Donanemab-azbt (Monograph)

Brand name: Kisunla
Drug class: Monoclonal Antibodies

Medically reviewed by Drugs.com on Sep 10, 2024. Written by ASHP.

Introduction

Donanemab-azbt is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against amyloid beta.

Uses for Donanemab-azbt

Donanemab has the following uses:

Donanemab-azbt is indicated for the treatment of Alzheimer's 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.

Donanemab-azbt Dosage and Administration

General

Donanemab-azbt is available in the following dosage form(s) and strength(s):

Injection: 350 mg/20 mL (17.5 mg/mL) in a single-dose vial for dilution prior to administration.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Confirm the presence of amyloid beta pathology prior to initiating treatment.

• The recommended dosage of donanemab-azbt is 700 mg administered as an IV infusion over approximately 30 minutes every four weeks for the first three doses, followed by 1400 mg every four weeks thereafter.

• Consider stopping dosing with donanemab based on reduction of amyloid plaques to minimal levels on amyloid PET imaging.

• Obtain a recent baseline brain MRI prior to initiating treatment.

• Obtain an MRI prior to the 2^nd, 3^rd, 4^th, and 7^th infusions. If radiographically observed ARIA occurs, treatment recommendations are based on type, severity, and presence of symptoms. See Full Prescribing Information for recommendations in patients with ARIA.

• Dilution to a final concentration of 4 mg/mL to 10 mg/mL with 0.9% sodium chloride injection, is required prior to administration. See Full Prescribing Information for additional details on preparation and administration.

Cautions for Donanemab-azbt

Contraindications

Donanemab-azbt is contraindicated in patients with known serious hypersensitivity to the drug or to any of the excipients.

Warnings/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’s 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 an 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, rarely can 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's disease and potential risk of serious adverse events associated with ARIA when deciding to initiate treatment with the drug.

Symptomatic ARIA occurred in 6% (52/853) of patients treated with donanemab in the principal clinical study. Clinical symptoms associated with ARIA resolved in approximately 85% (44/52) of patients.

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

Intracerebral hemorrhage greater than 1 cm in diameter was reported in 0.5% (4/853) of patients in the principal clinical study after treatment with donanemab-azbt compared to 0.2% (2/874) of patients on placebo. Fatal events of intracerebral hemorrhage in patients taking donanemab have been observed.

The risk of ARIA, including symptomatic and serious ARIA, is increased in apolipoprotein E ε4 (ApoE ε4) homozygotes. Approximately 15% of Alzheimer’s disease patients are ApoE ε4 homozygotes. In the principal clinical study, 17% (143/850) of patients in the donanemab-azbt 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-azbt, 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 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 a higher risk for ARIA. An FDA-authorized test for detection of ApoE ε4 alleles to identify patients at risk of ARIA if treated with donanemab is not currently available. Currently available tests used to identify ApoE ε4 alleles may vary in accuracy and design.

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

In the principal efficacy study, the baseline presence of at least 2 microhemorrhages or the presence of at least 1 area of superficial siderosis on MRI, which may be suggestive of CAA, were identified as risk factors for ARIA. Patients were excluded from enrollment in the study for findings on neuroimaging of prior intracerebral hemorrhage greater than 1 cm in diameter, more than 4 microhemorrhages, more than 1 area of superficial siderosis, severe white matter disease, and vasogenic edema. In the study, 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-azbt 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-azbt 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-azbt 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 (e.g., 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.

The radiographic severity of ARIA associated with donanemab was classified by the criteria shown in the following table.

Includes new or worsening superficial siderosis.

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 prior to 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 (e.g., registries) to help further the understanding of Alzheimer's disease and the impact of Alzheimer's 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 upon 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 the drug or to any of the excipients.

Infusion-related Reactions

In the principal efficacy study, infusion-related reactions were observed in 9% (74/853) of patients treated with donanemab-azbt compared to 0.5% (4/874) of patients on placebo; the majority (70%, 52/74) occurred within the first 4 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-azbt. 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 prior to subsequent dosing may be considered.

Specific Populations

Pregnancy

There are no adequate data on donanemab-azbt 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

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 the drug or from the underlying maternal condition.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

In the principal clinical study, the age of patients exposed to donanemab-azbt 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.

Common Adverse Effects

Most common adverse reactions (at least 10% and higher incidence compared to placebo): ARIA-E, ARIA-H microhemorrhage, ARIA-H superficial siderosis, and headache.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

Donanemab 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's disease. Donanemab reduces amyloid beta plaques, as evaluated in the principal efficacy study.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling).

• 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 prior to initiation of treatment to inform the risk of developing ARIA. Prior to 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.

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

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

• 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.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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Frequently asked questions

• How quickly does Kisunla start working?

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