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For current labeling information, please visit https://www.fda.gov/drugsatfda
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ADUHELM™ safely and effectively. See full prescribing information for
ADUHELM.

_____________ DOSAGE FORMS AND STRENGTHS ______________
Injection:• 170 mg/1.7 mL (100 mg/mL) solution in a single-dose vial (3)• 300 mg/3 mL (100 mg/mL) solution in a single-dose vial (3)ADUHELM™ (aducanumab-avwa) injection, for intravenous use
Initial U.S. Approval: 2021

None. (4)___________________ CONTRAINDICATIONS _____________________________________ INDICATIONS AND USAGE ________________________________ WARNINGS AND PRECAUTIONS _______________• Amyloid Related Imaging Abnormalities (ARIA): Enhanced clinicalvigilance for ARIA is recommended during the first 8 doses of treatment
with ADUHELM, particularly during titration. If a patient experiences
symptoms which could be suggestive of ARIA, clinical evaluation shouldbe performed, including MRI testing if indicated. (2.2, 5.1)
• Hypersensitivity Reactions: Angioedema and urticaria have occurred. If a
hypersensitivity reaction occurs, promptly discontinue the infusion of
ADUHELM and initiate appropriate therapy. (5.2)

ADUHELM is an amyloid beta-directed antibody indicated for the treatmentof Alzheimer’s disease. This indication is approved under accelerated
approval based on reduction in amyloid beta plaques observed in patientstreated with ADUHELM. Continued approval for this indication may becontingent upon verification of clinical benefit in confirmatory trial(s). (1)_______________DOSAGE AND ADMINISTRATION ______________• Titration is required for treatment initiation. (2.1)• The recommended maintenance dosage is 10 mg/kg administered as an
intravenous infusion over approximately one hour every four weeks. (2.1)• Obtain a recent (within one year) brain MRI prior to initiating treatment.
(2.2, 5.1)
• Obtain MRIs prior to the 7th and 12th infusions. If radiographic severe
ARIA-H is observed, treatment may be continued with caution only after aclinical evaluation and a follow-up MRI demonstrates radiographic
stabilization (i.e., no increase in size or number of ARIA-H). (2.2, 5.1)
• Dilution in 100 mL of 0.9% Sodium Chloride Injection, USP, is required
prior to administration. (2.4)• Administer as an intravenous infusion over approximately one hour via a
0.2 or 0.22 micron in-line filter. (2.5)___________________ ADVERSE REACTIONS ___________________
Most common adverse reactions (at least 10% and higher incidence comparedto placebo): ARIA-Edema, headache, ARIA-H microhemorrhage, ARIA-H
superficial siderosis, and fall. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1833-425-9360 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 6/2021

FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1 Dosing Instructions
2.2 Monitoring for Amyloid Related Imaging Abnormalities
2.3 Resuming ADUHELM After Missed Dose
2.4 Dilution Instructions
2.5 Administration Instructions
3
DOSAGE FORMS AND STRENGTHS
4CONTRAINDICATIONS5WARNINGS AND PRECAUTIONS
5.1 Amyloid Related Imaging Abnormalities
5.2 Hypersensitivity Reactions
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Immunogenicity
8
USE IN SPECIFIC POPULATIONS

11
12

13
14
16

17

8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
DESCRIPTION
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
CLINICAL STUDIESHOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage and Handling
PATIENT COUNSELING INFORMATION*Sections or subsections omitted from the full prescribing information are not listed.

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FULL PRESCRIBING INFORMATION
1

INDICATIONS AND USAGE

ADUHELM is indicated for the treatment of Alzheimer’s disease. This indication is approved
under accelerated approval based on reduction in amyloid beta plaques observed in patientstreated with ADUHELM [see Clinical Studies (14)]. Continued approval for this indication may
be contingent upon verification of clinical benefit in confirmatory trial(s).

2DOSAGE AND ADMINISTRATION

2.1

Dosing Instructions

After an initial titration, the recommended dosage of ADUHELM is 10 mg/kg (see Table 1).
ADUHELM is administered as an intravenous (IV) infusion over approximately one hour every
four weeks and at least 21 days apart.
Table 1: Dosing Schedule
IV Infusion(every 4 weeks)
Infusion 1 and 2
Infusion 3 and 4
Infusion 5 and 6
Infusion 7 and beyond

2.2

ADUHELM Dosage(administered overapproximately one hour)
1 mg/kg
3 mg/kg
6 mg/kg
10 mg/kg

Monitoring for Amyloid Related Imaging Abnormalities

Obtain recent (within one year) brain magnetic resonance imaging (MRI) prior to initiating
treatment. Obtain MRIs prior to the 7th infusion (first dose of 10 mg/kg) and 12th infusion (sixth
dose of 10 mg/kg). If 10 or more new incident microhemorrhages or > 2 focal areas of superficial
siderosis (radiographic severe ARIA-H) is observed, treatment may be continued with caution
only after a clinical evaluation and a follow-up MRI demonstrates radiographic stabilization (i.e.,
no increase in size or number of ARIA-H) [see Warnings and Precautions (5.1)].

2.3

Resuming ADUHELM After Missed DoseIf an infusion is missed, resume administration at the same dose as soon as possible [see Dosage
and Administration (2.1)]. Infusions are to be administered every 4 weeks and at least 21 days
apart.

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2.4

Dilution Instructions•

Use aseptic technique when preparing the ADUHELM diluted solution for intravenous
infusion. Each vial is for single-dose only. Discard any unused portion.

•

Calculate the dose, total volume of ADUHELM solution required, and the number of vials
needed based on the patient’s actual body weight. Each vial contains an ADUHELM
concentration of 100 mg per mL. More than one vial may be needed for a full dose.

•

Select the correct vial(s) for the required volume [see Dosage Forms and Strengths (3)].

•Check that the ADUHELM solution is clear to opalescent and colorless to yellow solution.
Do not use if opaque particles, discoloration, or other foreign particles are present.

•

Remove the flip-off cap from the vial. Insert the syringe needle into the vial through thecenter of the rubber stopper.

•

Withdraw the required volume of ADUHELM from the vial(s) and add to an infusion bag of
100 mL of 0.9% Sodium Chloride Injection, USP. Do not use other intravenous diluents to
prepare the ADUHELM diluted solution.

•

Gently invert the infusion bag containing the ADUHELM diluted solution to mix completely.
Do not shake.

•

After dilution, immediate use is recommended. If not administered immediately, store thediluted solution of ADUHELM in 0.9% Sodium Chloride Injection, USP refrigerated at 2°C
to 8°C (36°F to 46°F) for up to 3 days, or at room temperature up to 30°C (86°F) for up to 12hours.

•

Prior to infusion, allow the ADUHELM diluted solution to warm to room temperature.

2.5

Administration Instructions•

Visually inspect the ADUHELM diluted solution for particles or discoloration prior toadministration. Do not use if it is discolored, or opaque or foreign particles are seen.

•

Infuse ADUHELM diluted solution intravenously over approximately one hour through an
intravenous line containing a sterile, low-protein binding, 0.2 or 0.22 micron in-line filter.

•

Promptly discontinue the infusion upon the first observation of any signs or symptoms
consistent with a hypersensitivity-type reaction [see Warnings and Precautions (5.2)].

3

DOSAGE FORMS AND STRENGTHSADUHELM is a clear to opalescent and colorless to yellow solution, available as:•

Injection: 170 mg/1.7 mL (100 mg/mL) in a single-dose vial•

Injection: 300 mg/3 mL (100 mg/mL) in a single-dose vial

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4

CONTRAINDICATIONS

None.

5

WARNINGS AND PRECAUTIONS

5.1

Amyloid Related Imaging Abnormalities

ADUHELM can cause amyloid related imaging abnormalities-edema (ARIA-E), which can beobserved on MRI as brain edema or sulcal effusions, and amyloid related imaging abnormalitieshemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis.
Obtain recent (within one year) brain magnetic resonance imaging (MRI) prior to initiating
treatment [see Dosage and Administration (2.2)]. The safety of ADUHELM in patients with any
pre-treatment localized superficial siderosis, 10 or more brain microhemorrhages, and/or with abrain hemorrhage greater than 1 cm within one year of treatment initiation has not been
established.
In clinical studies of ADUHELM, the severity of ARIA was classified by radiographic criteria,
as shown in Table 2.
Table 2: ARIA MRI Classification Criteria
ARIA
Type

Radiographic Severity
Mild

Moderate

Severe

ARIA-EFLAIR hyperintensity
confined to sulcus and or
cortex/subcortical whitematter in one location< 5 cmFLAIR hyperintensity 5
to 10 cm, or more than
1 site of involvement,each measuring < 10cm

FLAIR hyperintensity
measuring > 10 cm, oftenwith significant subcorticalwhite matter and/or sulcal
involvement. One or more
separate sites of
involvement may be noted.

ARIA-H
microhemorrhage≤ 4 new incident
microhemorrhages

5 to 9 new incident
microhemorrhages

10 or more new incident
microhemorrhages

ARIA-H
1 focal area ofsuperficial siderosis superficial siderosis

2 focal areas ofsuperficial siderosis> 2 focal areas ofsuperficial siderosis

In Studies 1 and 2, ARIA (-E and/or -H) was observed in 41% of patients treated with
ADUHELM with a planned dose of 10 mg/kg (454 out of 1105), compared to 10% of patients onplacebo (111 out of 1087).
ARIA-E was observed in 35% of patients treated with ADUHELM 10 mg/kg, compared to 3%of patients on placebo. The incidence of ARIA-E was higher in apolipoprotein E ε4 (ApoE ε4)
carriers than in ApoE ε4 non-carriers (42% and 20%, respectively). The majority of ARIA-E
radiographic events occurred early in treatment (within the first 8 doses), although ARIA canoccur at any time. Among patients treated with a planned dose of ADUHELM 10 mg/kg who
had ARIA-E, the maximum radiographic severity was mild in 30%, moderate in 58%, and severe
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in 13% of patients. Resolution occurred in 68% of ARIA-E patients by 12 weeks, 91% by 20
weeks, and 98% overall after detection. 10% of all patients who received ADUHELM 10 mg/kg
had more than one episode of ARIA-E.
ARIA-H in the setting of ARIA-E associated with the use of ADUHELM 10 mg/kg wasobserved in 21% of patients treated with ADUHELM 10 mg/kg, compared to 1% of patients onplacebo. There was no imbalance in isolated ARIA-H (i.e., ARIA-H in patients who did not also
experience ARIA-E) between ADUHELM and placebo. There was no imbalance in hemorrhage
greater than 1 cm between ADUHELM and placebo.
Clinical symptoms were present in 24% of patients treated with ADUHELM 10 mg/kg who had
an observation of ARIA (-E and/or -H), compared to 5% of patients on placebo. The mostcommon symptom in patients treated with ADUHELM 10 mg/kg with ARIA was headache(13%). Other frequent symptoms were confusion/delirium/altered mental status/disorientation(5%), dizziness/vertigo (4%), visual disturbance (2%), and nausea (2%). Serious symptoms
associated with ARIA were reported in 0.3% of patients treated with ADUHELM 10 mg/kg.
Clinical symptoms resolved in the majority of patients (88%) during the period of observation.
Enhanced clinical vigilance for ARIA is recommended during the first 8 doses of treatment with
ADUHELM, particularly during titration, as this is the time the majority of ARIA was observedin Studies 1 and 2. If a patient experiences symptoms which could be suggestive of ARIA,
clinical evaluation should be performed, including MRI testing if indicated. If ARIA is observedon MRI in the presence of clinical symptoms, careful clinical evaluation should be performed
prior to continuing treatment.
Obtain brain MRIs prior to the 7th infusion (first dose of 10 mg/kg) and 12th infusion (sixth doseof 10 mg/kg) of ADUHELM to evaluate for the presence of asymptomatic ARIA. For patientswith radiographic findings of ARIA, enhanced clinical vigilance is recommended. Additional
MRIs may be considered if clinically indicated. If radiographically severe ARIA-H is observed,
treatment may be continued with caution only after a clinical evaluation and a follow-up MRI
demonstrates radiographic stabilization (i.e., no increase in size or number of ARIA-H). For
ARIA-E or mild/moderate ARIA-H, treatment may continue with caution. If dosing is
temporarily suspended, dosing may resume at that same dose and titration schedule. There are no
systematic data on continued dosing with ADUHELM following detection of radiographicallymoderate or severe ARIA. In Studies 1 and 2, temporary dose suspension was required forradiographically moderate or severe ARIA-E and radiographically moderate ARIA-H. In Studies
1 and 2, permanent discontinuation of dosing was required for radiographically severe ARIA-H.
The benefits of reaching and maintaining the 10 mg/kg dose should be considered whenevaluating a potential dose suspension.

5.2

Hypersensitivity Reactions

Angioedema and urticaria were reported in one patient in the placebo-controlled period ofStudies 1 and 2, and occurred during the ADUHELM infusion. Promptly discontinue theinfusion upon the first observation of any signs or symptoms consistent with a hypersensitivity
reaction, and initiate appropriate therapy.

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6ADVERSE REACTIONS

The following adverse reactions are described elsewhere in the labeling:• Amyloid Related Imaging Abnormalities [see Warnings and Precautions (5.1)]•

6.1

Hypersensitivity Reactions [see Warnings and Precautions (5.2)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in 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 clinical practice.
The safety of ADUHELM has been evaluated in 3,078 patients who received at least one dose of
ADUHELM. In two placebo-controlled studies (Studies 1 and 2) in patients with Alzheimer’s
disease, a total of 1105 patients received ADUHELM 10 mg/kg [see Clinical Studies (14)]. Of
these 1105 patients, approximately 52% were female, 76% were White, 10% were Asian, and
3% were of Hispanic or Latino ethnicity. The mean age at study entry was 70 years (range from50 to 85).
In the combined placebo-controlled and long-term extension periods of Studies 1 and 2, 834
patients received at least one dose of ADUHELM 10 mg/kg once monthly for at least 6 months,
551 patients for at least 12 months, and 309 patients for at least 18 months. In the combinedplacebo-controlled and long-term extension periods, 5% (66 out of 1386) of patients in the 10
mg/kg dose group withdrew from the study because of an adverse reaction. The most common
adverse reaction resulting in study withdrawal in the combined placebo-controlled and long-term
extension periods was ARIA-H superficial siderosis. Table 3 shows adverse reactions that werereported in at least 2% of patients treated with ADUHELM and at least 2% more frequently thanin patients on placebo.
Table 3: Adverse Reactions Reported in at Least 2% of Patients Treated with ADUHELM
10 mg/kg and at Least 2% Higher Than Placebo in Studies 1 and 2

Adverse Reaction
ARIA-E
Headachea
ARIA-H microhemorrhage
ARIA-H superficial siderosis
Fall
Diarrheab
Confusion/Delirium/Altered Mental
Status/Disorientationc

ADUHELM
10 mg/kg
N=1105
%
35
21
19
15
15
9
8

a

Placebo
N=1087
%
3
16
7
2
12
7
4

Headache includes the adverse reaction related terms headache, head discomfort, migraine, migraine with aura, and occipital neuralgia.
Diarrhea includes the adverse reaction related terms diarrhea and infectious diarrhea.
cConfusion/Delirium/Altered Mental Status/Disorientation includes the adverse reaction related terms confusional state, delirium, altered state ofconsciousness, disorientation, depressed level of consciousness, disturbance in attention, mental impairment, mental status changes,
postoperative confusion, and somnolence.
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6.2

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody
formation is highly dependent on the sensitivity and specificity of the assay. Additionally, theobserved incidence of antibody (including neutralizing antibody) positivity in an assay may be
influenced by several factors including assay methodology, sample handling, timing of sample
collection, concomitant medications, and underlying disease. For these reasons, comparison of
the incidence of antibodies in the studies described below with the incidence of antibodies inother studies or to other aducanumab products may be misleading.
The immunogenicity of ADUHELM has been evaluated using an in vitro assay for the detectionof binding anti-aducanumab-avwa antibodies.
In up to 41 months of treatment in the combined placebo-controlled and long-term extension
periods of Studies 1 and 2, up to 0.6% (15/2689) of patients receiving ADUHELM once monthly
developed anti-aducanumab-avwa antibodies.
Based on the limited number of patients who tested positive for anti-aducanumab-avwa
antibodies, no observations were made concerning a potential effect of neutralizing activity ofanti-aducanumab-avwa antibodies on exposure or efficacy; however, the available data are too
limited to make definitive conclusions regarding an effect on pharmacokinetics, safety, or
efficacy of ADUHELM. Quantification of neutralizing anti-aducanumab-avwa antibodies has notbeen assessed.

8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy

Risk Summary
There are no adequate data on ADUHELM use in pregnant women to evaluate for a drugassociated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.
In the U.S. general population, the estimated background risk of major birth defects andmiscarriage 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.
Data
Animal Data
Intravenous administration of aducanumab-avwa (0, 100, 300, or 1000 mg/kg/week) to female
rats through organogenesis had no adverse effect on embryofetal development.
Intravenous administration of aducanumab-avwa (0, 100, 300, or 1000 mg/kg/week) to female
rats throughout pregnancy and lactation had no adverse effects on pre- or postnatal development.
The relevance of these data to humans is limited because aggregated amyloid beta, thepharmacological target of aducanumab-avwa, is not present in rat.

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8.2

Lactation

Risk Summary
There are no data on the presence of aducanumab-avwa in human milk, the effects on thebreastfed infant, or the effects of the drug on milk production. The developmental and healthbenefits of breastfeeding should be considered along with the mother’s clinical need for
ADUHELM and any potential adverse effects on the breastfed infant from ADUHELM or fromthe underlying maternal condition.

8.4

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5

Geriatric Use

In Studies 1 and 2, the age of patients ranged from 50 to 85 years, with a mean age of 70 years;
79% were 65 and older, and 32% were 75 and older. There were no notable differences in theincidence of adverse reactions between these age groups, and no additional safety concerns inpatients 65 years of age and older compared to younger patients.

11

DESCRIPTION

Aducanumab-avwa is a recombinant human immunoglobulin gamma 1 (IgG1) monoclonal
antibody directed against aggregated soluble and insoluble forms of amyloid beta, and isexpressed in a Chinese hamster ovary cell line. Aducanumab-avwa has an approximate
molecular weight of 146 kDa.
ADUHELM (aducanumab-avwa) injection is a preservative-free, sterile, clear to opalescent, andcolorless to yellow solution for intravenous infusion after dilution supplied in single-dose vials
available in concentrations of 170 mg/1.7 mL (100 mg/mL) or 300 mg/3 mL (100 mg/mL) of
ADUHELM.
Each mL of solution contains 100 mg of aducanumab-avwa and L-arginine hydrochloride (31.60mg), L-histidine (0.60 mg), L-histidine hydrochloride monohydrate (3.39 mg), L-methionine(1.49 mg), polysorbate 80 (0.50 mg), and Water for Injection at an approximate pH of 5.5.

12

CLINICAL PHARMACOLOGY

12.1

Mechanism of Action

Aducanumab-avwa is a human, immunoglobulin gamma 1 (IgG1) monoclonal antibody directedagainst aggregated soluble and insoluble forms of amyloid beta. The accumulation of amyloid
beta plaques in the brain is a defining pathophysiological feature of Alzheimer’s disease.
ADUHELM reduces amyloid beta plaques, as evaluated in Studies 1, 2, and 3 [see ClinicalStudies (14)].

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12.2

Pharmacodynamics

Effect of ADUHELM on Amyloid Beta Pathology
ADUHELM reduced amyloid beta plaque in a dose- and time-dependent manner in Study 1,
Study 2, and Study 3, compared with placebo [see Dosage and Administration (2.1) and ClinicalStudies (14)].
The effect of ADUHELM on amyloid beta plaque levels in the brain was evaluated using 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 (frontal, parietal, lateral
temporal, sensorimotor, and anterior and posterior cingulate cortices), compared to a brain region
expected to be spared of such pathology (cerebellum). The SUVR was also expressed on theCentiloid scale.
In substudies of Study 1 and Study 2, ADUHELM reduced amyloid beta plaque levels in thebrain, producing reductions at both ADUHELM low dose and high dose levels and at bothWeeks 26 and 78 (p < 0.0001), compared to placebo. The magnitude of reduction was time- anddose-dependent. In the long-term extension of Study 1 and Study 2, a continued decrease in brain
amyloid beta plaque levels was observed at Week 132 in patients initially randomized to
ADUHELM.
In Study 3, ADUHELM reduced amyloid beta plaque levels in the brain, producing statisticallysignificant dose- and time-dependent reductions compared to placebo in the 3 mg/kg, 6 mg/kg,
and 10 mg/kg ADUHELM treatment groups at Week 26, and in all ADUHELM treatmentgroups at Week 54. Among those dosed with ADUHELM during the placebo-controlled period
in Study 3, amyloid beta plaque levels in the brain continued to decline in a time- and dosedependent manner in the long-term extension period through Week 222.
Effect of ADUHELM on Tau Pathophysiology
ADUHELM reduced markers of tau pathophysiology (CSF p-Tau and Tau PET) andneurodegeneration (CSF t-Tau) in Study 1 and Study 2 [see Clinical Studies (14)].
ADUHELM reduced CSF levels of p-Tau in substudies conducted in Study 1 and Study 2. The
adjusted mean change from baseline in CSF p-Tau levels relative to placebo was in favor of the
ADUHELM low (p<0.01) and high (p<0.001) dose groups at Week 78 in Study 1. Results inStudy 2 numerically favored ADUHELM but were not statistically significant.
ADUHELM reduced CSF levels of t-Tau in substudies conducted in Study 1 and Study 2. The
adjusted mean change from baseline in CSF t-Tau levels relative to placebo was in favor of the
ADUHELM low (p<0.05) and high (p<0.01) dose groups at Week 78 in Study 1. Results inStudy 2 numerically favored ADUHELM but were not statistically significant.
Substudies were conducted in both Study 1 and Study 2 to evaluate the effect of ADUHELM onneurofibrillary tangles composed of tau protein using PET imaging (18F-MK6240 tracer). The
PET signal was quantified using the SUVR method to estimate brain levels of tau in brain
regions expected to be affected by Alzheimer’s disease pathology (medial temporal, temporal,
frontal, cingulate, parietal, and occipital cortices) in the study population compared to a brain
region expected to be spared of such pathology (cerebellum). Data from the substudies were

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pooled, comprising 37 patients with longitudinal follow-up. The adjusted mean change frombaseline in tau PET SUVR relative to placebo at follow-up was in favor of ADUHELM highdose in the medial temporal (p<0.001), temporal (p<0.05), and frontal (p<0.05) brain regions. No
statistically significant differences were observed for the cingulate, parietal, or occipital cortices.
Exposure-Response Relationships
Model based exposure-response analyses for Studies 1 and 2 demonstrated that higher exposures
to ADUHELM were associated with greater reduction in clinical decline on CDR-SB, ADASCog13, and ADCS-ADL-MCI. In addition, higher exposures to ADUHELM were associatedwith greater reduction in amyloid beta plaque in Studies 1 and 2. An association between
reduction in amyloid beta plaque and clinical decline on CDR-SB was also observed.

12.3

Pharmacokinetics

The pharmacokinetics (PK) of ADUHELM were characterized using a population PK analysis
with concentration data collected from 2961 subjects with Alzheimer’s disease who received
ADUHELM in single or multiple doses.
Steady-state concentrations of ADUHELM were reached by 16 weeks of repeated dosing with an
every 4-week regimen, and the systemic accumulation was 1.7-fold. The peak concentration(Cmax), trough concentration (Cmin), and area under the plasma concentration versus time curve at
steady state (AUCss) of ADUHELM increased dose proportionally in the dose range of 1 to 10
mg/kg every 4 weeks.
Distribution
The mean value (95% CI) for volume of distribution at steady state is 9.63 L (9.48, 9.79).
Elimination
ADUHELM is expected to be degraded into small peptides and amino acids via catabolic
pathways in the same manner as endogenous IgG. ADUHELM clearance (95% CI) is 0.0159(0.0156, 0.0161) L/hr. The terminal half-life is 24.8 (14.8, 37.9) days.
Specific Populations
Body weight, age, sex, and race were found to impact exposure to ADUHELM. However, noneof these covariates were found to be clinically significant.
Patients with Renal or Hepatic Impairment
No studies were conducted to evaluate the pharmacokinetics of ADHUELM in patients withrenal or hepatic impairment. ADUHELM is not expected to undergo renal elimination or
metabolism by hepatic enzymes.

13

NONCLINICAL TOXICOLOGY

13.1

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
Carcinogenicity studies have not been conducted.
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Mutagenesis
Genotoxicity studies have not been conducted.
Impairment of Fertility
Intravenous administration of aducanumab-avwa (0, 100, 300, or 1000 mg/kg/week) to male andfemale rats prior to and during mating and continuing in females to gestation day 7 resulted in noadverse effects on fertility or reproductive performance.
The relevance of these data to humans is limited because aggregated amyloid beta, thepharmacological target of aducanumab-avwa, is not present in rat.

14

CLINICAL STUDIESThe efficacy of ADUHELM was evaluated in two double-blind, randomized, placebo-controlled,parallel group studies (Study 1, NCT 02484547 and Study 2, NCT 02477800) in patients with
Alzheimer’s 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’s
disease, stratified to include 80% Stage 3 patients and 20% Stage 4 patients). The effects of
ADUHELM were also supported by a double-blind, randomized, placebo-controlled, doseranging study (Study 3, NCT 01677572) in patients with Alzheimer’s disease (patients withconfirmed presence of amyloid pathology and prodromal or mild dementia stage of disease,consistent with Stage 3 and Stage 4 Alzheimer’s disease, with an enrolled distribution of 43%
Stage 3 patients and 57% Stage 4 patients), followed by an optional, dose-blind, long-term
extension period.
In Studies 1 and 2, patients were randomized to receive ADUHELM low dose (3 or 6 mg/kg for
ApoE ε4 carriers and noncarriers, respectively), ADUHELM high dose (10 mg/kg), or placebo
every 4 weeks for 18 months, followed by an optional, dose-blind, long-term extension period.
Both studies included an initial titration period of up to 6 months to the maximum target dose. At
the beginning of the study, ApoE ε4 carriers were initially titrated up to a maximum of 6 mg/kg
in the high dose group, which was later adjusted to 10 mg/kg.
In Studies 1 and 2, patients were enrolled with a Clinical Dementia Rating (CDR) global score of
0.5, a Repeatable Battery for Assessment of Neuropsychological Status (RBANS) delayed
memory index score ≤ 85, and a Mini-Mental State Examination (MMSE) score of 24-30. In
Study 3, patients were enrolled with a global CDR score of 0.5 or 1.0 and an MMSE score of 2030. Patients were enrolled with or without concomitant approved therapies (cholinesterase
inhibitors and the N-methyl-D-aspartate antagonist memantine) for Alzheimer’s disease.
Studies 1 and 2 were terminated prior to their planned completion. Study endpoints wereanalyzed based on the prespecified statistical analysis plan.
Study 1In Study 1, 1638 patients were randomized 1:1:1 to receive ADUHELM low dose, ADUHELM
high dose, or placebo. At baseline, the mean age of patients was 71 years, with a range of 50 to85 years.

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For current labeling information, please visit https://www.fda.gov/drugsatfda

A subgroup of 488 patients were enrolled in the amyloid PET substudy; of these, 302 were
evaluated at week 78. Results from the amyloid beta PET and CSF biomarker substudies aredescribed in Figure 1 and Table 4.
Figure 1:

Reduction in Brain Amyloid Beta Plaque (Change from Baseline in Amyloid
Beta PET Composite, SUVR and Centiloids) in Study 1*** p<0.001

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Table 4: Biomarker Results of ADUHELM in Study 1

Amyloid Beta PET Composite SUVR
Mean baseline
Change from baseline
Difference from placebo

ADUHELM
High dose
N=170
1.383
-0.264-0.278, p<0.0001

Amyloid Beta PET Centiloid
Mean baseline
Change from baseline (%)
Difference from placebo
CSF p-Tau (pg/mL)
Mean baseline
Change from baseline
Difference from placebo
CSF t-Tau (pg/mL)
Mean baseline
Change from baseline
Difference from placebo

N=170
85.3
-60.8 (-71%)-64.2, p<0.0001
N=17100.11-22.93-22.44, p=0.0005
N=17686.65-112.44-112.05, p=0.0088

Biomarker Endpoint at Week 781

Placebo
N=159
1.375
0.014
N=159
83.5
3.4
N=28
72.55
-0.49
N=28
484.00-0.39

1P-values were not statistically controlled for multiple comparisons.

The primary efficacy endpoint was the change from baseline on the CDR-Sum of Boxes (CDRSB) at Week 78. In Study 1, treatment with ADUHELM high dose demonstrated reduced clinicaldecline, as evidenced by a statistically significant treatment effect on change from baseline in
CDR-SB compared to placebo (-0.39 [-22%], p = 0.0120), as shown in Figure 2 and Table 5. The
estimate of the treatment effect favored ADUHELM across all prespecified subgroups ofinterest.

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Figure 2: Line Plot of Primary Efficacy Endpoint (Change From Baseline in CDR Sum ofBoxes) in Study 1* p<0.05

Secondary efficacy endpoints included the change from baseline in MMSE score at Week 78, thechange from baseline in the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (13items) (ADAS-Cog 13) at Week 78, and the change from baseline in the Alzheimer’s Disease
Cooperative Study – Activities of Daily Living Inventory (Mild Cognitive Impairment version)(ADCS-ADL-MCI) score at Week 78. In Study 1, statistically significant differences fromplacebo were observed in the ADUHELM high dose group on all secondary efficacy endpoints
evaluated. The estimate of the treatment effect favored ADUHELM across most prespecified
subgroups of interest for the secondary efficacy endpoints. The Neuropsychiatric Inventory-10
item (NPI-10) was the only tertiary endpoint that assessed efficacy. The results of the high dosegroup, compared to placebo, are presented in Table 5.

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Differences from placebo observed in the ADUHELM low dose group numerically favored
ADUHELM but were not statistically significant.
Table 5: Clinical Results of ADUHELM in Study 1
Clinical Endpoint at Week 78

ADUHELM High dose
(N=547)

Placebo(N=548)2.51
1.35-0.39 (-22%)
p=0.0120

2.47
1.74

26.3
-2.7
0.6 (-18%)
p=0.0493

26.4
-3.3

22.2463.763-1.400 (-27%)
p=0.0097

21.867
5.162

42.5
-2.5
1.7 (-40%)
p=0.0006

42.6
-4.3

4.5
0.2
-1.3 (-87%)
p=0.0215

4.3
1.5

CDR-SB
Mean baseline
Change from baseline
Difference from placebo (%)
MMSE
Mean baseline
Change from baseline
Difference from placebo (%)
ADAS-Cog 13
Mean baseline
Change from baseline
Difference from placebo (%)
ADCS-ADL-MCI
Mean baseline
Change from baseline
Difference from placebo (%)
NPI-101
Mean baseline
Change from baseline
Difference from placebo (%)
1

P-value was not statistically controlled for multiple comparisons.

Study 2
In Study 2, 1647 patients were randomized 1:1:1 to receive ADUHELM low dose, ADUHELM
high dose, or placebo. At baseline, the mean age of patients was 71 years, with a range of 50 to85 years.
A subgroup of 585 patients were enrolled in the amyloid PET subgroup; of these, 374 were
evaluated at week 78. Results from the amyloid beta PET and CSF biomarker substudies aredescribed in Figure 3 and Table 6.

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Reference ID: 4807032

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For current labeling information, please visit https://www.fda.gov/drugsatfda

Figure 3:

Reduction in Brain Amyloid Beta Plaque (Change from Baseline in Amyloid
Beta PET Composite, SUVR and Centiloids) in Study 2*** p<0.001

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Reference ID: 4807032

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For current labeling information, please visit https://www.fda.gov/drugsatfda

Table 6: Biomarker Results of ADUHELM in Study 2

Amyloid Beta PET Composite SUVR
Mean baseline
Change from baseline
Difference from placebo

ADUHELM
High dose
N=183
1.407
-0.235-0.232, p<0.0001

Amyloid Beta PET Centiloid
Mean baseline
Change from baseline (%)
Difference from placebo
CSF p-Tau (pg/mL)
Mean baseline
Change from baseline
Difference from placebo
CSF t-Tau (pg/mL)
Mean baseline
Change from baseline
Difference from placebo

N=183
90.8
-54.0 (-59%)-53.5, p<0.0001
N=18
121.81-13.19-10.95, p=0.3019
N=16618.50-102.51-69.25, p=0.3098

Biomarker Endpoint at Week 781

1

Placebo
N=204
1.376-0.003
N=204
83.8
-0.5
N=15
94.53
-2.24
N=14
592.57-33.26

P-values were not statistically controlled for multiple comparisons.

No statistically significant differences were observed between the ADUHELM-treated andplacebo-treated patients on the primary efficacy endpoint, the change from baseline in CDR-SB
score at 78 weeks.
Study 3
In Study 3, 197 patients were randomized to receive a fixed dose of ADUHELM 1 mg/kg(n=31), 3 mg/kg (n=32), 6 mg/kg (n=30), 10 mg/kg (n=32), titration of ADUHELM to 10 mg/kg
over 44 weeks (n=23), or placebo (n=48) for 12 months. At baseline, the mean age of patientswas 73 years, with a range of 51-91 years.
Results from the amyloid beta PET substudy are described in Figure 4 and Table 7.

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Figure 4:

Reduction in Brain Amyloid Beta Plaque (Change from Baseline in Amyloid
Beta PET Composite, SUVR and Centiloids ) in Study 3* p<0.05, ** p<0.01, *** p<0.001

Table 7: Biomarker Results of ADUHELM in Study 3
ADUHELM
10 mg/kg
N=28
1.432-0.263-0.277, p<0.0001

Biomarker Endpoint at Week 541
Amyloid Beta PET Composite SUVR
Mean baseline
Change from baseline
Difference from placebo
Amyloid Beta PET Centiloid
Mean baseline

N=28
94.5
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Placebo
N=42
1.441
0.014
N=42
96.5

This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda

Change from baseline (%)
Difference from placebo-58.0 (-61%)-61.1, p<0.0001

3.1

1

P-values were not statistically controlled for multiple comparisons.

Clinical assessments in Study 3 were exploratory. Results for clinical assessments weredirectionally aligned with the findings from Study 1, with less change from baseline in CDR-SB
and MMSE scores at 1 year in the ADUHELM 10 mg/kg fixed-dose group than in patients onplacebo (CDR-SB: -1.26, 95% CI [-2.356, -0.163]; MMSE: 1.9, 95% CI [0.06, 3.75]).

16

HOW SUPPLIED/STORAGE AND HANDLING

16.1

How Supplied

ADUHELM (aducanumab-avwa) injection is a preservative-free, sterile, clear to opalescent, andcolorless to yellow solution. ADUHELM is supplied one vial per carton as follows:
170 mg/1.7 mL (100 mg/mL) single-dose vial (with red flip cap) – NDC 64406-101-01
300 mg/3 mL (100 mg/mL) single-dose vial (with blue flip cap) – NDC 64406-102-02

16.2

Storage and Handling

Unopened Vial
•
•
•
•
•

Store in original carton until use to protect from light.
Store in a refrigerator at 2°C to 8°C (36°F to 46°F).
Do not freeze or shake.
If no refrigeration is available, ADUHELM may be stored unopened in its original carton toprotect from light at room temperature up to 25°C (77°F) for up to 3 days.
Prior to dilution, unopened vials of ADUHELM may be removed from and returned to therefrigerator if necessary, when kept in the original carton. Total combined time out of
refrigeration with protection from light should not exceed 24 hours at room temperature up to
25°C (77°F).

17

PATIENT COUNSELING INFORMATION

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication
Guide).
Amyloid Related Imaging Abnormalities
Inform patients that ADUHELM may cause Amyloid Related Imaging Abnormalities or“ARIA”. ARIA most commonly presents as temporary swelling in areas of the brain that usuallyresolves over time. Some people may also have small spots of bleeding in or on the surface ofthe 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, or nausea. Instruct patients to notify their healthcare provider if these19
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symptoms occur. Notify patients that their healthcare provider will perform MRI scans tomonitor for ARIA [see Warnings and Precautions (5.1)].
Hypersensitivity Reactions
Inform patients that ADUHELM may cause hypersensitivity reactions, including angioedema
and urticaria, and to contact their healthcare provider if hypersensitivity reactions occur [seeWarnings and Precautions (5.2)].
55093-01
Manufactured by:
Biogen Inc.
Cambridge, MA 02142
US License #1697
ADUHELM is a trademark of Biogen.
© 2021 Biogen and Eisai

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MEDICATION GUIDEADUHELM™ (AD-yew-helm)(aducanumab-avwa)
injection, for intravenous use
What is the most important information I should know about ADUHELM?
ADUHELM can cause serious side effects, including:
Amyloid Related Imaging Abnormalities or “ARIA”. ARIA is a common side effect that does not
usually cause any symptoms but can be serious. It is most commonly seen as temporary swelling inareas of the brain that usually resolves over time. Some people may also have small spots of bleeding inor on the surface of the brain with the swelling. Although most people with swelling in areas of the brain
do not have symptoms, some people may have symptoms, such as:o headacheo confusiono dizzinesso vision changes
o nauseaYour healthcare provider will do magnetic resonance imaging (MRI) scans before and during your treatment
with ADUHELM to check you for ARIA.
Call your healthcare provider or go to the nearest hospital emergency room right away if you haveany of the symptoms listed above.
What is ADUHELM?
• ADUHELM is a prescription medicine used to treat people with Alzheimer’s disease.
It is not known if ADUHELM is safe and effective in children.
Before receiving ADUHELM, tell your healthcare provider about all of your medical conditions,
including if you:• are pregnant or plan to become pregnant. It is not known if ADUHELM will harm your unborn baby. Tell
your healthcare provider if you become pregnant during your treatment with ADUHELM.
• are breastfeeding or plan to breastfeed. It is not known if aducanumab-avwa (the active ingredient in
ADUHELM) passes into your breast milk. Talk to your healthcare provider about the best way to feed yourbaby while receiving ADUHELM.
Tell your healthcare provider about all of the medicines you take, including prescription and over-thecounter medicines, vitamins, and herbal supplements.
How will I receive ADUHELM?
• ADUHELM is given through a needle placed in your vein (intravenous (IV) infusion) in your arm.
• ADUHELM is given every 4 weeks. Each infusion will last about 1 hour.
What are the possible side effects of ADUHELM?
ADUHELM can cause serious side effects, including:• See above “What is the most important information I should know about ADUHELM?”• Serious allergic reactions. Swelling of the face, lips, mouth, or tongue and hives have happened during
an ADUHELM infusion. Tell your healthcare provider if you have any of the symptoms of a serious
allergic reaction during or after ADUHELM infusion.
The most common side effects of ADUHELM include:• swelling in areas of the brain, with or without small spots of bleeding in or on the surface of the brain(ARIA)• headache• fallCall your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA1088.

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General Information about the safe and effective use of ADUHELM.
Medicines are sometimes prescribed for purposes other than those listed in this Medication Guide. You can
ask your pharmacist or healthcare provider for more information about ADUHELM that is written for healthprofessionals. For more information, go to www.aduhelm.com or call at 1-833-425-9360.
What are the ingredients in ADUHELM?
Active ingredient: aducanumab-avwa
Inactive ingredients: L-arginine hydrochloride, L-histidine, L-histidine hydrochloride monohydrate, Lmethionine, polysorbate 80, and water for injection
Manufactured by: Biogen Inc., Cambridge, MA 02142, U.S. License #1697
ADUHELM is a trademark of Biogen. ©2021 Biogen and Eisai
This Medication Guide has been approved by the U.S. Food and Drug Administration

Reference ID: 4807032

Approved: 6/2021