
IV:
Week 0 (first dose): 350 mg once.
Week 4: 700 mg once.
Week 8: 1,050 mg once.
Week 12 and thereafter: 1,400 mg once every 4 weeks until amyloid plaques are reduced to minimal levels on amyloid PET imaging (Ref).
Missed dose: If an infusion is missed, administer the same dose as soon possible and continue every 4 weeks.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; however, donanemab is not expected to undergo renal elimination.
There are no dosage adjustments provided in the manufacturer's labeling; however, donanemab is not expected to undergo hepatic metabolism.
|
Clinical symptom severity |
ARIA-E severity on MRI | ||
|---|---|---|---|
|
Mild |
Moderate |
Severe | |
|
Asymptomatic |
May continue current dose and schedule. |
Withhold donanemab until MRI displays radiographic resolution; use clinical judgement with resumption of dosing. Consider an MRI 2 to 4 months after initial identification to evaluate for resolution. | |
|
Mild (eg, discomfort with no change of normal daily activity) |
May continue current dose and schedule. |
Withhold donanemab until MRI displays radiographic resolution and symptoms resolve; use clinical judgement with resumption of dosing. Consider an MRI 2 to 4 months after initial identification to evaluate for resolution. | |
|
Moderate or severe (eg, symptoms ranging from discomfort that reduces or changes normal daily activity to incapacitating and not able to work or perform normal daily activity) |
Withhold donanemab until MRI displays radiographic resolution and symptoms resolve; use clinical judgement with resumption of dosing. Consider an MRI 2 to 4 months after initial identification to evaluate for resolution. | ||
|
Clinical symptom severity |
ARIA-H severity on MRI | ||
|---|---|---|---|
|
Mild |
Moderate |
Severe | |
|
Asymptomatic |
May continue current dose and schedule. |
Withhold donanemab until MRI displays radiographic resolution; use clinical judgement with resumption of dosing. Consider an MRI 2 to 4 months after initial identification to evaluate for resolution. |
Withhold donanemab until MRI demonstrates radiographic stabilization; use clinical judgment when considering whether to continue or permanently discontinue therapy. |
|
Symptomatic |
Withhold donanemab until MRI displays radiographic resolution and symptoms resolve; use clinical judgement with resumption of dosing. Consider an MRI 2 to 4 months after initial identification to evaluate for resolution. |
Withhold donanemab until MRI demonstrates radiographic stabilization and symptoms resolve; use clinical judgment when considering whether to continue or permanently discontinue therapy. | |
Hypersensitivity reaction signs/symptoms (eg, angioedema, anaphylaxis): Promptly discontinue infusion at first sign/symptom of hypersensitivity and initiate appropriate treatment.
Intracerebral hemorrhage (>1 cm in diameter): Withhold donanemab until MRI displays radiographic stabilization and symptoms (if present) resolve; use clinical judgement with resumption of dosing.
Infusion reaction signs/symptoms (eg, chills, nausea, vomiting, difficulty breathing, BP changes) : Consider reducing rate of administration, discontinuing the infusion, and/or initiating supportive therapy as clinically appropriate. Consider premedication with antihistamines, acetaminophen, nonsteroidal anti-inflammatory drugs, or corticosteroids prior to future infusions.
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, microhemorrhages, and macrohemorrhages (Ref) have been reported with donanemab therapy. Patients may develop ARIA-H with concomitant ARIA-E. In patients who developed ARIA (-E and/or -H) during donanemab clinical trials, most cases were asymptomatic with mild to moderate radiographic severity; however, serious and/or fatal symptoms have been reported (Ref). Recurrent episodes of ARIA-E have also been described. Clinical symptoms suggesting ARIA may include abnormal gait, confusion, dizziness, focal neurologic deficits, headache, nausea, visual disturbance, and seizures. Resolution of ARIA-E occurred by 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/periadventitial 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 24 weeks.
Risk factors:
ARIA-E:
• Apolipoprotein E ε4 carriers; specifically ApoE ε4 homozygotes (Ref)()
• Dose; risk increases with higher doses (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, >1 area of superficial siderosis, severe white matter disease, vasogenic edema)
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, superficial siderosis: 15% to 25%; higher in apolipoprotein E ε4 carriers) (table 1)
|
Drug (Aducanumab) |
Placebo |
Number of Patients (Aducanumab) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|
|
25% |
11% |
853 |
874 |
ARIA-H microhemorrhage |
|
15% |
3% |
853 |
874 |
ARIA-H superficial siderosis |
Immunologic: Antibody development (87%; neutralizing: 100%)
Nervous system: Brain edema (ARIA-E: 24%; higher in apolipoprotein E ε4 carriers) (table 2), headache (13%) (table 3)
|
Drug (Aducanumab) |
Placebo |
Number of Patients (Aducanumab) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|
|
24% |
2% |
853 |
874 |
ARIA-E |
|
Drug (Aducanumab) |
Placebo |
Number of Patients (Aducanumab) |
Number of Patients (Placebo) |
|---|---|---|---|
|
13% |
10% |
853 |
874 |
1% to 10%: Hypersensitivity: Hypersensitivity reaction (3%; including anaphylaxis, angioedema), infusion-related reaction (9%)
<1% Genitourinary: Intestinal obstruction
Serious hypersensitivity (eg, anaphylaxis) to donanemab or any component of the formulation.
Concerns related to adverse effects:
• Infusion reaction: Donanemab may cause infusion reactions, typically during infusion or within 30 minutes after infusion. Symptoms include chills, erythema, nausea, vomiting, difficulty breathing, dyspnea, sweating, BP changes, headache, and chest pain. The highest incidence of infusion reactions occurs within the first 4 infusions.
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 (Ref). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Ref). See manufacturer's labeling.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous [preservative free]:
Kisunla: Donanemab-azbt 350 mg/20 mL (17.5 mg/mL) (20 mL) [contains polysorbate 80]
No
Solution (Kisunla Intravenous)
350 mg/20 mL (per mL): $41.74
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: For IV infusion. Prior to infusion, allow the diluted solution to warm to room temperature if stored under refrigeration. Infuse over 30 minutes and flush line with NS after infusion is complete. Observe for infusion and hypersensitivity reactions during infusion and for at least 30 minutes post infusion. Discontinue infusion if hypersensitivity reaction.
Alzheimer disease: Treatment of Alzheimer disease; to be initiated in patients with mild cognitive impairment or mild dementia stage of disease.
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 drug interactions program by clicking on the “Launch drug interactions program” link above.
Anticoagulants: Donanemab may increase anticoagulant effects of Anticoagulants. Management: Avoid use of anticoagulants in patients being treated with donanemab when possible. If concurrent use is necessary, monitor closely for evidence of intracerebral hemorrhage or other bleeding. Risk D: Consider Therapy Modification
Efgartigimod Alfa: May decrease therapeutic effects of Fc Receptor-Binding Agents. Risk C: Monitor
Nipocalimab: May decrease therapeutic effects of Fc Receptor-Binding Agents. Risk C: Monitor
Rozanolixizumab: May decrease therapeutic effects of Fc Receptor-Binding Agents. Risk C: Monitor
Therapeutic Antiplatelets: Donanemab may increase antiplatelet effects of Therapeutic Antiplatelets. Risk C: Monitor
Thrombolytic Agents: Donanemab may increase adverse/toxic effects of Thrombolytic Agents. Specifically, the risk of hemorrhage may be increased. Management: Avoid use of thrombolytic agents in patients being treated with donanemab when possible. If concurrent use is necessary, monitor closely for evidence of intracerebral hemorrhage or other bleeding. Risk D: Consider Therapy Modification
Animal reproduction studies have not been conducted.
Donanemab is a humanized monoclonal antibody (IgG1). Human IgG crosses the placenta. Fetal exposure is dependent upon the IgG subclass, maternal serum concentrations, placental integrity, newborn birth weight, and GA, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis and the highest during the third trimester (Ref).
It is not known if donanemab is present in breast milk.
Donanemab is a humanized monoclonal antibody (IgG1). Human IgG is present in breast milk; concentrations are dependent upon IgG subclass and postpartum age (Ref).
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); apolipoprotein E ε4 (ApoE ε4) status testing (prior to initiation); brain MRI (prior to initiation [recent]; prior to 2nd, 3rd, 4th, and 7th infusions; periodically, as appropriate in the setting of amyloid-related imaging abnormalities [ARIA] [eg, 2 to 4 months following identification of ARIA]) or if symptoms of ARIA develop; monitor closely for clinical and MRI changes; monitor for symptoms suggestive of ARIA (eg, headache, altered mental status, visual changes, dizziness, nausea, gait difficulty, focal neurologic deficits, seizure) (Ref).
Donanemab is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against insoluble N-truncated pyroglutamate amyloid beta. Donanemab reduces amyloid beta plaques, the accumulation of which is a defining pathophysiological feature of Alzheimer disease.
Distribution: 3.36 L.
Metabolism: Degraded by proteolytic enzymes.
Half-life elimination: ~12.1 days.
