Highlights

Indications and usage

Donanemab-azbt (Kisunla^™) is indicated for the treatment of Alzheimer disease. Treatment with donanemab should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in the clinical trials.

Dosage and administration

Patient selection

Confirm the presence of amyloid beta pathology before initiating treatment.

Dosing Instructions

The recommended dosage of donanemab is 700 mg every four weeks for three doses, then 1400 mg every four weeks (see Table 1). Donanemab is administered every four weeks as an intravenous infusion over approximately 30 minutes. Donanemab must be diluted before administration (see Table 4).

Table 1. Dosing Schedule

Consider stopping dosing with donanemab based on the reduction of amyloid plaques to minimal levels on amyloid PET imaging. In Study 1, dosing was stopped based on a reduction of amyloid levels below predefined thresholds on PET imaging.

If an infusion is missed, resume administration every 4 weeks at the same dose as soon as possible.

Consider stopping dosing with donanemab based on the reduction of amyloid plaques to minimal levels on amyloid PET imaging. In Study 1, dosing was stopped based on a reduction of amyloid levels below predefined thresholds on PET imaging.

If an infusion is missed, resume administration every 4 weeks at the same dose as soon as possible.

Monitoring and dosing interruption for amyloid-related imaging abnormalities

Donanemab can cause amyloid-related imaging abnormalities -edema (ARIA-E) and -hemosiderin deposition (ARIA-H).

Monitoring for ARIA. Obtain a recent baseline brain MRI before initiating treatment with donanemab. Obtain an MRI before the 2nd, 3rd, 4th, and 7th infusions. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including an MRI if indicated.

Recommendations for dosing interruptions in patients with ARIA.

ARIA-E. The recommendations for dosing interruptions for patients with ARIA-E are provided in Table 2.

Table 2. Dosing Recommendations for Patients With ARIA-E

ARIA-H. The recommendations for dosing interruptions for patients with ARIA-H are provided in Table 3.

Table 3. Dosing Recommendations for Patients With ARIA-H

In patients who develop intracerebral hemorrhage greater than 1 cm in diameter during treatment with donanemab, suspend dosing until MRI demonstrates radiographic stabilization and symptoms, if present, resolve. Resumption of dosing should be guided by clinical judgment.

Dilution instructions

Table 4. Preparation and Reconstitution of Donanemab

Administration instructions

Dosage forms and strengths

Injection. 350 mg/20 mL (17.5 mg/mL) clear to opalescent, colorless to slightly yellow to slightly brown solution in a single-dose vial.

Contraindications

Donanemab is contraindicated in patients with known serious hypersensitivity to donanemab-azbt or to any of the excipients. Reactions have included anaphylaxis.

Warnings and precautions

Amyloid-related imaging abnormalities

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), 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 can occur spontaneously in patients with Alzheimer disease, particularly in patients with MRI findings suggestive of cerebral amyloid angiopathy, such as pretreatment microhemorrhage or superficial siderosis. ARIA-H associated with monoclonal antibodies directed against aggregated forms of beta amyloid generally occurs in association with the occurrence of ARIA-E. ARIA-H of any cause and ARIA-E can occur together.

ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events, including seizure and status epilepticus can rarely occur. When present, reported symptoms associated with ARIA may include, but are not limited to, headache, confusion, visual changes, dizziness, nausea, and gait difficulty. Focal neurologic deficits may also occur. Symptoms associated with ARIA usually resolve over time. In addition to ARIA, intracerebral hemorrhages greater than 1 cm in diameter have occurred in patients treated with donanemab.

Consider the benefit of donanemab for the treatment of Alzheimer disease and the potential risk of serious adverse events associated with ARIA when deciding to initiate treatment with donanemab.

Incidence of ARIA. Symptomatic ARIA occurred in 6% (52/853) of patients treated with donanemab in Study 1. Clinical symptoms associated with ARIA resolved in approximately 85% (44 of 52) of patients.

Including asymptomatic radiographic events, ARIA was observed in 36% (307 of 853) of patients treated with donanemab, compared to 14% (122 of 874) of patients on placebo in Study 1. ARIA-E was observed in 24% (201 of 853) of patients treated with donanemab compared with 2% (17 of 874) of patients on placebo. ARIA-H was observed in 31% (263 of 853) of patients treated with donanemab compared with 13% (111 of 874) of patients on placebo. There was no increase in isolated ARIA-H (ie, ARIA-H in patients who did not also experience ARIA-E) for donanemab compared to placebo.

Incidence of intracerebral hemorrhage. Intracerebral hemorrhage greater than 1 cm in diameter was reported in 0.5% (four of 853) of patients in Study 1 after treatment with donanemab compared to 0.2% (two of 874) of patients on placebo. Fatal events of intracerebral hemorrhage in patients taking donanemab have been observed.

Risk factors for ARIA and intracerebral hemorrhage.

ApoE ε4 carrier status. The risk of ARIA, including symptomatic and serious ARIA, is increased in apolipoprotein E ε4 (ApoE ε4) homozygotes. Approximately 15% of patients with Alzheimer disease are ApoE ε4 homozygotes. In Study 1, 17% (143/850) of patients in the donanemab arm were apolipoprotein E ε4 (ApoE ε4) homozygotes, 53% (452/850) were heterozygotes, and 30% (255/850) were noncarriers. The incidence of ARIA was higher in ApoE ε4 homozygotes (55% on donanemab vs. 22% on placebo) than in heterozygotes (36% on donanemab vs. 13% on placebo) and noncarriers (25% on donanemab vs. 12% on placebo). Among patients treated with donanemab, symptomatic ARIA-E occurred in 8% of ApoE ε4 homozygotes compared with 7% of heterozygotes and 4% of noncarriers. Serious events of ARIA occurred in 3% of ApoE ε4 homozygotes, 2% of heterozygotes, and 1% of noncarriers. The recommendations for management of ARIA do not differ between ApoE ε4 carriers and noncarriers. Testing for ApoE ε4 status should be performed before initiation of treatment to inform the risk of developing ARIA. Before 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 a higher risk for ARIA. An FDA-authorized test for the detection of ApoE ε4 alleles to identify patients at risk of ARIA if treated with donanemab is not available. Tests used to identify ApoE ε4 alleles may vary in accuracy and design.

Radiographic findings of cerebral amyloid angiopathy (CAA). Neuroimaging findings that may indicate CAA include evidence of prior intracerebral hemorrhage, cerebral microhemorrhage, and cortical superficial siderosis. CAA has an increased risk of intracerebral hemorrhage. The presence of an ApoE ε4 allele is also associated with cerebral amyloid angiopathy.

In Study 1, the baseline presence of at least two microhemorrhages or the presence of at least one area of superficial siderosis on MRI, which may be suggestive of CAA, was identified as a risk factor for ARIA. Patients were excluded from enrollment in Study 1 for findings on neuroimaging of prior intracerebral hemorrhage greater than 1 cm in diameter, more than four microhemorrhages, more than 1 area of superficial siderosis, severe white matter disease, and vasogenic edema.

Concomitant antithrombotic or thrombolytic medication. In Study 1, baseline use of antithrombotic medication (aspirin, other antiplatelets, or anticoagulants) was allowed. The majority of exposures to antithrombotic medications were to aspirin. The incidence of ARIA-H was 30% (106/349) in patients taking donanemab with a concomitant antithrombotic medication within 30 days compared to 29% (148/504) who did not receive an antithrombotic within 30 days of an ARIA-H event. The incidence of intracerebral hemorrhage greater than 1 cm in diameter was 0.6% (2/349 patients) in patients taking donanemab with a concomitant antithrombotic medication compared to 0.4% (2/504) in those who did not receive an antithrombotic. The number of events and the limited exposure to non-aspirin antithrombotic medications limit definitive conclusions about the risk of ARIA or intracerebral hemorrhage in patients taking antithrombotic medications.

One fatal intracerebral hemorrhage occurred in a patient taking donanemab in the setting of focal neurologic symptoms of ARIA and the use of a thrombolytic agent. Additional caution should be exercised when considering the administration of antithrombotics or a thrombolytic agent (eg, tissue plasminogen activator) to a patient already being treated with donanemab. 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.

Caution should be exercised when considering the use of donanemab in patients with factors that indicate an increased risk for intracerebral hemorrhage, and in particular for patients who need to be on anticoagulant therapy or patients with findings on MRI that are suggestive of cerebral amyloid angiopathy.

Radiographic severity. The radiographic severity of ARIA associated with donanemab was classified by the criteria shown in Table 5.

Table 5. ARIA MRI Classification Criteria

Most ARIA-E radiographic events in Study 1 occurred early in treatment (within the first 24 weeks), although ARIA can occur at any time, and patients can have more than one episode. The maximum radiographic severity of ARIA-E in patients treated with donanemab was mild in 7% (59/853) of patients, moderate in 15% (128/853) of patients, and severe in 2% (14/853) of patients. Resolution on MRI after the first ARIA-E event occurred in 63% of patients treated with donanemab by 12 weeks, 80% by 20 weeks, and 83% overall after detection. The maximum radiographic severity of ARIA-H microhemorrhage in patients treated with donanemab was mild in 17% (143/853) of patients, moderate in 4% (34/853) of patients, and severe in 5% (40/853) of patients. The maximum radiographic severity of ARIA-H superficial siderosis in patients treated with donanemab was mild in 6% (47/853) of patients, moderate in 4% (32/853) of patients, and severe in 5% (46/853) of patients. Among patients treated with donanemab, the rate of severe radiographic ARIA-E was highest in ApoE ε4 homozygotes at 3% (4/143) compared to heterozygotes at 2% (9/452) or noncarriers 0.4% (1/255). Among patients treated with donanemab, the rate of severe radiographic ARIA-H was highest in ApoE ε4 homozygotes, 22% (31/143), compared to heterozygotes at 8% (38/452) or noncarriers at 4% (9/255).

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 24 weeks of treatment with donanemab. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including MRI if indicated. If ARIA is observed on MRI, careful clinical evaluation should be performed before continuing treatment.

There is limited experience in patients who continued dosing through asymptomatic but radiographically mild to moderate ARIA-E. There are limited data for dosing patients who have experienced recurrent episodes of ARIA-E.

Providers should encourage patients to participate in real-world data collection (eg, registries) to help further the understanding of Alzheimer disease and the impact of Alzheimer disease treatments. Providers and patients can contact 1-800-LillyRx (1-800-545-5979) for a list of currently enrolling programs.

Hypersensitivity reactions

Hypersensitivity reactions, including anaphylaxis and angioedema, have occurred in patients who were treated with donanemab. Promptly discontinue the infusion on the first observation of any signs or symptoms consistent with a hypersensitivity reaction and initiate appropriate therapy. Donanemab is contraindicated in patients with a history of serious hypersensitivity to donanemab-azbt or to any of the excipients of donanemab.

Infusion-Related reactions

In Study 1, infusion-related reactions were observed in 9% (74/853) of patients treated with donanemab compared to 0.5% (4/874) of patients on placebo; the majority (70%, 52/74) occurred within the first four infusions. Infusion reactions typically occur during infusion or within 30 minutes post-infusion. Infusion-related reactions were mostly mild (57%) or moderate (39%) in severity. Infusion-related reactions resulted in discontinuations in 4% (31/853) of patients treated with donanemab. Signs and symptoms of infusion-related reactions include chills, erythema, nausea/vomiting, difficulty breathing/dyspnea, sweating, elevated blood pressure, headache, chest pain, and low blood pressure.

In the event of an infusion-related reaction, the infusion rate may be reduced, or the infusion may be discontinued, and appropriate therapy initiated as clinically indicated. Pre-treatment with antihistamines, acetaminophen, or corticosteroids before subsequent dosing may be considered.

Adverse reactions

The following clinically significant adverse reactions are described elsewhere in the labeling:

Clinical trials experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of donanemab has been evaluated in 2885 patients with Alzheimer disease who received at least one dose of donanemab intravenously. In the clinical studies of donanemab, 1912 patients with Alzheimer disease received donanemab once monthly for at least 6 months, 1057 patients for at least 12 months, and 432 patients for at least 18 months, at the recommended dosing schedule.

In Study 1 (NCT04437511), a total of 853 patients with Alzheimer disease received at least one dose of donanemab.

Thirteen percent of patients treated with donanemab, compared to 4% of patients on placebo, stopped study treatment because of an adverse reaction. The most common adverse reaction leading to discontinuation of donanemab was infusion-related reaction (4% of patients treated with donanemab compared to no patient on placebo).

Table 6 shows adverse reactions that were reported in at least 5% of patients treated with donanemab and at least 2% more frequently than in patients on placebo in Study 1.

Table 6. Adverse Reactions Reported in at Least 5% of Patients Treated With Donanemab and at Least 2% Higher Than Placebo in Study 1

Less common adverse reactions.

Hypersensitivity reactions. Hypersensitivity reactions, including anaphylaxis, occurred in 3% of patients treated with donanemab compared to 0.7% of patients on placebo.

Intestinal obstruction and intestinal perforation. Three patients (0.4%) treated with donanemab had serious adverse reactions of intestinal obstruction compared to no patients on placebo. Two patients (0.2%) treated with donanemab had serious adverse reactions of intestinal perforation compared to one patient (0.1%) on placebo.

Immunogenicity: anti-drug antibody-associated adverse reactions. In Study 1, approximately 10% of donanemab-treated patients who developed anti-drug antibodies reported infusion-related reactions compared to 2% of patients who did not develop anti-drug antibodies.

Use in specific populations

Pregnancy

Risk summary. There are no adequate data on donanemab use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. No animal studies have been conducted to assess the potential reproductive or developmental toxicity of donanemab.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Lactation

Risk summary. There are no data on the presence of donanemab-azbt in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Published data from other monoclonal antibodies generally indicate low passage of monoclonal antibodies into human milk and limited systemic exposure in the breastfed infant. The effects of this limited exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for donanemab and any potential adverse effects on the breastfed infant from donanemab or from the underlying maternal condition.

Pediatric use

Safety and effectiveness in pediatric patients have not been established.

Geriatric use

In Study 1, the age of patients exposed to donanemab ranged from 59 to 86 years, with a mean age of 73 years; 90% were 65 years and older, and 41% were 75 years and older. No overall differences in safety or effectiveness of donanemab have been observed between patients 65 years of age and older and younger adult patients.

Clinical pharmacology

Mechanism of action

Donanemab-azbt is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against insoluble N-truncated pyroglutamate amyloid beta. The accumulation of amyloid beta plaques in the brain is a defining pathophysiological feature of Alzheimer disease. Donanemab-azbt reduces amyloid beta plaques, as evaluated in Study 1.

Pharmacodynamics

Effect of donanemab on amyloid beta pathology. The effect of donanemab on amyloid beta plaque levels in the brain was evaluated using amyloid Positron Emission Tomography (PET) imaging (18F-florbetapir tracer). The PET signal was quantified using the Standard Uptake Value Ratio (SUVR) method to estimate brain levels of amyloid beta plaque in composites of brain areas expected to be widely affected by Alzheimer's disease pathology (precuneus, frontal, anterior cingulate, posterior cingulate, parietal, and temporal cortices), compared to a brain region expected to be spared of such pathology (cerebellum). Results of amyloid PET were also expressed on the Centiloid scale.

For details about the effects of donanemab on amyloid beta pathology in Study 1, see the Clinical pharmacology section of the DAILYMED drug label information.

Exposure-response relationships. Model-based exposure-response analyses for Study 1 demonstrated that exposures to donanemab-azbt were associated with a reduction in clinical decline on iADRS and CDR-SB. An association between a reduction in amyloid beta plaque from baseline and clinical decline on iADRS and CDR-SB was also observed.

Pharmacokinetics

The pharmacokinetics (PK) of donanemab were characterized using a population PK analysis with concentration data collected from 2131 patients with Alzheimer disease who received donanemab in single or multiple doses. Accumulation of <1.3-fold occurs with every-4-week dosing; steady-state exposures are achieved after a single dose. In single doses from 10 to 40 mg/kg (~2 times the approved recommended dosage of 1400 mg for 70 kg of body weight), and multiple 10 and 20 mg/kg doses, exposures (Cmax and AUC) increased proportionally.

Distribution. The central volume of distribution is 3.36 L.

Elimination. Donanemab is expected to be degraded by proteolytic enzymes in the same manner as endogenous IgG. The mean terminal half-life of donanemab-azbt is approximately 12.1 days. Donanemab-azbt clearance is 0.0255 L/h.

Specific populations. Age, sex, or race were not found to affect the pharmacokinetics of donanemab-azbt. Although body weight was found to influence both clearance and volume of distribution, the resulting changes were not clinically significant.

Patients with renal or hepatic impairment. No clinical studies were conducted to evaluate the pharmacokinetics of donanemab-azbt in patients with renal or hepatic impairment. Donanemab-azbt is degraded by proteolytic enzymes and is not expected to undergo renal elimination or metabolism by hepatic enzymes.

Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of donanemab-azbt or other donanemab products.

In up to 18 months of treatment in Study 1, 87% (691/792) of patients receiving donanemab once monthly developed anti-donanemab-azbt antibodies, and of those, 100% (691/691) had neutralizing antibodies.

Anti-donanemab-azbt antibody formation was associated with a higher incidence of infusion-related reactions compared to placebo.

Anti-drug antibody effects on pharmacokinetics and pharmacodynamics. The presence of anti-donanemab-azbt antibodies increased donanemab-azbt clearance. Among patients treated with donanemab in the placebo-controlled studies who developed anti-donanemab-azbt antibodies, mean donanemab-azbt serum trough concentrations at various time points were lower compared to patients who had not developed anti-donanemab-azbt antibodies. Patients with high anti-drug antibody titers showed less reduction in amyloid plaque compared to patients with low anti-drug antibody titers. However, there was no identified clinically significant effect of anti-donanemab-azbt antibodies on the effectiveness of donanemab over the treatment duration of 18 months.

Nonclinical toxicology

Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenesis. Carcinogenicity studies have not been conducted.

Mutagenesis. Genotoxicity studies have not been conducted.

Impairment of fertility. No studies in animals have been conducted to assess the effects of donanemab-azbt on male or female fertility.

Clinical studies

The efficacy of donanemab was evaluated in a double-blind, placebo-controlled, parallel-group study (Study 1, NCT04437511) in patients with Alzheimer disease (patients with confirmed presence of amyloid pathology and mild cognitive impairment or mild dementia stage of disease, consistent with Stage 3 and Stage 4 Alzheimer disease). Patients were enrolled with a Mini-Mental State Examination (MMSE) score of ≥20 and ≤28 and had a progressive change in memory function for at least 6 months. Patients were included in the study based on visual assessment of tau PET imaging with flortaucipir and standardized uptake value ratio (SUVR). Patients were enrolled with or without concomitant approved therapies (cholinesterase inhibitors and the N-methyl-D-aspartate antagonist memantine) for Alzheimer disease. Patients could enroll in an optional, long-term extension.

In Study 1, 1736 patients were randomized 1:1 to receive 700 mg of donanemab every 4 weeks for the first three doses, and then 1400 mg every 4 weeks (N = 860) or placebo (N = 876) for a total of up to 72 weeks. The treatment was switched to placebo based on amyloid PET levels measured at Week 24, Week 52, and Week 76. If the amyloid plaque level was <11 Centiloids on a single PET scan or 11 to <25 Centiloids on two consecutive PET scans, the patient was eligible to be switched to placebo.

Additionally, dose adjustments were allowed for treatment-emergent ARIA or symptoms that then showed ARIA-E or ARIA-H on MRI.

At baseline, mean age was 73 years, with a range of 59 to 86 years. Of the total number of patients randomized, 68% had low/medium tau levels, and 32% had high tau levels; 71% were ApoE ε4 carriers and 29% were ApoE ε4 noncarriers. Fifty-seven percent of patients were female, 91% were White, 6% were Asian, 4% were Hispanic or Latino, and 2% were Black or African American.

The primary efficacy endpoint was change in the integrated Alzheimer's Disease Rating Scale (iADRS) score from baseline to 76 weeks. The iADRS is a combination of two scores: the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog13) and the Alzheimer's Disease Cooperative Study – Instrumental Activities of Daily Living (ADCS-iADL) scale. The total score ranges from 0 to 144, with lower scores reflecting worse cognitive and functional performance. Other efficacy endpoints included Clinical Dementia Rating Scale – Sum of Boxes (CDR-SB), ADAS-Cog13, and ADCS-iADL.

There were two primary analysis populations based on tau PET imaging with flortaucipir: (1) low/medium tau level population (defined by visual assessment and SUVR of ≥1.10 and ≤1.46), and (2) combined population of low/medium plus high tau (defined by visual assessment and SUVR >1.46) population.

Patients treated with donanemab demonstrated a statistically significant reduction in clinical decline on iADRS compared to placebo at Week 76 in the combined population (2.92, p<0.0001) and the low/medium tau population (3.25, p<0.0001).

Patients treated with donanemab demonstrated a statistically significant reduction in clinical decline on CDR-SB compared to placebo at Week 76 in the combined population (-0.70, p<0.0001) (see Figure 2 and Table 8 in the Clinical studies section of the DAILYMED drug label information). There were also statistically significant differences (p<0.001) between treatment groups as measured by ADAS-Cog13 and ADCS-iADL at Week 76.

Dosing was continued or stopped in response to observed effects on amyloid imaging. The percentages of patients eligible for switch to placebo based on amyloid PET levels at Week 24, Week 52, and Week 76 timepoints were 17%, 47%, and 69%, respectively. Amyloid PET values may increase after treatment with donanemab is stopped. There is no data beyond the 76-week duration of Study 1 to guide whether additional dosing with donanemab may be needed for longer-term clinical benefit.

How supplied/storage and handling

How supplied

Donanemab (donanemab-azbt) injection is a sterile, preservative-free, clear to opalescent, colorless to slightly yellow to slightly brown solution. Donanemab is supplied in one vial per carton as follows: 350 mg/20 mL (17.5 mg/mL) single-dose vial: NDC 0002-9401-01.

Storage and handling

Unopened vial.

Diluted solution. For storage of the diluted infusion solution, see Dosage and administration.

Patient counseling information

Advise the patient to read the FDA-approved patient labeling (ie, Medication guide).

Amyloid-related imaging abnormalities

Inform patients that donanemab may cause Amyloid Related Imaging Abnormalities or “ARIA”. ARIA most commonly presents as temporary swelling in areas of the brain that usually resolves over time. Some people may also have small spots of bleeding in or on the surface of the brain. Inform patients that most people with swelling in areas of the brain do not experience symptoms; however, some people may experience symptoms such as headache, confusion, dizziness, vision changes, nausea, aphasia, weakness, or seizure. Instruct patients to notify their healthcare provider if these symptoms occur. Inform patients that events of intracerebral hemorrhage greater than 1 cm in diameter have been reported infrequently in patients taking donanemab, and that use of antithrombotic or thrombolytic medications while taking donanemab may increase the risk of bleeding in the brain. Notify patients that their healthcare provider will perform MRI scans to monitor for ARIA.

Inform patients that although ARIA can occur in any patient treated with donanemab, there is an increased risk in patients who are ApoE ε4 homozygotes, and that testing for ApoE ε4 status should be performed before initiation of treatment to inform the risk of developing ARIA. Before testing, discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results. Inform patients that if testing is not performed, it cannot be determined if they are ApoE ε4 homozygotes and at a higher risk for ARIA.

Inform patients that some symptoms of ARIA can mimic ischemic stroke and that their healthcare providers may need to perform additional testing to determine how to treat those symptoms in patients taking donanemab. Advise patients to carry information that they are being treated with donanemab.

Patient registry

Providers should encourage patients to participate in real-world data collection (eg, registries) to help further the understanding of Alzheimer disease and the impact of Alzheimer disease treatments. Providers and patients can contact 1-800-LillyRx (1-800-545-5979) for a list of currently enrolling programs.

Hypersensitivity reactions

Inform patients that donanemab may cause hypersensitivity reactions, including anaphylaxis and angioedema, and to contact their healthcare provider if hypersensitivity reactions occur.

Infusion-related reactions

Inform patients that donanemab may cause infusion-related reactions, including chills, erythema, nausea, vomiting, difficulty breathing, sweating, headache, chest pain, and high or low blood pressure, and to contact their healthcare provider if infusion-related reactions occur.

Medication guide

See the Medication guide section of the DAILYMED drug label information.