KISUNLA 350mg concentrate for solution for infusion medication leaflet

Kisunla 350 mg concentrate for solution for infusion

Each vial contains 350 mg donanemab in 20 mL (17.5 mg/mL).

Donanemab is a recombinant monoclonal humanised antibody produced in Chinese Hamster Ovary(CHO) cells.

Each 20 mL vial contains 11.5 mg sodium and 4 mg polysorbate 80.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

The solution is clear to opalescent, colourless to slightly yellow to slightly brown with a pH of5.5 - 6.5 and an osmolarity of approximately 300 mOsm/L.

Donanemab is indicated for the treatment of adult patients with a clinical diagnosis of mild cognitiveimpairment and mild dementia due to Alzheimer’s disease (Early symptomatic Alzheimer’s disease)who are apolipoprotein E ε4 (ApoE ε4) heterozygotes or non-carriers with confirmed amyloidpathology (see section 4.4).

Treatment should be initiated by a physician experienced in the diagnosis and treatment of

Alzheimer’s disease (AD) with timely access to Magnetic Resonance Imaging (MRI). Donanemabshould be administered under the supervision of a multidisciplinary team trained in detection,monitoring and management of amyloid-related imaging abnormalities (ARIA) and experienced indetecting and managing infusion related reactions (IRR).

Patients treated with donanemab must be given the patient card and be informed about the risks ofdonanemab (see also package leaflet).

ApoE ε4 Testing

ApoE ε4 genotype should be assessed by a CE-marked in vitro diagnostic (IVD) with thecorresponding intended purpose. If the CE-marked IVD is not available, an alternative validated testshould be used (see section 5.1).

Testing for ApoE ε4 status should be performed prior to initiation of treatment with donanemab toinform the risk of developing ARIA (see sections 4.1 and 4.4). Prior to testing patients should beappropriately counselled and consented according to national or local guidelines, as applicable.

Beta amyloid evidence consistent with AD should be confirmed using a validated test (e.g. positronemission tomography [PET] scan, cerebrospinal fluid [CSF] or another appropriate test).

Donanemab should be administered every 4 weeks. The recommended dose of donanemab is 350 mgfor the first dose, 700 mg for the second dose, 1 050 mg for the third dose, followed by 1 400 mgevery 4 weeks. Treatment should be maintained until amyloid plaques are cleared (e.g. at 6 or12 months, see section 5.1) as confirmed using a validated method. The maximum treatment durationis 18 months which should not be exceeded even if plaque clearance is not confirmed.

The benefit-risk of treatment should be reassessed at regular intervals on an individual basis andconsidering the rate of disease progression.

Consideration should be given to discontinuing treatment before the end of the 18 months maximumtreatment if patients progress to moderate AD.

If an infusion is missed, administration should be resumed every 4 weeks at the same dose as soon aspossible.

Monitoring, dosing interruption, and treatment discontinuation for amyloid related imagingabnormalities

Donanemab can cause ARIA, characterized as ARIA with oedema (ARIA-E), which can be observedon MRI as brain oedema or sulcal effusions, and ARIA with haemosiderin deposition (ARIA-H),which includes microhaemorrhage and superficial siderosis. In addition to ARIA, intracerebralhaemorrhages greater than 1 cm in diameter have occurred in patients treated with donanemab.

A recent (within 6 months) brain MRI should be available prior to initiating treatment withdonanemab to evaluate for pre-existing ARIA. An MRI should be performed prior to the second dose(at 1 month), prior to the third dose (at 2 months), prior to the fourth dose (at 3 months), and prior tothe seventh dose (at 6 months). An additional MRI at one year of treatment (prior to the twelfth dose)in patients with ARIA risk factors such as ApoE ε4 heterozygotes, and/or patients with previous ARIAevents earlier in treatment, should be performed. If a patient experiences symptoms suggestive of

ARIA at any time during treatment, clinical evaluation should be performed including an MRI (seesection 4.4).

The recommendations for dosing interruptions or treatment discontinuation for patients with ARIA-Eand ARIA-H are provided in Table 1.

Table 1: Dosing recommendations for patients with ARIA-E and ARIA-H

ARIA-E and ARIA-H severitya on MRI

Clinical symptom Mild Moderate Severe

Asymptomatic Consider suspending Suspend dosing Discontinue dosingdosing

Symptomatic Suspend dosing Suspend dosing Discontinue dosingaSee Table 2 for ARIA MRI radiographic severity classification criteria

In case of asymptomatic mild ARIA, consider dose suspension based on radiological features of

ARIA, number of ARIA episodes and clinical condition.

In case of asymptomatic moderate ARIA and symptomatic mild/moderate ARIA, suspend dose until

MRI demonstrates radiographic resolution (ARIA-E) or stabilisation (ARIA-H) and symptoms, ifpresent, resolve. A follow-up MRI to assess for resolution (ARIA-E) or stabilization (ARIA-H) shouldbe performed 2 to 4 months after initial identification. Resumption of dosing or permanentdiscontinuation after ARIA-E resolution and ARIA-H stabilization should be guided by clinicaljudgment including re-evaluation of risk factors (see section 4.4). Standard supportive treatment,including corticosteroids may be considered in case of ARIA-E (see section 4.8).

In the event of radiographically or symptomatic severe ARIA-E or ARIA-H, treatment withdonanemab should be permanently discontinued.

Donanemab should also be permanently discontinued after clinically serious ARIA-E, serious ARIA-

H, or intracerebral haemorrhage greater than 1 cm.

Clinical judgment should be used in considering whether to continue dosing in patients with recurrent

ARIA. Treatment with donanemab should be discontinued following recurrent symptomatic orradiographically moderate or severe ARIA events.

Renal impairment/hepatic impairment

No dose adjustment is required in patients with renal impairment or hepatic impairment (seesection 5.2).

There is no relevant use of donanemab in the paediatric population for the treatment of Alzheimer’sdisease.

Donanemab is for intravenous use only. Each vial is for single use only. Diluted solution should beadministered over a period of at least 30 minutes. Patients should be observed post-infusion for aminimum of 30 minutes. For instructions on dilution of the medicinal product before administration,see section 6.6.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Baseline MRI findings of prior intracerebral haemorrhage, more than 4 microhaemorrhages,superficial siderosis or vasogenic oedema (ARIA-E), or other findings, which are suggestive ofcerebral amyloid angiopathy (CAA) (see section 4.4).

- Patients with bleeding disorders that are not under adequate control.

- Initiation in patients receiving ongoing anticoagulant therapy (see section 4.4).

- Severe white matter disease (see section 4.4).

- Patients with poorly controlled hypertension.

- Conditions that do not allow MRI assessment, including claustrophobia or the presence of metal(ferromagnetic) implants/cardiac pacemaker.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Controlled access programme

In order to promote the safe and effective use of donanemab, initiation of treatment in all patientsshould be through a central registration system implemented as part of a controlled access programme.

Prescribers should be familiar with the educational material prepared for the detection andmanagement of ARIA, and discuss the benefits and risks of donanemab therapy with thepatient/caregiver. MRI scans and signs or symptoms of adverse reactions, and when to seek attentionfrom a healthcare professional must also be discussed with the patient. The patient will be providedwith the patient card and instructed to carry the card at all times.

Amyloid beta pathology

The presence of amyloid beta pathology must be confirmed via an appropriate test prior to initiatingtreatment.

Amyloid-related imaging abnormalities (ARIA)

ARIA-H generally occurs in association with an occurrence of ARIA-E.

ARIA has been observed very commonly in donanemab clinical studies. ARIA usually occurs early intreatment and is usually asymptomatic. When present, reported symptoms associated with ARIA mayinclude headache, confusion, nausea, vomiting, unsteadiness, dizziness, tremor, visual disturbances,speech disturbances, worsening cognitive function, alteration of consciousness, and seizures.

Symptoms associated with ARIA usually resolve over time (see section 4.8). Following an initialevent of ARIA, the rate of recurrence on resumption of treatment with donanemab is very common;24.3 % in those with ARIA-E and 35.9 % in those with ARIA-H (see section 4.8). Serious cases of

ARIA have been observed and some have been fatal (see section 4.8). ARIA can be detected by MRIand while ARIA-E typically resolves on imaging, ARIA-H may persist and stabilise.

Most ARIA events were first observed within 24 weeks of initiation of treatment. Most serious ARIAevents occurred within 12 weeks of initiation of treatment. Access to MRI should be available duringthe treatment period of donanemab. Given preexisting risk factors, patients who are eligible foramyloid treatment therapies are also at risk for spontaneous ARIA. ARIA should be considered as apossible aetiology for neurological symptoms.

The benefit of donanemab for the treatment of AD and potential risk of serious adverse reactionsassociated with ARIA should be considered when deciding to initiate treatment with donanemab (seesection 4.8).

MRI monitoring for ARIA

Baseline brain MRI and periodic monitoring with MRI are recommended (see section 4.2). Enhancedclinical vigilance for ARIA is recommended during the first 24 weeks of treatment with donanemab.

If a patient experiences symptoms suggestive of ARIA (see section 4.8), clinical evaluation should beperformed, including additional MRI testing (see sections 4.2 and 4.4 “Amyloid-related imagingabnormalities - ARIA”).

Recommendations for dosing interruptions and treatment discontinuations in patients with ARIA

If symptoms of ARIA-H occur, it is often in the presence of ARIA-E and managed as for ARIA-E.

The recommendations for dosing interruptions and treatment discontinuations for patients with

ARIA-E and ARIA-H are provided in Table 1 (see section 4.2).

Donanemab should be permanently discontinued if serious ARIA-E, serious ARIA-H, intracerebralhaemorrhage greater than 1 cm, or recurrent symptomatic or radiographically moderate or severe

ARIA events occur.

Radiographic severity

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

Table 2.

Table 2: ARIA MRI Classification criteria

ARIA Type Radiographic Severity

Mild Moderate Severe

ARIA-E FLAIR hyperintensity FLAIR hyperintensity FLAIR hyperintensityconfined to sulcus and/or 5 to 10 cm in single > 10 cm with associatedcortex/subcortex white greatest dimension, or gyral swelling and sulcalmatter in one location more than 1 site of effacement. One or more< 5 cm. involvement, each separate/independent sites ofmeasuring < 10 cm. involvement may be noted.

ARIA-H ≤ 4 new incident 5 - 9 new incident ≥ 10 new incidentmicrohaemorrhage microhaemorrhages microhaemorrhages microhaemorrhages

ARIA-H 1 new or increased focal 2 new or increased > 2 new or increased focalsuperficial area of superficial focal areas of areas of superficial siderosissiderosis siderosis superficial siderosis

Abbreviations: FLAIR = fluid-attenuated inversion recovery; ARIA-E = amyloid-related imaging abnormalities-oedema/effusions; ARIA-H = amyloid-related imaging abnormalities haemorrhage/hemosiderin deposition

ApoE ε4 carrier status and risk of ARIA

ApoE ε4 carriers have a higher frequency (homozygotes greater than heterozygotes) of ARIA-E and

ARIA-H, including serious and symptomatic ARIA, compared to non-carriers. Donanemab is notindicated in patients who are ApoE ε4 homozygotes (see section 4.1). Testing for ApoE ε4 carrierstatus should be performed prior to initiation of treatment to inform the risk of developing ARIA (seesection 4.2). Prior to testing, prescribers should discuss with patients the risk of ARIA acrossgenotypes.

Increased intracerebral haemorrhage risk

Caution should be exercised when considering the use of donanemab in patients with factors thatindicate an increased risk for intracerebral haemorrhage.

Intracerebral haemorrhages greater than 1 cm in diameter including fatal events have occurred inpatients treated with donanemab (see section 4.8).

Concomitant antithrombotic treatment

Baseline use of antithrombotic medicinal products (aspirin, other antiplatelets, or anticoagulants) wasallowed in clinical trials with donanemab. The majority of exposures to antithrombotic medicines wereto acetylsalicylic acid.

Patients who received donanemab and an antithrombotic medicine (acetylsalicylic acid, otherantiplatelets, or anticoagulants), did not present with an increased frequency of ARIA. The number ofevents and the limited exposure to non-acetylsalicylic acid antithrombotic medicines limit definitiveconclusions about the risk of ARIA or intracerebral haemorrhage in patients taking antithromboticmedicines.

Because intracerebral haemorrhages greater than 1 cm in diameter have been observed in patientstaking donanemab and in patients receiving antithrombotic agents during donanemab treatment,additional caution should be exercised when considering the administration of antithrombotics or athrombolytic agent (e.g., tissue plasminogen activator) to a patient already being treated withdonanemab:

* If anticoagulation needs to be commenced during therapy with donanemab (for exampleincident arterial thromboses, acute pulmonary embolism or other life-threatening indications)then donanemab should be paused. Donanemab can be reinstated if anticoagulation is no longermedically indicated. The use of concomitant aspirin and other antiplatelet therapy is permitted.

* Although, there was only limited exposure to thrombolytic agents in the clinical trials, there is aplausible risk of severe intracranial haemorrhage resulting from concomitant use withthrombolytics. Use of thrombolytic agents should be avoided except for immediately life-threatening indications with no alternative management (e.g., pulmonary embolism withhaemodynamic compromise) when the benefits could outweigh the risks. The benefits and risksof treatment should be individually reconsidered by the specialist physician and the patient.

ARIA can cause focal neurologic deficits similar to those observed in an ischaemic stroke. Clinicianstreating ischemic stroke should consider whether such symptoms could be due to ARIA before givingthrombolytic therapy to a patient being treated with donanemab. MRI or identification of vascularocclusion can help identify that ischemic stroke rather than ARIA is the etiology, and inform use ofthrombolytics or thrombectomy when appropriate.

Treatment with donanemab must not be initiated in patients receiving ongoing anticoagulant therapy(see section 4.3).

Other risk factors for ARIA and intracerebral haemorrhage

In the donanemab clinical trials, the safety of donanemab has not been established in patients with pre-treatment MRI showing ARIA-E, more than 4 microhaemorrhages, more than 1 area of superficialsiderosis, severe white matter disease or intracerebral haemorrhage greater than 1 cm (see section 4.3).

A higher frequency of ARIA has been observed in patients with pre-treatment cerebralmicrohaemorrhage and/or superficial siderosis. Donanemab treatment is contra-indicated in patientswith baseline superficial siderosis and patients with > 4 microhaemorrhages at baseline (seesection 4.3).

The presence of an ApoE ε4 allele is associated with CAA, which has an increased risk forintracerebral haemorrhage.

Individual benefit-risk based on tau pathology

The benefit-risk may depend on the level of baseline tau. Numerically higher levels of efficacy havebeen observed in patients with low-medium tau compared to high tau (see section 5.1). The clinicalefficacy in patients with no or very low levels of tau has not been established. The results of taupathology testing, if performed, should be considered in individual patient benefit-risk discussions.

Infusion-related reactions have been observed commonly with administration of donanemab (seesection 4.8). These reactions may uncommonly be severe or life-threatening and/or includeanaphylaxis, and typically occur during infusion or within 30 minutes post infusion. Signs andsymptoms of infusion-related reactions may include erythema, chills, nausea, vomiting, sweating,headache, chest tightness, dyspnoea, and changes in blood pressure.

Administration of donanemab should be discontinued immediately and appropriate treatment shouldbe initiated in case of serious infusion-related reactions or as clinically indicated.

In placebo controlled clinical studies, 88.1 % of donanemab-treated patients developed anti-drugantibodies (ADA) and all of the patients with ADA had neutralising antibodies. All patients reportinginfusion-related reactions had ADA. Higher ADA titre was associated with increased incidence ofinfusion-related reactions/immediate hypersensitivity events.

Patients excluded from clinical trials (see also section 5.1)

Patients with Down syndrome may be associated with a higher rate of CAA and ARIA events. Patientswith Down syndrome have not been studied in clinical trials with donanemab. The safety and efficacyof donanemab in these patients is unknown.

This medicinal product contains 46 mg sodium per 1 400 mg dose, equivalent to 2 % of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

When prepared with sodium chloride 9 mg/mL (0.9 %) solution for injection, the amount of sodiumcontributed by the sodium chloride diluent will range from 53 mg (for 350 mg dose diluted to10 mg/mL) to 956 mg (for 1 400 mg dose diluted to 4 mg/mL), equivalent to 3 % - 48 % of the WHOrecommended maximum daily intake. This is in addition to the amount contributed by the medicinalproduct.

Polysorbate 80

This medicinal product contains 16 mg of polysorbate 80 in each 1 400 mg dose of medicinal productwhich is equivalent to approximately 0.23 mg/kg. Polysorbates may cause allergic reactions.

No interaction studies have been performed. No pharmacokinetic drug interactions are expected basedon the characteristics of donanemab.

ARIA-H and intracerebral haemorrhages greater than 1 cm in diameter have been observed in patientstaking donanemab. Therefore, caution should be exercised when considering the administration ofantithrombotics since the risk for intracerebral haemorrhages with donanemab may be increased (seesections 4.3 and 4.4).

There are no or limited amount of data from the use of donanemab in pregnant women. A weight-of-evidence approach does not indicate direct or indirect harmful effects with respect to reproductivetoxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of donanemab during pregnancy.

It is unknown whether donanemab is excreted in human milk. Human immunoglobulin G (IgG) isknown to be excreted in breast milk during the first days after birth, which is decreasing to lowconcentrations soon afterwards; consequently, a risk to breast-fed infants cannot be excluded duringthis short period. Afterwards, use of donanemab could be considered during breast-feeding only ifclinically needed.

There are no data on the effects of donanemab on human fertility. No animal studies have beenperformed to test donanemab for potential fertility impairment.

Donanemab has major influence on the ability to drive and use machines if neurological deficits occur,for example visual disturbances, alteration of consciousness and seizures (section 4.4).

In a placebo-controlled pivotal study including patients with mild cognitive impairment due to

Alzheimer’s disease or mild Alzheimer’s disease (see section 5.1), a total of 853 adult subjectsreceived at least one dose of donanemab. Of these, 710 participants concerned the indicated population(ApoE ε4 heterozygotes and non-carriers).

Based on the ApoE ε4 carrier status of the patients treated with donanemab, 29.9 % (255/853) werenon-carriers, 53.0 % (452/853) were heterozygotes and 16.8 % (143/853) were homozygotes. With theexception of events of ARIA, the safety profile was similar across genotypes.

The most frequently reported adverse reactions were ARIA-E (20.6 %), ARIA-H (27.6 %), andheadache (14.6 %). The most important serious adverse reactions were: Serious ARIA-E (1.3 %),serious ARIA-H (0.3 %), and serious hypersensitivity, including infusion-related reactions (0.4 %).

Anaphylactic reaction was uncommonly reported (0.4 %) (see section 4.4).

Adverse reactions from clinical studies with donanemab (Table 3) are listed by MedDRA systemorgan class. Within each system organ class, the adverse reactions are ranked by frequency, with themost frequent reactions first. In addition, the corresponding frequency category for each reaction isbased on the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon(≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000).

Table 3. Adverse reactions

System organ class Very common Common Uncommon

Nervous system ARIA-Ea,b Intracranialdisorders ARIA-Ha,b haemorrhagec

Microhaemorrhage

Superficial siderosis

Gastrointestinal Nauseadisorders Vomiting

Injury, poisoning and Infusion-related Anaphylactic reactionprocedural reactiondcomplications Hypersensitivitya As assessed by MRI.b Symptoms may include headache, confusion, nausea, vomiting, unsteadiness, dizziness, tremor, visualdisturbances, speech disturbances, worsening cognitive function, alteration of consciousness, and seizures.c Includes subdural haematoma, subarachnoid haemorrhage, cerebral haemorrhage, haemorrhagic stroke andcerebrovascular accident.d Signs and symptoms of infusion-related reactions and hypersensitivity may include erythema, chills, nausea,vomiting, sweating, headache, chest tightness, dyspnoea, and changes in blood pressure.

Amyloid-related imaging abnormalities in the indicated population

In the pivotal placebo-controlled study, where donanemab was administered at the dosing regimen of700 mg every 4 weeks for the first 3 doses, and then 1 400 mg every 4 weeks, ARIA (ARIA-E or

ARIA-H) was observed in 33 % (234/710) of ApoE ε4 heterozygotes and non-carrier patients treatedwith donanemab, compared to 13.5 % (98/728) of heterozygotes and non-carrier patients on placebo.

Serious ARIA events were reported for 1.4 % (10/710) of patients treated with donanemab. Fatal casesof ARIA due to donanemab occurred uncommonly in the pivotal study (0.4 %, three patients). Clinicalsymptoms associated with ARIA-E resolved in approximately 80 % of patients. ARIA-E symptomsmay include headache, confusion, nausea, vomiting, unsteadiness, dizziness, tremor, visualdisturbances, speech disturbances, worsening cognitive function, alteration of consciousness, andseizures.

ARIA-E was observed in 20.6 % (146/710) of ApoE ε4 heterozygotes and non-carrier patients treatedwith donanemab compared with 1.8 % (13/728) of patients on placebo. The maximum radiographicseverity for ARIA-E was mild in 6.2 % (44/710) of patients, moderate in 12.7 % (90/710) of patients,and severe in 1.4 % (10/710) of patients. Symptomatic ARIA-E was reported for 5.6 % (40/710) ofpatients treated with donanemab in the pivotal study. The median time to resolution of ARIA-E wasapproximately 8.3 weeks. Of the donanemab-treated patients with ARIA-E, approximately 24.3 %(35/144) experienced multiple episodes of ARIA-E.

ARIA-H was observed in 27.6 % (196/710) of ApoE ε4 heterozygotes and non-carrier patients treatedwith donanemab compared with 12.2 % (89/728) of patients on placebo. The maximum radiographicseverity for ARIA-H was mild in 14.4 % (102/710) of patients, moderate in 5.5 % (39/710) of patients,and severe in 7.6 % (54/710) of patients. Symptomatic ARIA-H was reported for 1.1 % (8/710) ofpatients treated with donanemab compared with 0.3 % (2/728) of patients on placebo. Isolated

ARIA-H (i.e., ARIA-H in patients who did not also experience ARIA-E) was observed in 12.4 %(88/710) of donanemab-treated patients compared to 11.5 % (84/728) on placebo. Of the donanemab-treated patients with ARIA-H, approximately 35.9 % (70/195) of participants experienced multipleepisodes of ARIA-H.

The majority of first ARIA radiographic events in the placebo-controlled studies occurred early intreatment (within 24 weeks of initiation of treatment), although ARIA can occur at any time andpatients can have more than one episode.

Standard supportive treatment, including corticosteroids may be considered in case of ARIA-E,however the effectiveness of treatment has not been established.

Intracranial haemorrhage in the indicated population

Intracranial haemorrhage was reported in 1.4 % (10/710) of ApoE ε4 heterozygotes and non-carrierpatients after treatment with donanemab compared to 0.8 % (6/728) of patients on placebo. Of these,intracerebral haemorrhage greater than 1 cm was observed in 0.4% (3/710) of donanemab-treatedpatients and in 0.3 % (2/728) in placebo treated patients. Additionally, in a participant with baselinesuperficial siderosis treated with donanemab in the pivotal study, fatal ARIA-H was reported withconcurrent intracerebral haemorrhage.

ApoE ε4 carrier status and risk of ARIA

In the pivotal study, the overall incidence of ARIA was lower in non-carriers (24.7 % donanemab vs.12.0 % placebo) and heterozygotes (37.6 % donanemab vs. 14.1 % placebo) than in homozygotes(55.9 % donanemab vs. 21.9 % placebo). Among patients on donanemab, ARIA-E occurred in 15.7 %of non-carriers and 23.2 % of heterozygotes compared to 41.3 % of homozygotes. Symptomatic

ARIA-E occurred in 3.9 % of non-carriers and 6.6 % of heterozygotes compared to 8.4 % ofhomozygotes. ARIA-H occurred in 18.8 % of non-carriers and 32.5 % of heterozygotes compared to50.3 % of homozygotes. Symptomatic ARIA-H occurred in 0.4 % of non-carriers, in 1.5 % ofheterozygotes and in 1.4 % of homozygotes. Serious ARIA occurred in 0.8 % of non-carriers and1.8 % of heterozygotes compared to 2.8 % of homozygotes.

Infusion-related reactions in the indicated population

In the pivotal placebo-controlled study, infusion reactions were observed in 8.3 % of patients treatedwith donanemab compared to 0.4 % on placebo. Anaphylactic reaction was uncommonly reported(0.4 %). Serious infusion reactions or hypersensitivity occurred in 0.4 % of patients treated withdonanemab compared to 0.1 % on placebo.

All patients reporting infusion-related reactions had ADA. Higher ADA titre was associated withincreased incidence of infusion-related reactions/immediate hypersensitivity events.

The majority of infusion reactions and hypersensitivity reactions have occurred within the first 4 dosesof donanemab, although they can occur at any time. Treatment discontinuations in donanemab treatedpatients included IRR (3.5 %), hypersensitivity (0.6 %), and anaphylactic reaction (0.4 %), with nodiscontinuations due to these events in the placebo group.

Rechallenge led to subsequent IRR/hypersensitivity events in about 46.9 % of patients, with severityand type of symptoms usually similar to that of initial events.

Prophylactic medicines prior to subsequent infusions did not prevent IRR recurrence.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Single doses up to 40 mg/kg (approximately 2 800 mg in a 70 kg person) have been administered.

ARIA-E occurred in 2 out of 4 patients administered this dose and resolved. In case of an overdose,

MRI monitoring and supportive therapy may be initiated if necessary.

Pharmacotherapeutic group: Psychoanaleptics, anti-dementia drugs ATC code: N06DX05

Donanemab is an immunoglobulin gamma 1 (IgG1) monoclonal antibody with high affinity for amodified, N-terminal truncated form of amyloid beta (N3pE Aβ). N3pE Aβ is present in brain amyloidplaques at low levels, and not detected in plasma and CSF. Donanemab binds to N3pE Aβ and aidsplaque removal through microglial-mediated phagocytosis.

The percentage of donanemab treated patients who achieved amyloid clearance (that is, less than24.1 Centiloids) in Study TRAILBLAZER-ALZ 2 was 32.5 % at week 24, 69.5 % at week 52 and80.8 % at week 76 in the indicated population.

In study TRAILBLAZER-ALZ 2, the difference between donanemab and placebo in the change frombaseline amyloid level at week 76 was statistically significant in the indicated population(- 89.24 Centiloids).

In Study TRAILBLAZER-ALZ 6, similar amyloid plaque reduction was observed at week 24 for thedosing regimen of 350/700/1 050 mg, then 1 400 mg every 4 weeks thereafter, when compared withthe dosing regimen of 700 mg for the first three infusions, then 1 400 mg every 4 weeks thereafter,studied in the pivotal study.

Donanemab exposure decreased with increasing ADA titre. Amyloid beta reduction was foundirrespective of ADA titre. No association was observed between the presence of ADA and outcomeson the iADRS and CDR-SB (see also section 4.4, pct. 4.8 and 5.2).

Phase III Study TRAILBLAZER-ALZ 2

The safety and efficacy of donanemab were evaluated in a Phase III (TRAILBLAZER-ALZ 2) study.

The study was double-blind placebo-controlled, parallel-group, in patients 60 to 85 years of age withearly symptomatic AD (Mild Cognitive Impairment (MCI) due to AD or mild AD dementia, MMSEscore 20 to 28 inclusive) and evidence of amyloid beta pathology confirmed by amyloid PET scan.

The participants also had evidence of pathologic tau deposition on a flortaucipir PET scan.

In this study, 1 736 patients, were randomized 1:1 to receive 700 mg of donanemab every 4 weeks forthe first 3 doses, and then 1 400 mg every 4 weeks via intravenous infusion (N = 860) or placebo(N = 876) for a total of up to 72 weeks. 1 447 (83.4 %) patients in the indicated population wererandomised. Dosing was continued until study completion or amyloid plaque was cleared, defined asdemonstrating a plaque level of less than 25 Centiloids for two consecutive amyloid PET scans or asingle PET scan demonstrating a plaque level of less than 11 Centiloids. Additionally, dose suspensionwas allowed for treatment-emergent ARIA. If patients were already on symptomatic treatment(acetylcholinesterase inhibitors (AChEI) and/or the N-Methyl-D-aspartate inhibitor, memantine) atstudy entry, these treatments could continue. Symptomatic treatments could be added or changedduring the study, at the investigator’s discretion. The study excluded patients with pre-existing ARIA-

E, greater than 4 microhaemorrhages, more than 1 area of superficial siderosis, any intracerebralhaemorrhage > 1 cm or severe white matter disease.

At baseline, mean (SD) age was 73 (6.2) years, with a range of 59 to 86 years, with a mean (SD)baseline weight of 71.7 kg (15.7), with a gradual and progressive change in memory function for atleast 6 months and with a mean (SD) Mini-Mental State Examination (MMSE) score of 22.29 (3.88).

At baseline, 59.4 % had a MMSE score < 24. 57.4 % were female, 91.5 % were White, 5.7 % were of

Hispanic or Latino ethnicity, 6.0 % were Asian, and 2.3 % were Black. Of the total number of patientsrandomized, 29 % were ApoE ε4 non-carriers, 54 % were heterozygotes, and 17 % were homozygotes.55.6 % of patients were on AChEI, and 20.3 % on memantine. 61.0 % of patients were on either

AChEI or memantine use. Mean (SD) of amyloid Centiloids at baseline was 102.5 (34.5). 68.2 % and31.8 % were in the low-medium and high tau categories, respectively. A total of 24.7 % of patientsdiscontinued treatment in the study. Of those, 29.3 % were patients in the donanemab arm and 20.1 %of patients in the placebo arm.

There were two primary analysis populations based on tau PET imaging at screening withflortaucipir: 1) low-medium tau level population, and 2) overall population (low-medium plus high taulevel population).

The primary efficacy endpoint was change in cognition and function as measured by the integrated

Alzheimer’s Disease Rating Scale (iADRS) score from baseline to 76 weeks. The iADRS is anintegrated assessment of cognition and daily function comprised of items from the Alzheimer’s

Disease Assessment Scale-Cognitive subscale (ADAS-Cog13: score range 0-85) and the Alzheimer’s

Disease Cooperative Study - instrumental Activities of Daily Living (ADCS-iADL: score range 0-59)scale, measuring the core domains across the AD clinical continuum. The total score ranges from 0 to144, with lower scores reflecting worse cognitive and functional performance. Other efficacyendpoints included Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB), ADAS-Cog13,

ADCS-iADL.

Important findings from the study for the indicated population in a post hoc analysis using aconservative method for the handling of missing data are presented in Table 4 below.

For the overall population, using the same conservative method, the difference between donanemaband placebo in the change from baseline in iADRS was 2.38 (95% CI: 0.985, 3.782), and in CDR-SBwas -0.61 (95% CI: -0.850, -0.366). The effect was similar in the overall and the indicated restrictedpopulation.

Table 4: Efficacy analysis results of donanemab study TRAILBLAZER-ALZ 2 at week 76, inthe indicated population (ApoE ε4 heterozygotes and non-carriers) using conservative methodfor handling of missing dataa

Clinical Endpoint ApoE ε4 heterozygotes and noncarriers

Dona Placebo

N = 717 N = 730iADRS (MMRM)

Mean baseline (SD) 104.35 (14.23) 103.48 (14.23)

LS Mean change from baseline -10.82 -13.47

Difference from placebo (95 % CI) 2.65 (1.04, 4.26)

CDR-SB (MMRM)

Mean baseline (SD) 3.97 (2.10) 3.98 (2.08)

LS Mean change from baseline 1.73 2.42

Difference from placebo (95 % CI) -0.69 (-0.95, -0.43)

ADAS-Cog13 (MMRM)

Mean baseline (SD) 28.53 (8.88) 29.14 (8.98)

LS Mean change from baseline 5.67 7.03

Difference from placebo (95 % CI) -1.35 (-2.19, -0.51)

ADCS-iADL (MMRM)

Mean baseline (SD) 47.84 (7.90) 47.65 (7.97)

LS Mean change from baseline -4.91 -6.37

Difference from placebo (95 % CI) 1.46 (0.50, 2.42)

Abbreviations: ApoE ε4 = allele subtype 4 of the gene coding for apolipoprotein Class E; CDR-SB = Clinical

Dementia Rating Scale - Sum of Boxes; CI = confidence interval; Dona=donanemab; iADRS = integrated

Alzheimer’s Disease Rating Scale; LS = Least-Square; MMRM = mixed model for repeated measures; N =number of participants; SD = standard deviation.a Analyses performed in ITT (intent-to-treat) population that included all randomized participants; post hocsensitivity analyses using conservative methods for handling missing data (multiple imputation with jump toreference and copy increments in reference).

Low-medium tau population

In the low-medium tau population (588 patients on donanemab vs 594 patients on placebo), using aconservative method for the handling of missing data, LS mean difference between donanemab andplacebo was 3.15 (32.2 %) (95 % CI: 1.738, 4.557) on iADRS, and -0.61 (32.0 %)(95 % CI: -0.891, -0.330) on CDR-SB at Week 76.

High tau population

In a post-hoc analysis in the high-tau population, (271 patients on donanemab vs 281 patients onplacebo), using a conservative method for the handling of missing data, LS mean difference betweendonanemab and placebo was 0.41 ( 2.1 %) (95 % CI: -2.518, 3.338) on iADRS, and -0.54 (16.0 %)(95 % CI: -1.014, -0.066) on CDR-SB at Week 76.

Phase III Study TRAILBLAZER-ALZ 6

The donanemab dosing regimen of 350/700/1 050 mg, followed by 1 400 mg every 4 weeks wasevaluated in a Phase IIIb (TRAILBLAZER-ALZ 6) multicenter, randomized, double-blind, study inadults with early symptomatic AD (MCI due to AD or mild AD dementia, MMSE score 20 to 28inclusive) and evidence of amyloid beta pathology confirmed by amyloid PET scan.

843 patients were randomized at a 1:1:1:1 ratio into four donanemab dosing regimens for a total of72 weeks: 700 mg for the first three infusions, then 1 400 mg every 4 weeks thereafter (n=207), or oneof the three alternative donanemab dosing regimens (including the dosing regimen: 350/700/1 050 mg,followed by 1 400 mg every 4 weeks; n=212), with the same total drug administered in all regimens.

The primary endpoint of the study was the proportion of participants with any occurrence of ARIA-Eby week 24. The results showed that 14 % of patients receiving 350/700/1050 mg, followed by1 400 mg every 4 weeks, compared with 24 % receiving 700/700/700 mg, followed by 1 400 mg every4 weeks, experienced ARIA-E by week 24, a 41 % lower relative risk. Similar amyloid plaquereductions were seen at 24 weeks in all dosing regimens.

The European Medicines Agency has waived the obligation to submit the results of studies withdonanemab in all subsets of the paediatric population in the treatment of Alzheimer’s disease (seesection 4.2 for information on paediatric use).

Donanemab is for intravenous administration only.

Following intravenous dosing, donanemab undergoes biphasic elimination. The central volume ofdistribution is 3.36 L with 18.7 % inter-individual variability. Peripheral volume of distribution is4.83 L, with 93.9 % inter-individual variability. In a clinical pharmacology study, the ratio ofcerebrospinal fluid to serum concentration was observed at approximately 0.2 %.

Donanemab is a monoclonal antibody and is expected to be degraded into small peptides and aminoacids via catabolic pathways in the same manner as an endogenous IgG, hence there is no metabolicinhibition or induction of enzymatic pathways. Donanemab is not expected to be metabolized by thecytochrome P450 families of drug-metabolizing enzymes responsible for metabolism and eliminationof small molecules and would, therefore, not produce any active metabolites.

The half-life of donanemab is approximately 12.1 days. Donanemab clearance was 0.0255 L/h (24.9 %inter-individual variability).

Donanemab showed dose proportional increase and time linearity in serum exposure in dose range350 mg to1 400 mg.

Other intrinsic factors

The PK of donanemab was not affected by age (54-88), sex (55.0 % female), or race (89.9 % White,6.3 % Asian, 2.9 % Black and 0.3 % American Indian or Other), based on a population PK analysis.

While body weight (range 39 to 157 kg, mean of 74 kg) was found to influence both clearance andvolume of distribution, the resulting changes do not suggest a need for dose adjustment.

Donanemab clearance increased linearly with log (ADA titre). This increase in clearance with titreresulted in a 17 % decrease in AUCτ,ss, and a 31 % decrease in drug concentration before the nextdose (Ctrough,ss) (see sections 4.4 and 5.1). Although donanemab exposure decreased with increasing

ADA titer, the development of ADA was not associated with loss of clinical efficacy of donanemab.

Renal and hepatic impairment did not affect the PK of donanemab based on population PK analysis.

No dose adjustment is necessary in patients with renal or hepatic impairments.

Model based exposure-response analyses demonstrated that donanemab treatment was associated witha reduction in clinical decline on iADRS and CDR-SB. An association between reduction in amyloidbeta plaque from baseline and clinical decline on iADRS and CDR-SB was also observed.

In addition, model based association between donanemab treatment and ARIA-E was demonstratedand identified risk factors such as ApoE ε4 genotype, number of baseline microhaemorrhages andpresence of superficial siderosis at baseline.

During an off-treatment period, amyloid PET values began to increase with a median rate of2.80 Centiloids/year.

In single doses from 350 to 2 800 mg (approximately 2 times the dosage of 1 400 mg for 70 kg ofbody weight studied in the pivotal study), and multiple 350 to 1 400 mg doses, exposures (Cmax and

AUC) increased proportionally. Similar exposure was observed for the donanemab dosing regimen of350/700/1 050 mg, then 1 400 mg every 4 weeks thereafter, compared with the dosing regimen of700 mg for the first three infusions, then 1 400 mg every 4 weeks thereafter, that established clinicalefficacy in the pivotal study.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology and repeated dose toxicity. No animal studies have been performed to test donanemabfor potential of carcinogenicity, genotoxicity, reproductive toxicity or fertility impairment.

A weight-of-evidence assessment of all data, including evaluation of the target biology (residing indeposited Aβ plaques only), the nature of the product (high specificity of the monoclonal antibodymolecule for the target and composition of naturally occurring amino acids and monosaccharides), themechanism of action (phagocytic removal of amyloid plaque in the CNS) and the lack of effects in thetoxicology studies, suggest a low potential for risk of reproductive toxicity or carcinogenicity.

Citric acid (E 330)

Polysorbate 80 (E 433)

Sodium citrate (E 331)

Sucrose

Water for injections

Kisunla contains polysorbate 80. Polysorbates are known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC). Materials used for the preparation andadministration of donanemab dosing solution should be DEHP-free.

3 years

Store in a refrigerator (2 °C to 8 °C) until time of use.

May be stored unrefrigerated for up to 3 days at room temperature (up to 25 °C).

Keep the vial in the outer carton in order to protect from light.

Do not freeze or shake.

Use prepared dosing solution immediately.

If not used immediately, store the donanemab dosing solution in a refrigerator (2 °C to 8 °C) for up to72 hours or for up to 12 hours at room temperature (up to 25 °C) assuming dilution has taken placeusing aseptic techniques.

Storage times include the duration of infusion.

Do not freeze the donanemab dosing solution.

Kisunla is supplied in a type I clear glass, 20 mL, single dose vial, with a chlorobutyl elastomerstopper and an aluminium seal with a polypropylene cap, individually packaged in a carton.

Pack sizes of 1 vial and multipacks containing 2 (2 packs of 1) vials. Not all pack sizes may bemarketed.

Kisunla contains polysorbate 80; therefore, appropriate materials for preparation and administrationmust be used (see section 6.2). Donanemab solution for infusion should be prepared and administeredby a qualified healthcare professional using aseptic technique:

Allow donanemab to equilibrate to room temperature for approximately 30 minutes beforepreparation.

Parenteral medicinal products should be inspected visually for particulate matter and discolourationprior to administration, whenever solution and container permit. Do not use donanemab if it is cloudyor there are visible particles.

After dilution and preparation in sodium chloride 9 mg/mL (0.9 %) solution for injection (see

Table 5), donanemab is administered as an intravenous infusion.

Table 5: Preparation of donanemab

Kisunla Kisunla Volume of sodium Final volume of Final concentration of diluted

Dose (mg) Volume chloride 9 mg/mL diluted solution to solution (mg/mL)a(mL) (0.9 %) solution be infused (mL)for injection (mL)350 mg 20 mL 15 mL to 67.5 mL 35 mL to 87.5 mL 350 mg/87.5 mL (4 mg/mL) to350 mg/35 mL (10 mg/mL)700 mg 40 mLb 30 mL to 135 mL 70 mL to 175 mL 700 mg/175 mL (4 mg/mL) to700 mg/70 mL (10 mg/mL)1 050 mg 60 mLc 45 mL to 105 mL to 262.5 mL 1 050 mg/262.5 mL (4 mg/mL)202.5 mL to1 050 mg/105 mL (10 mg/mL)1 400mg 80 mLd 60 mL to 270 mL 140 mL to 350 mL 1 400 mg/350 mL (4 mg/mL) to1 400 mg/140 mL (10 mg/mL)a final concentration of 4 mg/mL to 10 mg/mLb 2 vials of Kisunlac 3 vials of Kisunlad 4 vials of Kisunla

Gently invert the infusion bag to mix.

Administer diluted solution over a period of at least 30 minutes. Administer the entire infusionsolution.

Flush the line with sodium chloride 9 mg/mL (0.9 %) solution for injection at the end of the infusion.

Observe the patient post-infusion for a minimum of 30 minutes.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Eli Lilly Nederland B.V., Orteliuslaan 1000, 3528 BD Utrecht, The Netherlands.

EU/1/25/1926/001

EU/1/25/1926/002

Date of first authorisation: 24 September 2025

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.