Fitusiran

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 )

QFITLIA is a clear, colorless to pale yellow solution in a single-dose: Injection: 50 mg/0.5 mL prefilled pen Injection: 20 mg/0.2 mL vial Injection: 50 mg/0.5 mL (100 mg/mL) in a single-dose prefilled pen 20 mg/0.2 mL (100 mg/mL) in a single-dose vial ( 3 )

None. None ( 4 )

Hepatotoxicity: Obtain liver tests at baseline and then monthly for at least 6 months after initiating QFITLIA and after dose increases, and periodically thereafter. Liver test elevations may require QFITLIA interruption or discontinuation ( 5.3 ).

5.1 Thrombotic Events Serious thrombotic events have been reported in QFITLIA-treated patients. Thrombotic events were reported in 2.6% of patients receiving the 80 mg once monthly dose (2.3 events per 100 person-years), including a fatal event of cerebral venous sinus thrombosis. The 80 mg once monthly dose is not approved or recommended for use. Thrombotic events were reported in 1.4% of patients receiving QFITLIA prophylaxis using the antithrombin-based dose regimen (AT-DR) that targeted AT activity 15-35% (0.8 events per 100 person-years). Participants with established thrombophilia or a history of thrombosis were generally excluded from studies with QFITLIA. The risk of thrombosis is greater in patients with persistent AT activity <15%, with comorbidities that predispose to thrombosis, when bleed management guidelines are not followed in the post-operative setting, when there is an indwelling venous catheter, and with use of the 80 mg once monthly (non-AT-based) dose. Treatment of breakthrough bleeding episodes with CFC or BPA at a dose greater or more frequent than recommended may also increase thrombotic risk [see Dosage and Administration (2.3) ] . The decision to utilize higher dosing regimens of CFC or BPA in the setting of inadequate hemostasis requires an assessment of the benefits and risks and close clinical monitoring. Monitor AT activity using an FDA-cleared test and target AT activity 15–35% to reduce the risk of thrombosis [see Dosage and Administration (2.1 , 2.2) and Warnings and Precautions (5.1) ] . Monitor patients for signs and symptoms of thrombotic events. Interrupt QFITLIA prophylaxis in patients with a thrombotic event and manage as clinically indicated. Inform patients treated with QFITLIA to monitor for and report signs and symptoms of thrombotic events. Consider the benefits and risks of resuming QFITLIA prophylaxis following resolution of the thrombotic event.

5.2 Acute and Recurrent Gallbladder Disease Treatment with QFITLIA is associated with an increased occurrence of acute and recurrent gallbladder disease including cholelithiasis and cholecystitis. QFITLIA at a fixed dose (including 80 mg once monthly) is not approved or recommended for use. In the 270 patients in the QFITLIA clinical studies who received the fixed dose (non-AT-based dose) once monthly regimen, 17% experienced gallbladder events and 4% (11 patients) underwent cholecystectomy. In 286 patients who received the AT-DR, 3.8% experienced gallbladder events and 0.3% (1 patient) underwent cholecystectomy. All but one of the patients who underwent cholecystectomy resumed QFITLIA after surgery. One patient who started on fixed dosing experienced cholangitis and pancreatitis caused by gallstone disease more than a year after cholecystectomy while receiving AT-DR. Patients diagnosed with acute or recurrent gallbladder disease most commonly presented with epigastric pain, generalized abdominal pain, indigestion, nausea and/or vomiting. If gallbladder disease is suspected, appropriate imaging and clinical follow-up are indicated. Consider alternative treatment for hemophilia in patients with a history of symptomatic gallbladder disease. Consider interruption or discontinuation of QFITLIA if gallbladder disease occurs.

5.3 Hepatotoxicity In the two randomized studies testing QFITLIA 80 mg once monthly, serum alanine transaminase (ALT) and aspartate transaminase (AST) elevations above 3 times the upper limit of normal (ULN) occurred in 32% of patients with hemophilia with inhibitors and 18% of patients with hemophilia without inhibitors compared to no events of AST or ALT elevation greater than 3× ULN in the control groups. There was one case of moderate hepatic injury (ALT elevation >300 U/L and total serum bilirubin >3 mg/dL) attributable to QFITLIA use. This patient had elevation of liver tests after a single 80 mg dose that continued to rise with repeated dosing of QFITLIA 80 mg once monthly. This patient's liver tests recovered with drug discontinuation. QFITLIA 80 mg once monthly is not approved or recommended for use. On the AT-DR, 3.4% of patients treated with QFITLIA had at least one ALT value greater than 3× ULN with a median onset of 89 days after initial dosing (range 15 to 768 days). Avoid use of QFITLIA in patients with hepatic impairment (Child-Pugh Class A, B and C). Obtain baseline liver tests including AST, ALT, and total bilirubin prior to initiating QFITLIA, monthly for at least the first 6 months of QFITLIA use, and monthly for at least 6 months after a dose increase, and periodically thereafter as clinically indicated. If new or worsening liver test abnormalities occur, perform appropriate diagnostic evaluations, initiate medical management as appropriate and monitor laboratory parameters until they return to baseline. If ALT or AST elevations greater than 5× ULN occur, interrupt QFITLIA treatment. Consider the benefits and risks of resuming QFITLIA prophylaxis following resolution of transaminase elevations. If you decide to restart QFITLIA, wait until liver tests have returned to baseline. If QFITLIA is restarted and ALT or AST elevations greater than 5× ULN reoccur or the patient experiences jaundice (total bilirubin ≥2.5 mg/dL) thought to be from hepatotoxicity with other causes of liver test elevation ruled out, permanently discontinue QFITLIA.

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) ] .

Avoid use in patients with established hepatic impairment (Child-Pugh Class A, B and C) ( 8.6 ). To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation 1-800-745-4447 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8.1 Pregnancy Risk Summary There are no available data on QFITLIA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Reproduction studies in pregnant animals have not been conducted with fitusiran. It is not known whether QFITLIA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. QFITLIA should be used during pregnancy only if the potential benefit justifies the potential risks, including those to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

8.2 Lactation Risk Summary There are no data on the presence of fitusiran or its metabolite in human milk, the effects on the breastfed child, or the effects on milk production. It is not known whether QFITLIA is safe for use during breastfeeding. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for QFITLIA and any potential adverse effects on the breastfed infant from QFITLIA or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential Contraception Females Use of QFITLIA in women using hormonal contraceptives may increase the risk of thrombotic events. Estrogen based hormonal contraceptives are an established risk factor for thrombosis in women with inherited AT deficiency. Advise patients using hormonal contraceptives to use an alternative non-hormonal contraception prior to starting treatment with and while receiving QFITLIA.

8.4 Pediatric Use The safety and effectiveness of QFITLIA for the treatment of hemophilia A or B with or without factor VIII or IX inhibitors have been established in pediatric patients aged 12 years and older. Use of QFITLIA in pediatric patients with hemophilia A and B is supported by evidence from adequate and well-controlled studies in adult and pediatric patients [see Adverse Reactions (6.1) and Clinical Studies (14) ] . A total of 60 pediatric patients ages 12 to 17 were treated with QFITLIA in the clinical studies. The safety and effectiveness of QFITLIA have not been established in pediatric patients below 12 years of age.

8.5 Geriatric Use There were 3 patients with hemophilia 65 years of age and older in the clinical studies on QFITLIA. Clinical studies of QFITLIA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Hepatic Impairment Serum transaminase elevations have been observed in the clinical studies [see Warnings and Precautions (5.3) ] . Avoid use of QFITLIA in patients with established hepatic impairment (Child-Pugh Class A, B and C).

QFITLIA is a double-stranded siRNA that causes degradation of AT messenger RNA (mRNA) through RNA interference, reducing plasma AT levels.