Kisunla

1 INDICATIONS AND USAGE KISUNLA TM is indicated for the treatment of Alzheimer's disease. Treatment with KISUNLA should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in the clinical trials. KISUNLA is an amyloid beta-directed antibody indicated for the treatment of Alzheimer's disease. Treatment with KISUNLA should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in the clinical trials. ( 1 )

2 DOSAGE AND ADMINISTRATION Confirm the presence of amyloid beta pathology prior to initiating treatment. ( 2.1 ) Administer KISUNLA as an intravenous infusion over approximately 30 minutes every four weeks as follows ( 2.2 ): Infusion 1: 350 mg Infusion 2: 700 mg Infusion 3: 1,050 mg Infusion 4 and beyond: 1,400 mg Consider stopping dosing with KISUNLA based on reduction of amyloid plaques to minimal levels on amyloid PET imaging. ( 2.2 ) Obtain a recent baseline brain MRI prior to initiating treatment. ( 2.3 , 5.1 ) Obtain an MRI prior to the 2nd, 3rd, 4th, and 7th infusions. If radiographically observed ARIA occurs, treatment recommendations are based on type, severity, and presence of symptoms. ( 2.3 , 5.1 ) Dilution to a final concentration of 4 mg/mL to 10 mg/mL with 0.9% Sodium Chloride Injection, is required prior to administration. ( 2.4 ) 2.1 Patient Selection Confirm the presence of amyloid beta pathology prior to initiating treatment [see Clinical Pharmacology ( 12.1 )] . 2.2 Dosing Instructions Administer KISUNLA every four weeks as an intravenous infusion over approximately 30 minutes with the recommended dosage and dosing schedule described in Table 1 . KISUNLA must be diluted prior to administration ( see Table 4 ). Table 1: Recommended Dosage* and Dosing Schedule *Dosing Regimen 2 [see Warnings and Precautions ( 5.1 ) and Clinical Studies ( 14 )] Intravenous Infusion (every 4 weeks) KISUNLA Dosage (administered over approximately 30 minutes) Infusion 1 350 mg Infusion 2 700 mg Infusion 3 1,050 mg Infusion 4 and beyond 1,400 mg Consider stopping dosing with KISUNLA based on reduction of amyloid plaques to minimal levels on amyloid PET imaging. In Study 1 and Study 2, dosing was stopped based on a reduction of amyloid levels below predefined thresholds on PET imaging [see Clinical Studies ( 14 )] . If an infusion is missed, resume administration every 4 weeks at the same dose as soon as possible. 2.3 Monitoring and Dosing Interruption for Amyloid Related Imaging Abnormalities KISUNLA can cause amyloid related imaging abnormalities -edema (ARIA-E) and -hemosiderin deposition (ARIA-H) [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 )] . Monitoring for ARIA Obtain a recent baseline brain magnetic resonance imaging (MRI) prior to initiating treatment with KISUNLA. Obtain an MRI prior to the 2 nd , 3 rd , 4 th , and 7 th infusions. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including an MRI if indicated. Recommendations for Dosing Interruptions in Patients with ARIA ARIA-E The recommendations for dosing interruptions for patients with ARIA-E are provided in Table 2 . Table 2: Dosing Recommendations for Patients With ARIA-E c a Mild: discomfort noticed, but no disruption of normal daily activity. Moderate: discomfort sufficient to reduce or affect normal daily activity. Severe: incapacitating, with inability to work or to perform normal daily activity. b Suspend until MRI demonstrates radiographic resolution and symptoms, if present, resolve; consider a follow-up MRI to assess for resolution 2 to 4 months after initial identification. Resumption of dosing should be guided by clinical judgment. c See Table 5 for MRI radiographic severity [Warning and Precautions ( 5.1 )] . Clinical Symptom Severity a ARIA-E Severity on MRI Mild Moderate Severe Asymptomatic May continue dosing at current dose and schedule Suspend dosing b Suspend dosing b Mild May continue dosing based on clinical judgment Suspend dosing b Moderate or Severe Suspend dosing b ARIA-H The recommendations for dosing interruptions for patients with ARIA-H are provided in Table 3 . Table 3: Dosing Recommendations for Patients With ARIA-H c a Suspend until MRI demonstrates radiographic stabilization and symptoms, if present, resolve; resumption of dosing should be guided by clinical judgment; consider a follow-up MRI to assess for stabilization 2 to 4 months after initial identification. b Suspend until MRI demonstrates radiographic stabilization and symptoms, if present, resolve. Use clinical judgment when considering whether to continue treatment or permanently discontinue KISUNLA. c See Table 5 for MRI radiographic severity [Warning and Precautions ( 5.1 )] . Clinical Symptom Severity ARIA-H Severity on MRI Mild Moderate Severe Asymptomatic May continue dosing at current dose and schedule Suspend dosing a Suspend dosing b Symptomatic Suspend dosing a Suspend dosing a In patients who develop intracerebral hemorrhage greater than 1 cm in diameter during treatment with KISUNLA, suspend dosing until MRI demonstrates radiographic stabilization and symptoms, if present, resolve. Use clinical judgment when considering whether to continue treatment or permanently discontinue KISUNLA after radiographic stabilization and resolution of symptoms. 2.4 Dilution Instructions Prior to administration, KISUNLA must be diluted with 0.9% sodium chloride injection ( see Table 4 ). Use aseptic technique when preparing the diluted KISUNLA solution for intravenous infusion. Allow KISUNLA to equilibrate to room temperature before preparation. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. KISUNLA solution is clear to opalescent, colorless to slightly yellow to slightly brown. Do not use if particulate matter or discolorations are present. Withdraw required volume of KISUNLA and mix with 0.9% sodium chloride injection, to the recommended total volume for a final concentration of 4 mg/mL to 10 mg/mL ( see Table 4 ). Use only 0.9% sodium chloride injection for dilution. Table 4: Preparation of KISUNLA a final concentration of 4 mg/mL to 10 mg/mL b 2 vials of KISUNLA c 3 vials of KISUNLA d 4 vials of KISUNLA KISUNLA Dose (mg) KISUNLA Volume (mL) Volume of 0.9% Sodium Chloride Injection Diluent (mL) Final Volume of Diluted Solution to be Infused (mL) Final Concentration of Diluted Solution (mg/mL) a 350 mg 20 mL 15 mL to 67.5 mL 35 mL to 87.5 mL 350 mg/87.5 mL (4 mg/mL) to 350 mg/35 mL (10 mg/mL) 700 mg 40 mL b 30 mL to 135 mL 70 mL to 175 mL 700 mg/175 mL (4 mg/mL) to 700 mg/70 mL (10 mg/mL) 1,050 mg 60 mL c 45 mL to 202.5 mL 105 mL to 262.5 mL 1,050 mg/262.5 mL (4 mg/mL) to 1,050 mg/105 mL (10 mg/mL) 1,400 mg 80 mL d 60 mL to 270 mL 140 mL to 350 mL 1,400 mg/350 mL (4 mg/mL) to 1,400 mg/140 mL (10 mg/mL) Each vial is for one-time use only. Discard any unused portion left in the vial. Gently invert the diluted KISUNLA solution to mix completely. Do not shake. After dilution, immediate use is recommended [see Description ( 11 )] . If the diluted KISUNLA solution is not administered immediately, store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 72 hours or at room temperature (20°C to 25°C [68°F to 77°F]) for up to 12 hours. Do not freeze the diluted KISUNLA solution. Storage times include the duration of infusion. 2.5 Administration Instructions Visually inspect the diluted KISUNLA solution for particles or discoloration prior to administration. Do not use if it is discolored, or opaque or foreign particles are seen. Prior to infusion, if the diluted solution has been stored under refrigeration, allow the diluted KISUNLA solution to warm to room temperature. Administer the entire diluted solution intravenously over approximately 30 minutes. Flush the line only with 0.9% sodium chloride injection at the end of the infusion per access specific line maintenance protocol. Observe the patient post-infusion for a minimum of 30 minutes, and consider longer periods of observation if clinically indicated, to evaluate for infusion reactions and hypersensitivity reactions. The infusion rate may be reduced, or the infusion may be discontinued, and appropriate therapy administered as clinically indicated. Consider pre-medication at subsequent dosing with antihistamines, non-steroidal anti-inflammatory drugs, or corticosteroids [see Warnings and Precautions ( 5.2 )] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Amyloid Related Imaging Abnormalities [see Warnings and Precautions ( 5.1 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.2 )] Infusion-Related Reactions [see Warnings and Precautions ( 5.3 )] Most common adverse reactions (at least 10% and higher incidence compared to placebo): ARIA-E, ARIA-H microhemorrhage, ARIA-H superficial siderosis, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 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 practice. Dosing Regimen and Safety A lower incidence of ARIA occurred with the dosing regimen administered in Study 2 (350 mg/700 mg/1,050 mg/1,400 mg; Dosing Regimen 2) as compared to the regimen administered in Study 1 (700 mg/700 mg/700 mg/1,400 mg; Dosing Regimen 1); therefore, Dosing Regimen 2 is recommended for administration of KISUNLA [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 ), Clinical Pharmacology ( 12.2 ), Clinical Studies ( 14 )] . The safety of KISUNLA has been evaluated in 3727 patients with Alzheimer's disease who received at least one dose of KISUNLA intravenously. In the other clinical studies of KISUNLA, 1912 patients with Alzheimer's disease received KISUNLA once monthly for at least 6 months, 1057 patients for at least 12 months, and 432 patients for at least 18 months, at the Dosing Regimen 1. Study 1 In Study 1 (NCT04437511), a total of 853 patients with Alzheimer's disease received at least one dose of KISUNLA; patients were randomized to receive KISUNLA Dosing Regimen 1 or placebo. Thirteen percent of patients treated with KISUNLA compared to 4% of patients on placebo stopped study treatment because of an adverse reaction. The most common adverse reaction leading to discontinuation of KISUNLA was infusion-related reaction (4% of patients treated with KISUNLA compared to no patient on placebo). Table 7 shows adverse reactions that were reported in at least 5% of patients treated with KISUNLA and at least 2% more frequently than in patients on placebo in Study 1. Table 7: Adverse Reactions Reported in at Least 5% of Patients Treated With KISUNLA and at Least 2% Higher Than Placebo in Study 1 a Administered as a different titration regimen (700 mg/700 mg/700 mg/1,400 mg) than the currently recommended dosing regimen (350 mg/700 mg/1,050 mg/1,400 mg) b As assessed by MRI. A participant could have both microhemorrhage and superficial siderosis. Adverse Reaction KISUNLA a N = 853 % Placebo N = 874 % ARIA-H microhemorrhage b 25 11 ARIA-E 24 2 ARIA-H superficial siderosis b 15 3 Headache 13 10 Infusion-related reaction 9 0.5 Study 2 In Study 2 (NCT05738486), a total of 842 patients received at least one dose of KISUNLA; 212 patients were randomized to receive KISUNLA Dosing Regimen 2. In Study 2, compared to the rates reported with Dosing Regimen 1, higher rates of hypersensitivity reactions (8% of patients treated with Dosing Regimen 2) and infusion-related reactions (16% of patients treated with Dosing Regimen 2), and a lower rate of ARIA-E (16% of patients treated with Dosing Regimen 2) were observed [see Warnings and Precautions ( 5.1 ) and Clinical Studies ( 14 )]. Less Common Adverse Reactions Hypersensitivity Reactions [see Warnings and Precautions ( 5.2 )] Hypersensitivity reactions, including anaphylaxis, occurred in 3% of patients treated with KISUNLA compared to 0.7% of patients on placebo in Study 1 and in 8% of patients treated with KISUNLA Dosing Regimen 2 in Study 2. Intestinal Obstruction and Intestinal Perforation Serious adverse reactions of intestinal obstruction occurred in three patients (0.4%) treated with KISUNLA compared to no patients on placebo in Study 1 and one patient (0.5%) treated with KISUNLA Dosing Regimen 2 in Study 2. Serious adverse reactions of intestinal perforation occurred in two patients (0.2%) treated with KISUNLA compared to one patient (0.1%) on placebo in Study 1. Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions [see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.6 )] Infusion-related reactions occurred more frequently in patients treated with KISUNLA who developed anti-drug antibodies (ADAs) compared to patients who did not develop ADAs (Study 1, Dosing Regimen 1: 10% compared to 2%; Study 2, Dosing Regimen 2: 20% compared to 8%).

16.2 Storage and Handling Unopened Vial Store refrigerated at 2°C to 8°C (36°F to 46°F). Keep the vial in the outer carton to protect from light. Do not freeze or shake. If refrigeration is not available, may be stored at room temperature (20°C to 25°C [68°F to 77°F]) for up to 3 days. Diluted Solution For storage of the diluted infusion solution see Dosage and Administration ( 2.4 ) .