QFITLIA

QFITLIA injection contains fitusiran, an antithrombin-directed double-stranded small interfering ribonucleic acid (siRNA), which is covalently linked to a ligand containing a triantennary N-acetylgalactosamine (GalNAc) moiety. The molecular formula of fitusiran sodium is C 520 H 636 F 21 N 175 Na 43 O 309 P 43 S 6 and the molecular weight is 17,193 Da. Fitusiran drug substance is a white to pale yellow powder and freely soluble in water and phosphate buffered saline. The pH of a 1% aqueous solution of fitusiran drug substance in 50 mM KCl is 5.4 (4.4–7.3). It has the following structural formula: QFITLIA is supplied as a sterile, preservative-free, clear, colorless to pale yellow solution for subcutaneous administration. Each 50 mg single-dose prefilled pen delivers 50 mg fitusiran (equivalent to 53.0 mg fitusiran sodium) in 0.5 mL, and also contains dibasic sodium phosphate (0.585 mg), monobasic sodium phosphate (0.044 mg), sodium chloride (2.455 mg), and Water for Injection, USP. Phosphoric acid (concentrated) and sodium hydroxide may be added to adjust to pH 7.0. Each 20 mg single-dose vial delivers 20 mg fitusiran (equivalent to 21.2 mg fitusiran sodium) in 0.2 mL, and also contains dibasic sodium phosphate (0.234 mg), monobasic sodium phosphate (0.018 mg), sodium chloride (0.982 mg), and Water for Injection, USP. Phosphoric acid (concentrated) and sodium hydroxide may be added to adjust to pH 7.0. Chemical Structure

QFITLIA is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients aged 12 years and older with hemophilia A or B with or without factor VIII or IX inhibitors. QFITLIA is an antithrombin-directed small interfering ribonucleic acid indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients aged 12 years and older with hemophilia A or B with or without factor VIII or IX inhibitors. ( 1 )

For subcutaneous use only. Starting dose: 50 mg once every 2 months ( 2.1 ). Monitor AT activity using an FDA-cleared test. Maintain AT activity between 15–35% by adjusting the dose and/or frequency of administration ( 2.2 ). See Full Prescribing Information for important preparation and administration instructions ( 2.4 ). 2.1 Recommended Dosage For subcutaneous use only. Use of QFITLIA is recommended under the supervision of a healthcare professional experienced in the treatment of hemophilia or bleeding disorders. Measure AT activity prior to initiation of QFITLIA. Do not initiate QFITLIA dosing if AT activity is <60%. Monitor AT activity using an FDA-cleared test. Information on FDA-cleared tests for AT activity is available at http://www.fda.gov/CompanionDiagnostics. After QFITLIA is initiated, patients may continue their prior clotting factor concentrates (CFC) or bypassing agent (BPA) prophylaxis for the first 7 days of treatment. Discontinue CFC or BPA prophylaxis no later than 7 days after the initial dose of QFITLIA. The starting dose of QFITLIA is 50 mg once subcutaneously every two months. Adjust the dose and/or dosing interval, if needed, to maintain AT activity between 15–35% [see Boxed Warning , Dosage and Administration (2.2) and Warnings and Precautions (5.1) ] . 2.2 Dosage Modification Measure AT activity using an FDA-cleared test at Weeks 4 (Month 1), 12 (Month 3), 20 (Month 5) and 24 (Month 6) following the starting dose and after any dose modification. If any AT activity is <15%, a dose reduction is required. The lower dose should be initiated 3 months after the prior dose. AT measurements should be restarted after a dose reduction. If AT activity is >35% after 6 months, or if the patient has not achieved satisfactory bleed control, dose escalation should be considered. AT measurements should be restarted after a dose escalation. Refer to Table 1 below for modified dosage based on AT activity levels. Table 1: Dose Modification Based on Antithrombin Activity Levels Last Dosage Administered Antithrombin Activity Level Dose Modification 50 mg every 2 months Less than 15% 20 mg every 2 months 15% to 35% Continue current dosage Greater than 35% after 6 months 50 mg every month 20 mg every 2 months Less than 15% 10 mg every 2 months 15% to 35% Continue current dosage Greater than 35% after 6 months 20 mg every month 10 mg every 2 months Less than 15% Discontinue QFITLIA 15% to 35% Continue current dosage Greater than 35% after 6 months 10 mg every month Once the patient's target dose is identified based on AT activity 15–35%, measure AT activity annually. Additional AT measurements can be considered if bleeding control is not adequate. After cessation of QFITLIA dosing, routine AT monitoring is not needed unless the patient is bleeding and treatment with CFC/BPA is required. Based on data from the clinical studies, a majority of patients have AT activity >60% by 6 months after the last QFITLIA dose, after which standard doses of CFC/BPA may be used. Missed dose If a dose of QFITLIA is missed, administer as soon as possible; thereafter, resume the patient's usual dosing schedule of either once every month or once every two months, as applicable, from the last dose. 2.3 Bleed Management Breakthrough Bleed Management If breakthrough bleeding requiring on-demand treatment with CFC or BPA occurs during the first 7 days after QFITLIA initiation, manage the bleed using the patient's prior dosing regimen of CFC or BPA. If breakthrough bleeding occurs after 7 days from the first QFITLIA dose, bleeds should be managed with a reduced dose and frequency of CFC/BPA to minimize the risk of thrombotic events. Initially, the weight-based dose of a CFC/BPA should be reduced, and the dosing interval doubled compared to the standard dose. This reduced dosing is shown in Table 2. If adequate hemostatic control is not achieved, higher doses may be used based on clinical judgement. Combination use of antifibrinolytics with CFC or BPA has not been studied. Table 2: Breakthrough Bleed Management While Treated with QFITLIA Factor VIII Factor IX (SHL) Factor IX (EHL) aPCC rFVIIa aPCC = activated prothrombin complex concentrate, EHL = extended half-life, rFVIIa = activated recombinant FVII, SHL = standard half-life. Recommended dose 10 IU/kg (maximum: 20 IU/kg) Use clinical judgement for situations requiring higher doses, more frequent administration, or multiple repeat doses. Use standard of care for adjunctive management of bleeding episodes and thrombotic events. 20 IU/kg (maximum: 30 IU/kg) 20 IU/kg (maximum: 30 IU/kg) 30 U/kg (maximum: 50 U/kg) ≤45 μg/kg Repeat dosing Should not repeat in <24 hours Should not repeat in <24 hours Should not repeat in <5–7 days Should not repeat in <24 hours Should not repeat in <2 hours Use of QFITLIA During Surgical Interventions In clinical studies, patients with hemophilia A or B with or without inhibitors have undergone both major (N=60) and minor (N=71) surgical procedures without discontinuing QFITLIA prophylaxis. Utilize bleed management guidelines during the perioperative period for hemostatic management. 2.4 Preparation and Administration Instructions QFITLIA is intended for use under the guidance of a healthcare provider. Provide proper training to patients and/or caregivers on the preparation and administration of QFITLIA prior to use, according to the Instructions for Use (IFU). A patient may self-inject QFITLIA or the patient's caregiver may administer QFITLIA. In pediatric patients 12 to 17 years of age, it is recommended that QFITLIA be administered by or under the supervision of an adult. QFITLIA for subcutaneous administration is a clear, colorless to pale yellow solution. Do not use if the solution is discolored or cloudy, or if it contains visible flakes or particles. Do not use QFITLIA if it has been dropped or damaged. If QFITLIA is stored at room temperature, it is ready for use. If QFITLIA is stored in the refrigerator, remove from the refrigerator and allow QFITLIA to reach room temperature, for at least 30 minutes. Administer QFITLIA by subcutaneous injection in the thigh or abdomen region, except for the 2 inches (5 cm) around the navel. A caregiver can also inject QFITLIA in the outer area of the patient's upper arm. QFITLIA should not be injected into skin that is tender, damaged, bruised, or scarred. Do not inject into a vein. To inject 10 mg or 20 mg of QFITLIA from the single-dose vial, it is recommended to use a sterile 1 mL Luer Lock syringe (polypropylene or polycarbonate), and a sterile 27 gauge ½ inch (13 mm) Luer Lock needle to withdraw and inject QFITLIA solution subcutaneously (see the Instructions for Use). Discard unused product remaining in the prefilled pen or vial.

None. None ( 4 )

The following clinically significant adverse reactions are described elsewhere in the labeling: Thrombotic Events [see Boxed Warning and Warnings and Precautions (5.1) ] Acute and Recurrent Gallbladder Disease [see Boxed Warning and Warnings and Precautions (5.2) ] Hepatotoxicity [see Warnings and Precautions (5.3) ] Common adverse reactions (incidence >10%) are viral infection, nasopharyngitis, and bacterial infection ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation 1-800-745-4447 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. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to QFITLIA as fixed doses and AT-DR (N=335). The safety of the QFITLIA AT-DR was assessed in 286 adult and pediatric male patients with hemophilia A or B with or without inhibitors [see Clinical Studies (14) ] . Among patients who received the AT-DR, 93% were exposed for 6 months or longer and 83% were exposed for 12 months or longer. The median duration of exposure across the studies was 674 days (with a maximum of 896 days). Serious adverse reactions occurred in 4/286 (1.4%) patients who received the AT-DR, two of whom had serious adverse reactions of cholecystitis. Permanent discontinuation of QFITLIA due to an adverse reaction occurred in 4/286 (1.4%) patients receiving the AT-DR and included liver injury, post-operative deep vein thrombosis, cerebral infarction and pruritus. Dosage interruptions of QFITLIA due to an adverse reaction occurred in 2/286 (0.7%) patients receiving the AT-DR and included increased serum transaminases. The most common adverse reactions (≥10%) reported in patients treated with the AT-DR were viral infection, nasopharyngitis, and bacterial infection. Table 3: Adverse Reactions Reported in ≥5% of Patients from Pooled Clinical Studies with QFITLIA AT-DR Adverse Reaction Number of Patients (%) N=286 Viral infection Includes similar terms. 29 Nasopharyngitis 26 Bacterial infection 11 Hepatic Injury Hepatic injury includes: alanine aminotransferase increased, aspartate aminotransferase increased, liver injury. 8 Arthralgia 8 Prothrombin fragment 1.2 increased 7 Injection site reaction injection site reactions: includes injection site bruising, injection site erythema, injection site pain, injection site hematoma, injection site atrophy, injection site hemorrhage, injection site discomfort, injection site swelling, injection site discoloration, injection site pruritus, injection site induration, injection site nodule, injection site mass, injection site vesicles, injection site deformation, injection site rash, injection site joint pain and application site erythema. 6 Headache 5 Cough 5 Clinically relevant adverse reactions in less than 5% of patients include: Dyspepsia Abdominal pain

7.1 Hypercoagulability with Concomitant Use of CFC or BPA QFITLIA prophylaxis leads to increased thrombin generation with additive increase in peak thrombin when used concomitantly with CFC or BPA [see Boxed Warning , Dosage and Administration (2.3) and Warnings and Precautions (5.1) ] .

16.2 Storage and Handling 50 mg Prefilled Pen Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. QFITLIA may be stored at room temperature between 15°C to 30°C (59°F to 86°F) for a single period of up to 3 months within the expiration date printed on the label. Discard no later than 3 months after removal from the refrigerator or at the expiration date, whichever comes first. After storage at room temperature, do not return the product to the refrigerator. 20 mg Vial Store QFITLIA either in the refrigerator at 2°C to 8°C (36°F to 46°F) or at room temperature between 15°C to 30°C (59°F to 86°F), in the original carton to protect from light. After storage at room temperature, do not return the product to the refrigerator. Do not shake QFITLIA at any time. Do not heat QFITLIA. Do not freeze. Do not put into direct sunlight.