Kisunla Special Precautions

Pre-treatment screening: The efficacy and relative safety of KISUNLA have been demonstrated in a population of patients with evidence of early symptomatic Alzheimer's disease based on a clinical history of cognitive decline over six months and on radiologically imaged pathological amyloid deposits in the brain (see Pharmacology: Pharmacodynamics: Clinical trials under Actions).
Monoclonal antibodies directed against aggregated forms of beta amyloid, including KISUNLA, can cause amyloid related imaging abnormalities (ARIA). ARIA includes amyloid related imaging abnormalities-oedema/effusions (ARIA-E; also known as cerebral vasogenic oedema) and amyloid-related imaging abnormalities haemorrhage/hemosiderin deposition (ARIA-H; includes cerebral microhaemorrhage and cortical superficial siderosis). Intracerebral haemorrhage greater than 1 cm has been observed. ARIA can occur spontaneously in patients with Alzheimer's disease, particularly in patients with MRI findings suggestive of cerebral amyloid angiopathy, such as pretreatment microhaemorrhage or superficial siderosis. ARIA-H associated with monoclonal antibodies directed against aggregated forms of beta amyloid generally occurs in association with an occurrence of ARIA-E. ARIA-H of any cause and ARIA-E can occur together.
The safety of donanemab has not been examined in patients with pre-treatment MRI showing ARIA-E, more than 4 microhaemorrhages, more than 1 area of superficial siderosis, severe white matter disease or intracerebral haemorrhage greater than 1 cm (see Contraindications).
Apolipoprotein E (ApoE) genotype: KISUNLA is not indicated in ApoE ε4 homozygous patients (see Indications/Uses). In study TRAILBLAZER-ALZ-2, 17% (143/850) of patients with known genotype in the KISUNLA arm were ApoE ε4 homozygotes, 53% (452/850) were heterozygotes, and 30% (255/850) were non-carriers. The incidence of ARIA was higher in ApoE ε4 homozygotes (55% on KISUNLA vs. 22% on placebo) than in heterozygotes (36% on KISUNLA vs. 13% on placebo) and non-carriers (25% on KISUNLA vs. 12% on placebo). Among patients treated with KISUNLA, symptomatic ARIA-E occurred in 8% of ApoE ε4 homozygotes compared with 7% of heterozygotes and 4% of non-carriers. Serious events of ARIA occurred in 3% of ApoE ε4 homozygotes, 2% of heterozygotes and 1% of noncarriers. The recommendations for management of ARIA do not differ between ApoE ε4 heterozygotes and noncarriers (see Dosage & Administration). Screening for ApoE ε4 alleles prior to treatment is required.
Cerebral amyloid angiopathy: Neuroimaging findings that may indicate cerebral amyloid angiopathy (CAA) include evidence of prior intracerebral haemorrhage, cerebral microhaemorrhage, and cortical superficial siderosis. CAA has an increased risk for intracerebral haemorrhage. The presence of an ApoE ε4 allele is also associated with CAA.
Amyloid-related imaging abnormalities (ARIA): Serious cases of amyloid-related imaging abnormalities (ARIA) have been observed in donanemab clinical studies and some have been fatal (see Adverse Reactions).
Most ARIA events were first observed within 24 weeks of initiation of treatment. Most serious ARIA events occurred within 12 weeks of initiation of treatment. Access to MRI should be available during the treatment period of donanemab. An MRI should be performed at baseline (within 6 months of initiating treatment), prior to the second dose, prior to third dose, prior to fourth dose and prior to the seventh dose (see Dosage & Administration). MRI may also be indicated if ARIA symptoms occur. ARIA is often asymptomatic, although serious and life-threatening events including seizure and status epilepticus may occur. When present, symptoms may include, but are not limited to, headache, confusion, nausea, vomiting, unsteadiness, dizziness, tremor, visual disturbances, speech disturbances, worsening cognitive function, and alteration of consciousness.
Recommendations for Dosing Interruptions 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 for patients with ARIA-E and ARIA-H are provided in Table 3 (see Dosage & Administration).
Donanemab should be permanently discontinued if serious ARIA-E, serious ARIA-H or intracerebral haemorrhage greater than 1 cm occurs (see Contraindications).
Concomitant antithrombotic medication: Patients who received donanemab and an antithrombotic medicine (acetylsalicylic acid, other antiplatelets, or anticoagulants), did not have an increased frequency of ARIA. The majority of exposures to antithrombotic medicines were to acetylsalicylic acid (81%). The incidence of ARIA-H was 30% (106/349) in patients taking KISUNLA with a concomitant antithrombotic medication within 30 days compared to 29% (148/504) who did not receive an antithrombotic within 30 days of an ARIA-H event.
The incidence of intracerebral haemorrhage greater than 1 cm in diameter was 0.6% (2/349 patients) in patients taking KISUNLA with a concomitant antithrombotic medication compared to 0.4% (2/504) in those who did not receive an antithrombotic. The number of events and the limited exposure to non-acetylsalicylic acid antithrombotic medicines limit definitive conclusions about the risk of ARIA or intracerebral haemorrhage in patients taking antithrombotic medicines.
Because ARIA-H and intracerebral haemorrhages greater than 1 cm in diameter have been observed in patients taking donanemab, additional caution should be exercised when considering the administration of antithrombotics or a thrombolytic agent (e.g., tissue plasminogen activator) to a patient already being treated with donanemab.
In the long-term extension of the Phase 3 study, a fatal intracerebral haemorrhage occurred in a patient taking KISUNLA in the setting of focal neurologic symptoms of ARIA and the use of a thrombolytic agent. Additional caution should be exercised when considering the administration of antithrombotics or a thrombolytic agent (e.g., tissue plasminogen activator) to a patient already being treated with KISUNLA. Because ARIA can cause focal neurologic deficits similar to those observed in an ischaemic stroke, treating clinicians should consider whether such symptoms could be due to ARIA before giving thrombolytic therapy in a patient being treated with donanemab.
Immunogenicity: In clinical studies, 88.1% of donanemab-treated patients developed anti-drug antibodies (ADA) and all of the patients with ADA had neutralising antibodies. Although donanemab exposure decreased with increasing ADA titre, the development of ADA was not associated with loss of clinical efficacy of donanemab. All patients reporting infusion-related reactions had ADA. Higher ADA titre was associated with increased incidence of infusion-related reactions/immediate hypersensitivity events.
Infusion related reactions: Infusion-related reactions, including anaphylaxis have been observed with administration of KISUNLA (see Adverse Reactions). These reactions may be severe or life-threatening and typically occur during infusion or within 30 minutes post infusion. Signs and symptoms of infusion-related reactions may include erythema, chills, nausea, vomiting, sweating, headache, chest tightness, dyspnoea, and changes in blood pressure. If serious infusion-related reactions occur, discontinue administration of KISUNLA immediately and initiate appropriate treatment.
Sodium: This medicinal product contains 46 mg sodium per 1400 mg dose, equivalent to 2% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Use in hepatic impairment: Hepatic impairment did not affect the PK of KISUNLA based on population PK analysis. No dose adjustment is necessary in patients with hepatic impairment.
Use in renal impairment: Renal impairment did not affect the PK of KISUNLA based on population PK analysis. No dose adjustment is necessary in patients with renal impairment.
Effects on laboratory tests: No data available.
Effects on ability to drive and use machines: There have been no studies conducted to determine the effects of KISUNLA on the ability to drive and use machines.
Use in Children: Safety and effectiveness of KISUNLA in paediatric patients have not been established.
Use in the Elderly: Clinical studies with KISUNLA did not include sufficient numbers of younger adult patients to determine if patients 65 years of age and older responded differently than younger adult patients.