Donanemab-azbt (Monograph)

Brand name: Kisunla
Drug class: Monoclonal Antibodies

Warning

Monoclonal antibodies targeting aggregated forms of beta amyloid, such as donanemab, can cause amyloid-related imaging abnormalities (ARIA), including ARIA with edema (ARIA-E) and ARIA with hemosiderin deposition (ARIA-H).
ARIA typically presents without symptoms, but can cause rare, life-threatening events such as intracerebral hemorrhages >1 cm.
ARIA-E may also present with focal neurologic deficits that mimic ischemic stroke; consider whether such symptoms can be due to ARIA-E prior to administering thrombolytic therapy in patients being treated with donanemab.
Patients who are apolipoprotein E ε4 (ApoE ε4) homozygotes have a higher incidence of ARIA, including symptomatic and serious cases, than heterozygotes or noncarriers.
Test for ApoE ε4 status before starting treatment to assess risk of ARIA.
Before testing, discuss genotype-related ARIA risk and the implications of genetic results with the patient.
Consider benefit of treatment versus risk of ARIA when deciding whether to treat with donanemab.

Introduction

Humanized IgG₁ monoclonal antibody directed against insoluble N-truncated pyroglutamate amyloid beta.

Uses for Donanemab-azbt

Alzheimer's Disease

Treatment of Alzheimer’s disease; limit use to patients with mild cognitive impairment or mild dementia stage of the disease (the population that was studied in clinical trials).

The American Academy of Neurology (AAN) Quality Committee provides recommendations on the use of antiamyloid antibodies in Alzheimer’s disease. Appropriate patient selection for these therapies is important. Baseline and ongoing MRI monitoring is also important to support safe administration; MRI monitoring recommendations are provided by expert consensus guidelines. In addition, the Alzheimer’s Disease and Related Disorders Therapeutic Work Group, in collaboration with expert advisors, have developed recommendations for appropriate use of donanemab.

Donanemab-azbt Dosage and Administration

General

Pretreatment Screening

Confirm presence of amyloid beta pathology prior to initiating treatment.
Obtain baseline brain MRI.
Perform genetic testing to determine apolipoprotein E ε4 (ApoE ε4) status prior to treatment to determine risk of developing amyloid related imaging abnormalities (ARIA).

Patient Monitoring

Obtain brain MRI prior to the 2nd, 3rd, 4th, and 7th infusions. Evaluate clinically if symptoms suggestive of ARIA occur, including need for MRI.
Consider discontinuing if amyloid positron emission tomography (PET) imaging shows minimal amyloid plaque levels.

Premedication and Prophylaxis

Administer premedication with an antihistamine, acetaminophen, or corticosteroid before the next infusion if a prior infusion-related reaction occurred.

Administration

IV Administration

Administer by IV infusion.

Commercially available as a 350 mg/20 mL (17.5 mg/mL) solution; must dilute prior to administration.

Dilution

Allow vial to reach room temperature.

Dilute with 0.9% sodium chloride injection to a final concentration of 4–10 mg/mL.

To prepare a 700 mg dose, withdraw 40 mL of donanemab-azbt (from 2 vials) and mix with 30–135 mL of 0.9% sodium chloride injection diluent to a final infusion volume of 70–175 mL.

To prepare a 1400 mg dose, withdraw 80 mL of donanemab-azbt (from 4 vials) and mix with 60–270 mL of 0.9% sodium chloride injection diluent to a final infusion volume of 140–350 mL.

Gently invert diluted solution to mix; do not shake.

Vials are for single use only; discard any unused portion.

Administration

If the diluted solution is refrigerated, allow solution to reach room temperature before infusion.

Administer entire diluted solution by IV infusion over approximately 30 minutes.

Discontinue immediately if hypersensitivity occurs. Flush IV line with 0.9% sodium chloride after the infusion and observe patient for at least 30 minutes post-infusion for infusion or hypersensitivity reactions.

Dosage

Adults

Alzheimer's Disease

IV Infusion

700 mg administered as a 30-minute IV infusion every 4 weeks for 3 doses, then 1400 mg every 4 weeks thereafter. Consider discontinuation of therapy based on reduction of amyloid plaques to minimal levels on amyloid PET imaging.

If a dose is missed, administer missed dose as soon as possible and then resume administration every 4 weeks.

Dosage Modification for Toxicity

Dosage interruption may be required for ARIA-E, ARIA-H, or intracerebral hemorrhage. Adjust dosage according to results of MRI and severity of symptoms (see Tables 1 and 2).

Mild: discomfort without affecting daily activities; Moderate: discomfort interferes with or limits daily activities; Severe: incapacitating discomfort, preventing work or normal function.

Suspend treatment until MRI shows resolution and symptoms, if any, have resolved; consider repeat MRI in 2–4 months, with dosing resumed based on clinical judgment.

Table 1. Dosing Recommendations for Patients with ARIA-E.1
Clinical Symptom Severity	Mild ARIA-E Severity on MRI	Moderate ARIA-E Severity on MRI	Severe ARIA-E Severity on MRI
Asymptomatic	May continue current dosage and schedule	Suspend dosing	Suspend dosing
Mild	May continue current dosage based on clinical judgment	Suspend dosing	Suspend dosing
Moderate or Severe	Suspend dosing	Suspend dosing	Suspend dosing

Suspend treatment until MRI shows stabilization and symptoms, if present, resolve; consider repeat MRI in 2–4 months, with dosing resumption based on clinical judgment.

Suspend treatment until MRI shows stabilization and symptoms, if present, resolve. Use clinical judgment to determine whether to continue or permanently discontinue donanemab-azbt.

Table 2. Dosing Recommendations for Patients with ARIA-H.1
Clinical Symptom Severity	Mild ARIA-H Severity on MRI	Moderate ARIA-H Severity on MRI	Severe ARIA-H Severity on MRI
Asymptomatic	May continue current dosage and schedule	Suspend dosing	Suspend dosing
Symptomatic	Suspend dosing	Suspend dosing	Suspend dosing

If intracerebral hemorrhage >1 cm occurs, stop donanemab-azbt until MRI shows stabilization and symptoms resolve; use clinical judgment to determine whether to resume or permanently discontinue treatment.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Donanemab-azbt

Contraindications

Patients with known serious hypersensitivity to the drug or to any excipients.

Warnings/Precautions

Amyloid Related Imaging Abnormalities

Risk of ARIA, characterized as amyloid related imaging abnormalities-edema (ARIA-E), which can be observed on MRI as brain edema or sulcal effusions, and amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis. (See Boxed Warning).

ARIA can occur spontaneously in Alzheimer’s disease. ARIA-H generally occurs in association with ARIA-E.

ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events, including seizures, can occur. Symptoms include headache, confusion, visual changes, dizziness, nausea, and gait difficulty.

Risk of ARIA is increased in apolipoprotein E ε4 (ApoE ε4) homozygotes.

Intracerebral hemorrhage >1 cm, with fatal cases reported.

Perform testing for ApoE ε4 status prior to initiation of treatment to inform risk of developing ARIA. Prior to testing, discuss with patients the risk of ARIA across genotypes and implications of genetic testing results.

If genotype testing is not performed, patients can still be treated with donanemab; however, it cannot be determined if they are ApoE ε4 homozygotes and at higher risk for ARIA. FDA-authorized test for detection of ApoE ε4 alleles not currently available.

Perform baseline brain MRI and periodic monitoring with MRI during donanemab treatment. Enhanced clinical vigilance for ARIA recommended during first 24 weeks of treatment.

If a patient experiences symptoms suggestive of ARIA, perform a clinical evaluation, including MRI if indicated. If ARIA observed on MRI, perform a careful clinical evaluation prior to continuing treatment.

Monitoring and dosing decisions should consider symptoms, radiographic severity, and ARIA type. Conduct baseline and periodic MRI scans, especially in first 24 weeks.

No experience in patients who continued dosing through symptomatic ARIA-E, or through asymptomatic but radiographically severe ARIA-E. Limited experience in patients who continued dosing through asymptomatic but radiographically mild to moderate ARIA-E. Limited data in dosing patients who experienced recurrent ARIA-E; use clinical judgment in considering whether to continue dosing in patients with recurrent ARIA-E.

Caution is advised when considering use of antiplatelets, anticoagulants, or thrombolytics in patients receiving donanemab, especially those at increased risk for intracerebral hemorrhage or with MRI findings suggestive of cerebral amyloid angiopathy. Evaluate for ARIA-E prior to administering thrombolytics.

Providers are encouraged to support real-world data collection to improve care by contacting 1-800-LillyRx (1-800-545-5979).

Other Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis and angioedema, occurred. Stop infusion immediately at first sign of a reaction and begin appropriate treatment.

Infusion Related Reactions

Infusion-related reactions reported; most were mild to moderate and occurred within first few infusions.

Symptoms included chills, nausea, dyspnea, and changes in BP, typically during or shortly after infusion. Some reactions led to treatment discontinuation.

Infusion rate may be reduced or stopped, and appropriate treatment initiated. Premedication may be considered for future doses.

Immunogenicity

Anti-donanemab antibodies with neutralizing activity detected. Infusion-related reactions were more common in patients with antibodies than those without.

Specific Populations

Pregnancy

Pregnancy data not unavailable, and risks to mother or fetus are unknown.

Lactation

Breastfeeding data not unavailable. Infant exposure through breast milk is expected to be low, but effects are unknown. Weigh benefits of breastfeeding against the mother’s treatment needs and potential infant risks.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

In the principal efficacy study, patients 59–86 years of age (mean, 73 years of age) received donanemab-azbt. Safety and efficacy were similar across age groups.

Hepatic Impairment

Not studied in hepatic impairment, but liver metabolism is unlikely since donanemab is catabolized by proteolytic enzymes.

Renal Impairment

Not studied in renal impairment, but renal clearance is unlikely due to proteolytic metabolism.

Common Adverse Effects

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

Drug Interactions

No formal drug-drug interaction studies performed.

Anticoagulants and Antithrombotics

In patients requiring anticoagulant therapy, use caution with donanemab-azbt due to an increased risk of intracerebral hemorrhage.

Donanemab-azbt Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations and AUC of donanemab-azbt increase dose proportionally following a single dose of 10-40 mg/kg (approximately 2 times the approved recommend dosage) and with multiple doses of 10 and 20 mg/kg.

Steady-state concentrations are reached after a single dose.

Systemic accumulation with every 4-week dosing is <1.3-fold.

Distribution

Special Populations

Age, race, and sex do not affect distribution; body weight affects volume of distribution, but not considered to be clinically significant.

Elimination

Metabolism

Degraded by proteolytic enzymes in the same manner as endogenous IgG.

Half-life

12.1 days.

Special Populations

Age, sex, and race have no impact on clearance; body weight affects clearance, but not considered to be clinically significant.

Anti-donanemab antibodies increase clearance and lower serum concentrations, with reduced plaque reduction in high-titer patients; however, no clinically significant impact on effectiveness was observed over 18 months.

Stability

Storage

Parenteral

Injection Concentrate

Unopened vials: store at 2-8°C in original carton to protect from light until ready to use; do not freeze or shake. May store at room temperature (20-25°C) for up to 3 days.

Diluted solution: administer immediately or store refrigerated (2–8°C) for ≤72 h or at room temperature (20–25°C) for ≤12 hour, including infusion time. Do not freeze.

Actions

Recombinant humanized IgG₁monoclonal antibody directed against insoluble N-truncated pyroglutamate amyloid beta.
Reduces amyloid beta plaques in a dose- and time-dependent manner.
Accumulation of amyloid beta plaques in the brain is a defining pathophysiological feature of Alzheimer’s disease.

Advice to Patients

Advise patients to read the FDA-approved patient labeling.
Inform patients that donanemab-azbt 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 >1 cm in diameter have been reported infrequently in patients taking donanemab-azbt, and that use of antithrombotic or thrombolytic medications while taking donanemab-azbt 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-azbt, there is an increased risk in patients who are apolipoprotein E ε4 (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-azbt.
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-azbt may cause hypersensitivity reactions, including anaphylaxis and angioedema, and to contact their healthcare provider if hypersensitivity reactions occur.
Inform patients that donanemab-azbt 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.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

Donanemab-azbt is obtained through designated specialty pharmacies. Contact the manufacturer or consult the KISUNLA website ([Web]) for specific availability information.