Aducanumab (Monograph)

Brand name: Aduhelm
Drug class: Monoclonal Antibodies

Introduction

Amyloid beta-directed monoclonal antibody.

Uses for Aducanumab

Alzheimer's Disease

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

Accelerated approval based on reduction in amyloid beta plaques (a surrogate marker of response). Continued approval may be contingent upon verification of clinical benefit (e.g., long-term cognitive changes) in confirmatory studies.

Reduction of amyloid beta plaques with aducanumab-avwa was clearly and consistently demonstrated across trials. However, there is controversy regarding whether this is an appropriate surrogate end point to predict clinical benefit; several organizations and expert panels have published appropriate use criteria or position statements expressing concerns over the available evidence supporting use.

Aducanumab Dosage and Administration

General

Pretreatment Screening

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

• Obtain a recent (within 1 year) brain MRI.

Patient Monitoring

• Discontinue the infusion if signs or symptoms of a hypersensitivity reaction (e.g., angioedema, urticaria) occur.

• Obtain an MRI prior to the 5th, 7th, 9th, and 12th infusions.

• Monitor for symptoms suggestive of ARIA; if symptoms occur, perform clinical evaluation, including MRI if indicated.

Administration

IV Administration

Administer by IV infusion once every 4 weeks. Use a 0.2- or 0.22-micron inline filter.

Dilute injection solution prior to administration.

If an infusion is missed, resume administration at the same dose as soon as possible and at least 21 days apart.

Vials are for single use only; discard unused portions.

Dilution

Must dilute with 0.9% sodium chloride injection prior to IV infusion.

Determine the number of vials needed based on the patient’s actual body weight and recommended dosage.

Withdraw the required volume of aducanumab and add to infusion bag containing 100 mL of 0.9% sodium chloride injection; do not use any other diluents.

Mix the final diluted solution for infusion by gentle inversion; do not shake.

Administer immediately after dilution. If immediate administration is not possible, the diluted solution may be stored at 2–8°C for up to 3 days or at room temperature (up to 30°C) for up to 12 hours; do not freeze.

Allow the diluted solution to warm up to room temperature prior to infusion if necessary.

Rate of Administration

Administer by IV infusion over approximately 1 hour.

Dosage

Calculate dose based on actual body weight.

Adults

Alzheimer's Disease

Initial Titration

IV

Titrate dosage according to the following schedule; administer IV infusions every 4 weeks:

Infusion 1 (at week 0) and infusion 2 (at week 4): 1 mg/kg

Infusion 3 (at week 8) and infusion 4 (at week 12): 3 mg/kg

Infusion 5 (at week 16) and infusion 6 (at week 20): 6 mg/kg

Maintenance Dosing

IV

Recommended maintenance dosage starting with infusion 7 (week 24) is 10 mg/kg every 4 weeks. Separate doses by at least 21 days.

Therapy Interruption for Toxicity

Dosage interruption may be required for patients with amyloid related imaging abnormalities-edema (ARIA-E), amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H), or intracerebral hemorrhage. Recommendations for dosage interruption in patients with ARIA-E are provided in Table 1.

Severity of ARIA-E on MRI is defined as mild (fluid attenuated inversion recovery [FLAIR] hyperintensity confined to sulcus and/or cortex/subcortex white matter in one location <5 cm); moderate (FLAIR hyperintensity 5–10 cm in single greatest dimension, or >1 site of involvement, each measuring <10 cm); or severe (FLAIR hyperintensity >10 cm with associated gyral swelling and sulcal effacement; 1 or more separate/independent sites of involvement may be noted).

Clinical symptoms are classified as mild (discomfort noticed, but no disruption of normal daily activity), moderate (discomfort sufficient to reduce or affect normal daily activity), or severe (incapacitating, with inability to work or perform normal daily activity).

Suspend until MRI demonstrates radiographic resolution and symptoms, if present, resolve; consider a follow-up MRI to assess for resolution 2–4 months after initial identification. Resumption of dosing should be guided by clinical judgment.

Recommendations for dosage interruption in patients with ARIA-H are provided in Table 2.

Severity of ARIA-H on MRI is defined as mild (≤4 new incident microhemorrhages or 1 focal area of superficial siderosis); moderate (5–9 new incident microhemorrhages or 2 focal areas of superficial siderosis); or severe (≥10 new incident microhemorrhages or >2 areas of superficial siderosis).

Suspend until MRI demonstrates radiographic stabilization and symptoms, if present, resolve; resumption of dosing should be guided by clinical judgment; consider a follow-up MRI to assess for stabilization 2–4 months after initial identification.

Suspend until MRI demonstrates radiographic stabilization and symptoms, if present, resolve; use clinical judgment in considering whether to continue treatment or permanently discontinue aducanumab.

If intracerebral hemorrhage >1 cm in diameter develops during treatment, suspend dosing until MRI demonstrates radiographic stabilization and symptoms, if present, resolve. Use clinical judgment in considering whether to continue treatment after radiographic stabilization and symptom resolution or permanently discontinue aducanumab.

Special Populations

Hepatic Impairment

No special population dosage recommendations.

Renal Impairment

No special population dosage recommendations.

Geriatric Patients

No special population dosage recommendations.

Cautions for Aducanumab

Contraindications

• None.

Warnings/Precautions

Amyloid Related Imaging Abnormalities (ARIA)

Risk of ARIA, characterized as amyloid related imaging abnormalities-edema (ARIA-E), which can be observed on MRI as brain edema or sulcaleffusions, and amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H), which includesmicrohemorrhage 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 seizure and status epilepticus, can occur. Symptoms include headache, confusion, visual changes, dizziness, nausea, and gait difficulty. Focal neurologic deficits may also occur. Symptoms associated with ARIA usually resolve over time.

Risk of ARIA is increased in apolipoprotein E e4 (ApoE e4) homozygotes.

Intracerebral hemorrhages >1 cm in diameter, some fatal, also reported in patients treated with aducanumab.

Consider benefit of aducanumab and potential risk of serious adverse events associated with ARIA when deciding whether to initiate treatment.

Perform testing for ApoE e4 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 aducanumab; however, it cannot be determined if they are ApoE e4 homozygotes and at higher risk for ARIA. FDA-authorized test for the detection of ApoE e4 alleles not currently available.

Recommendations on management of ARIA do not differ between ApoE e4 carriers and noncarriers.

Perform baseline brain MRI and periodic monitoring with MRI during treatment. Enhanced clinical vigilance for ARIA recommended during the first 8 doses, especially during titration.

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.

Recommendations for dosing in patients with ARIA-E depend on clinical symptoms and radiographic severity.

Limited experience in patients who continued dosing through symptomatic ARIA-E, or through asymptomatic moderate to severe ARIA-E. Limited data in dosing patients who experience recurrent ARIA-E.

Recommendations for dosing in patients with ARIA-H depend on the type of ARIA-H and radiographic severity.

Exercise additional caution when considering administration of anticoagulants or thrombolytic agents (e.g., tissue plasminogen activator) to patients already being treated with aducanumab. Exercise caution when considering use of aducanumab in patients with risk factors for intracerebral hemorrhage, particularly in patients who require anticoagulant therapy.

The Alzheimer’s Network for Treatment and Diagnostics (ALZ-NET) is a patient registry that collects information on treatments for Alzheimer’s disease. Providers may obtain information about the registry at [Web] or contact alz-net@acr.org.

Hypersensitivity

Hypersensitivity reactions (e.g., angioedema, urticaria) reported.

Discontinue IV infusion promptly and initiate appropriate medical treatment if hypersensitivity reaction occurs.

Immunogenicity

Development of anti-drug antibodies reported; however, effects on pharmacokinetics, safety, or efficacy not known.

Specific Populations

Pregnancy

Not known whether aducanumab is associated with risk if used during pregnancy.

Lactation

Not known whether aducanumab is distributed into milk, affects milk production, or affects the breast-fed infant.

Consider known benefits of breast-feeding along with mother's clinical need for aducanumab and any potential adverse effects of the drug or disease on the infant.

Pediatric Use

Not studied in pediatric patients.

Geriatric Use

No safety differences noted between patients ≥65 years of age and patients ≥75 years of age, or in older versus younger patients.

Hepatic Impairment

Not studied; not expected to be metabolized by hepatic enzymes.

Renal Impairment

Not studied; not expected to be eliminated renally.

Common Adverse Effects

Most common adverse reactions (≥10%) include ARIA-E, headache, ARIA-H microhemorrhage, ARIA-H superficial siderosis, fall.

Drug Interactions

There is no information regarding drug interactions with aducanumab in the prescribing information.

Aducanumab Pharmacokinetics

Absorption

Bioavailability

Steady-state concentrations reached by 16 weeks following repeated dosing. Exposure increases proportionally with increasing doses.

Elimination

Metabolism

Degraded into small peptides and amino acids through catabolic pathways.

Half-life

24.8 days.

Stability

Storage

Parenteral

Injection

Unopened vials: 2–8°C; do not freeze. Protect from light; store in original carton until use.

Unopened vials may be stored at room temperature (up to 25°C) for a maximum of 3 days. May be returned to the refrigerator if the total time at room temperature does not exceed 24 hours.

Diluted solution: May store at 2–8°C for up to 3 days or at room temperature (up to 30°C) for up to 12 hours.

Actions

• Human IgG₁ monoclonal antibody that targets aggregated forms of amyloid beta.

• Reduces amyloid beta plaques in a dose- and time-dependent manner.

• Amyloid beta plaque accumulation in the brain is a hallmark feature of Alzheimer's disease and is hypothesized to contribute to the pathogenesis of cognitive decline.

Advice to Patients

• Advise patients that aducanumab can cause amyloid related imaging abnormalities (ARIA). ARIA typically presents as temporary swelling of areas in the brain that usually resolves over time. Some patients may also develop small spots of bleeding in or on the surface of the brain. Inform patients that most cases are asymptomatic, but some patients may experience symptoms such as headache, confusion, dizziness, vision changes, and nausea, and should notify their healthcare provider if these symptoms occur. Inform patients that they will be scheduled for MRI scans to monitor for ARIA.

• Inform patients that events of intracerebral hemorrhage >1 cm in diameter have been reported infrequently in patients taking aducanumab, and that the use of anticoagulant or thrombolytic medications while taking aducanumab may increase the risk of bleeding in the brain.

• Inform patients that although ARIA can occur in any patient treated with aducanumab, there is an increased risk in patients who are apolipoprotein E e4 (ApoE e4) homozygotes and that testing for ApoE e4 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 e4 homozygotes and at a higher risk for ARIA.

• Advise patients that the Alzheimer’s Network for Treatment and Diagnostics (ALZ-NET) is a voluntary provider-enrolled patient registry that collects information on treatments for Alzheimer’s disease, including aducanumab. Encourage patients to participate in the ALZ-NET registry.

• Inform patients that aducanumab can cause hypersensitivity reactions, such as angioedema and urticaria.

• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.

• Advise 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.

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