Kisunla (donanemab-azbt)

Dosage interruption may be required for patients with amyloid related imaging abnormalities-edema (ARIA-E), amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H), or intracerebral hemorrhage.

The manufacturer's recommended dosage modifications for ARIA are provided in Tables 1 and 2.

Table 1. Dosing Recommendations for Patients with ARIA-E.

Clinical Symptom Mild ARIA-E Moderate ARIA-E Severe ARIA-E Severity Severity on MRI Severity on MRI Severity on MRI Asymptomatic May continue Suspend dosing Suspend dosing current dosage and schedule Mild May continue Suspend dosing Suspend dosing current dosage based on clinical judgment Moderate or Suspend dosing Suspend dosing Suspend dosing Severe

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

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

Table 2. Dosing Recommendations for Patients with ARIA-H.

Clinical Symptom Mild ARIA-H Moderate ARIA-H Severe ARIA-H Severity Severity on MRI Severity on MRI Severity on MRI Asymptomatic May continue Suspend dosing Suspend dosing current dosage and schedule Symptomatic Suspend dosing Suspend dosing Suspend dosing

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

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

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

Donanemab-azbt is administered by IV infusion. The drug is available in a 20 mL single-dose vial containing donanemab-azbt 350 mg/20 mL (17.5 mg/mL) that must be diluted prior to infusion.

Store unopened vials of donanemab in the refrigerator (2-8degreesC); vials may also be stored at room temperature (20-25degreesC) for up to 3 days. Keep unopened vials in their outer carton to protect the drug from light; do not freeze or shake.

If the solution is refrigerated after dilution, allow the solution to reach room temperature before infusion. Administer the entire diluted solution by IV infusion over approximately 30 minutes.

Discontinue the infusion immediately if signs of hypersensitivity occur. Flush the line with 0.9% sodium chloride injection at the end of the infusion per specific line maintenance protocol and observe the patient for at least 30 minutes post-infusion for infusion or hypersensitivity reactions.

No dosing information is available for this tab.

No formal drug-drug interaction studies have been performed with donanemab-azbt.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Donanemab/Thrombolytics

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Microhemorrhage has been reported with the use of donanemab. Radiographic changes on brain MRI have been noted as amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H) which included microhemorrhage. In addition, intracerebral hemorrhages (ICH) greater than 1 cm in diameter have occurred in patients treated with donanemab.(1)

CLINICAL EFFECTS: Concurrent use of donanemab with thrombolytic agents may increase the risk of hemorrhage.(1)

PREDISPOSING FACTORS: Patients with ongoing amyloid-related imaging abnormalities (ARIA) may be at increased risk for post-thrombolytic intracranial hemorrhage (ICH). The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The American Heart Association and American Stroke Association guidelines for the early management of patients with acute ischemic stroke states patients on amyloid immunotherapy is an absolute contraindication for use of thrombolysis. The guidelines state that the risk of thrombolysis related intracranial hemorrhage (ICH) in patients on amyloid immunotherapy or with ARIA is unknown and thrombolysis should be avoided in such patients.(2) The manufacturer of donanemab states that donanemab should be used with extreme caution in patients treated with thrombolytics. Evaluate the risks and benefits of concurrent use of donanemab with thrombolytics.(1) The manufacturer of donanemab recommends testing for AP0E4 status prior to initiation of treatment.(1) Use of thrombolytics in patients who are homozygous for the APOE4 gene, may have an increased risk of ARIA with donanemab therapy.(1,3-5) If thrombolytics are warranted, patients receiving concurrent therapy with donanemab and thrombolytics should be closely monitored for signs and symptoms of bleeding and changes in platelet count or symptoms associated with ARIA-H.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of microhemorrhage, including headache, nausea/vomiting, confusion, dizziness, visual disturbance, gait difficulties, and loss of coordination. General signs of blood loss include decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform computed tomography (CT) scans and magnetic resonance imaging (MRIs) to monitor efficacy and safety of thrombolytic use with lecanemab. Discontinue thrombolytics in patients with active pathologic bleeding.(1) Instruct patients to report any signs and symptoms of bleeding, such as confusion, headache, dizziness, nausea, visual changes, unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a double-blind, placebo-controlled clinical study of 1736 participants randomized to receive donanemab (n = 860) or placebo (n = 876), donanemab was observed to increase amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H), including microhemorrhage and intracerebral hemorrhage (ICH). One fatal ICH occurred in a patient taking donanemab in the setting of focal neurologic symptoms of ARIA and the use of a thrombolytic agent.(1) Radiographic changes were classified as mild (<=4 new incidences), moderate (5 to 9 new incidences), or severe (10 or more new incidences). The maximum severity of ARIA-H microhemorrhage was observed as mild in 17% (143/853), moderate in 4% (34/853), and severe in 5% (40/853) of patients taking donanemab.(1) Baseline use of antithrombotic medication (aspirin, other antiplatelets, or anticoagulants) was allowed. The majority of exposures to antithrombotic medications were to aspirin. The incidence of ARIA-H was 30% (106/349) in patients taking donanemab 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.(1) The incidence of ICH greater than 1 cm in diameter was 0.6% (2/349 patients) in patients taking donanemab with a concomitant antithrombotic medication compared to 0.4% (2/504) in those who did not receive an antithrombotic.(1) The manufacturer of donanemab states the number of events and the limited exposure to non-aspirin antithrombotic medications limit definitive conclusions about the risk of ARIA or ICH in patients taking antithrombotic medications concurrently with donanemab. If concurrent therapy is warranted, patients should be closely monitored for signs and symptoms of bleeding and changes in platelet count or INR.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Donanemab/Anticoagulants

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Microhemorrhage has been reported with the use of donanemab. Radiographic changes on brain MRI have been noted as amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H) which included microhemorrhage. In addition, intracerebral hemorrhages (ICH) greater than 1 cm in diameter have occurred in patients treated with donanemab.(1)

CLINICAL EFFECTS: Concurrent use of donanemab with anticoagulants agents may increase the risk of hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Donanemab should be used with extreme caution in patients treated with anticoagulants. Evaluate the risks and benefits of concurrent use of donanemab with anticoagulants.(1) The manufacturer of donanemab recommends testing for AP0E4 status prior to initiation of treatment.(1) Use of anticoagulant agents in patients who are homozygous for the APOE4 gene, may have an increased risk of ARIA with donanemab therapy.(1-3) If concurrent therapy is warranted, patients receiving concurrent therapy with donanemab and anticoagulants should be closely monitored for signs and symptoms of bleeding and changes in platelet count or International Normalized Ratio (INR).(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of microhemorrhage, including headache, nausea/vomiting, confusion, dizziness, visual disturbance, gait difficulties, and loss of coordination. General signs of blood loss include decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as confusion, headache, dizziness, nausea, visual changes, unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a double-blind, placebo-controlled clinical study of 1736 participants randomized to receive donanemab (n = 860) or placebo (n = 876), donanemab was observed to increase amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H), including microhemorrhage and intracerebral hemorrhage (ICH). Radiographic changes were classified as mild (<=4 new incidences), moderate (5 to 9 new incidences), or severe (10 or more new incidences). The maximum severity of ARIA-H microhemorrhage was observed as mild in 17% (143/853), moderate in 4% (34/853), and severe in 5% (40/853) of patients taking donanemab.(1) Baseline use of antithrombotic medication (aspirin, other antiplatelets, or anticoagulants) was allowed. The majority of exposures to antithrombotic medications were to aspirin. The incidence of ARIA-H was 30% (106/349) in patients taking donanemab 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.(1) The incidence of ICH greater than 1 cm in diameter was 0.6% (2/349 patients) in patients taking donanemab with a concomitant antithrombotic medication compared to 0.4% (2/504) in those who did not receive an antithrombotic. One fatal ICH occurred in a patient taking donanemab in the setting of focal neurologic symptoms of ARIA and the use of a thrombolytic agent.(1) The manufacturer of donanemab states the number of events and the limited exposure to non-aspirin antithrombotic medications limit definitive conclusions about the risk of ARIA or ICH in patients taking antithrombotic medications concurrently with donanemab. If concurrent therapy is warranted, patients should be closely monitored for signs and symptoms of bleeding and changes in platelet count or INR.(1)

Igg Antibodies And Derivatives/Efgartigimod-Alfa

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The neonatal Fc receptor (FcRn) prevents catabolism and mediates recycling of IgG and albumin, which leads to their long persistence in the body.(1,2) Efgartigimod-alfa binds to FcRn and may decrease systemic exposure of other ligands of FcRn, like immunoglobulins and IgG-based antibodies.(3)

CLINICAL EFFECTS: The effectiveness of medicines that bind to FcRn may be decreased.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of efgartigimod-alfa states that efgartigimod-alfa should not be combined with long-term use of FcRn-binding medications. If the medication is essential for the patient, efgartigimod-alfa should be discontinued.(3)

DISCUSSION: Clinical drug interaction studies with efgartigimod-alfa have not been performed. Efgartigimod-alfa may decrease concentrations of compounds that bind to the human FcRn.(3)

Igg Antibodies And Derivatives/Nipocalimab-Aahu

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The neonatal Fc receptor (FcRn) prevents catabolism and mediates recycling of IgG and albumin, which leads to their long persistence in the body.(1,2) Nipocalimab-aahu binds to FcRn and may decrease systemic exposure of other ligands of FcRn, like immunoglobulins and IgG-based antibodies.(3)

CLINICAL EFFECTS: The effectiveness of medicines that bind to FcRn may be decreased.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of nipocalimab-aahu states that nipocalimab-aahu should not be combined with long-term use of FcRn-binding medications. If the medication is essential for the patient, nipocalimab-aahu should be discontinued.(3)

DISCUSSION: Clinical drug interaction studies with nipocalimab-aahu have not been performed. Nipocalimab-aahu may decrease concentrations of compounds that bind to the human FcRn.(3)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Donanemab/Antiplatelets

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Microhemorrhage has been reported with the use of donanemab. Radiographic changes on brain MRI have been noted as amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H) which included microhemorrhage. In addition, intracerebral hemorrhages (ICH) greater than 1 cm in diameter have occurred in patients treated with donanemab.(1)

CLINICAL EFFECTS: Concurrent use of donanemab with antiplatelets may increase the risk of hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Donanemab should be used with extreme caution in patients treated with antiplatelets. Evaluate the risks and benefits of concurrent use of donanemab with antiplatelets.(1) The manufacturer of donanemab recommends testing for AP0E4 status prior to initiation of treatment.(1) Use of antiplatelet agents in patients who are homozygous for the APOE4 gene, may have an increased risk of ARIA with donanemab therapy.(1-3) Patients receiving concurrent therapy with donanemab and antiplatelets should be closely monitored for signs and symptoms of bleeding and changes in platelet count.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of microhemorrhage, including headache, nausea/vomiting, confusion, dizziness, visual disturbance, gait difficulties, and loss of coordination. General signs of blood loss include decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Instruct patients to report any signs and symptoms of bleeding, such as confusion, headache, dizziness, nausea, visual changes, unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a double-blind, placebo-controlled clinical study of 1736 participants randomized to receive donanemab (n = 860) or placebo (n = 876), donanemab was observed to increase amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H), including microhemorrhage and intracerebral hemorrhage (ICH). Radiographic changes were classified as mild (<=4 new incidences), moderate (5 to 9 new incidences), or severe (10 or more new incidences). The maximum severity of ARIA-H microhemorrhage was observed as mild in 17% (143/853), moderate in 4% (34/853), and severe in 5% (40/853) of patients taking donanemab.(1) Baseline use of antithrombotic medications (aspirin, other antiplatelets, or anticoagulants) was allowed. The majority of exposures to antithrombotic medications were to aspirin. The incidence of ARIA-H was 30% (106/349) in patients taking donanemab 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.(1) The incidence of ICH greater than 1 cm in diameter was 0.6% (2/349 patients) in patients taking donanemab with a concomitant antithrombotic medication compared to 0.4% (2/504) in those who did not receive an antithrombotic. One fatal ICH occurred in a patient taking donanemab in the setting of focal neurologic symptoms of ARIA and the use of a thrombolytic agent.(1)

Igg Antibodies And Derivatives/Rozanolixizumab-Noli

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The neonatal Fc receptor (FcRn) prevents catabolism and mediates recycling of IgG and albumin, which leads to their long persistence in the body.(1,2) Rozanolixizumab-noli binds to FcRn and may decrease systemic exposure of other ligands of FcRn, like immunoglobulins and IgG-based antibodies.(3)

CLINICAL EFFECTS: The effectiveness of medications that bind to FcRn may be decreased.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of rozanolixizumab-noli states that concurrent use with medications that bind to the human neonatal Fc receptor (FcRn) should be closely monitored for reduced effectiveness of these medications. If long-term use of such medications is essential for the patient, consider discontinuing rozanolixizumab-noli and use alternative therapies.(3)

DISCUSSION: Clinical drug interaction studies with rozanolixizumab-noli have not been performed. Rozanolixizumab-noli may decrease concentrations of compounds that bind to the human FcRn.(3)

*Donanemab-azbt is contraindicated in patients with known serious hypersensitivity to the drug or to any of the excipients.

There are no contraindication contraindications for this drug.

• Cerebral amyloid angiopathy
• Cerebral edema
• Intracerebral hemorrhage

There are no moderate contraindications for this drug.

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

More Frequent

• Amyloid-related imaging abnormality
• Amyloid-related imaging abnormality with edema
• Amyloid-related imaging abnormality with microhemorrhage
• Amyloid-related imaging abnormality with superficial siderosis

Less Frequent

• Anaphylaxis
• Angioedema
• Hypersensitivity drug reaction

Rare or Very Rare

• Intestinal obstruction

More Frequent

• Headache disorder

Less Frequent

• Chest pain
• Chills
• Dyspnea
• Erythema
• Hyperhidrosis
• Hypotension
• Nausea
• Vomiting

No enhanced messaging available.

Safety and effectiveness in pediatric patients have not been established.

There are no adequate data on donanemab-azbt use in pregnant women to assess the risk of birth defects, miscarriage, or other maternal or fetal outcomes, and no animal studies have evaluated its reproductive or developmental toxicity.

There are no data on the presence of donanemab-azbt in human milk, its effects on the breastfed infant, or its impact on milk production. Based on data from other monoclonal antibodies, transfer into breast milk is expected to be low with minimal infant exposure, though the effects are unknown. The benefits of breastfeeding should be weighed against the mother's need for donanemab-azbt and any potential risks to the infant.

The manufacturer makes no specific dosage recommendations for geriatric patients.

In the Trailblazer-Alz 2 study, patients treated with donanemab-azbt ranged from 59-86 years of age with a mean of 73 years of age; 90% were >=65 years, and 41% were >=75 years. No overall differences in safety or effectiveness were observed between older and younger adults.