QFITLIA- fitusiran_injection, solution

QFITLIA is a double-stranded siRNA that causes degradation of AT messenger RNA (mRNA) through RNA interference, reducing plasma AT levels. In clinical studies with QFITLIA in hemophilia patients, the primary pharmacodynamic (PD) measure was plasma AT activity. Lower AT activity levels were associated with lower annualized bleeding rates (ABR); however, persistent AT activity <15% is a risk factor for thrombotic events. In Study LTE15174, the mean (SD) AT activity on the AT-DR was 24% (4. Simulations to estimate time for AT activity to reach steady state found that regardless of the dose regimen, more than 99% of participants reached steady state AT levels (defined as <10% variability among consecutive measures) within 23 weeks following initiation of QFITLIA dosing or following dose escalation or de-escalation. The duration of persistent AT activity <60% (non-negligible impact of QFITLIA on coagulation) following QFITLIA treatment discontinuation was estimated to be approximately 6 months, after which standard doses of CFC/BPA may be administered. In patients with AT activity <15%, the time required prior to initiation of a lower dose was estimated to be 12 weeks to maximize the AT activity recovery to the target range of 15% to 35%. Extent of AT reduction with QFITLIA did not differ between patients with hemophilia A or B, with or without inhibitors. The pharmacokinetic (PK) properties of fitusiran were evaluated following administration of QFITLIA in patients with hemophilia A or B, with or without inhibitors as summarized in Table 4. QFITLIA PD is driven by liver PK rather than plasma PK. The QFITLIA dosing strategy is based on maintaining plasma AT activity levels between 15en dash35% with 10, 20 or 50 mg dosing every month or every two months. Table 4: Pharmacokinetic Parameters of QFITLIA PK Parameters Unless otherwise indicated, the PK parameters in this table are from Study LTE15174. All PK parameters are estimated using non-compartmental analysis and are presented as Mean (SD) [CV%], except for t max QFITLIA 20 mg QFITLIA 50 mg AUC = area under the plasma concentration-time curve extrapolated to infinity; CL/F = apparent clearance; C max 1/2 max General Information Steady State Exposure: C max 34. 1) [29%] 84. 7) [70%] AUC (ng ∙ 491 (83. 8) [17%] 1290 (377) [29%] Dose Proportionality QFITLIA exhibited a dose proportional increase in plasma exposure after SC administration. Accumulation Study TDR14767 (ALN-AT3SC-001) No accumulation of QFITLIA was observed following multiple once monthly dosing. Absorption t max 2. 5 en dash 4. 42 en dash 11. 9) Distribution QFITLIA distributes primarily to the liver after subcutaneous injection. Vss/F 431 (135) [31%] 570 (713) [125%] Protein Binding In vitro 96. 6% at clinically relevant exposure (0. 5 microgram/ml) Elimination t 1/2 5. 36) [42%] 7. 74) [59%] CL/F 41. 39) [20%] 50. 1) [140%] Metabolism Primary Pathway QFITLIA is metabolized by endo- and exo-nucleases to oligonucleotides of varying lengths, which are further metabolized to oligonucleotides of even shorter lengths. Main Metabolite AS(N-1)3' Excretion Primary Pathway Not evaluated 14. 6% (mean) of the administered 50 mg dose of QFITLIA is recovered unchanged in 0en dash24 hour urine Specific Populations QFITLIA has only been studied in male patients. The pharmacokinetics of fitusiran is not influenced by race. QFITLIA has not been studied in children <12 years old. No clinical study to evaluate the effect of hepatic impairment or renal impairment on the pharmacokinetics of QFITLIA was conducted. In the pivotal studies, 12 patients had mild renal impairment (eGFR >=60 to <90 mL/min/1. 73 m 2 2 2 max Drug Interaction Studies Clinical Studies No clinical drug-drug interaction studies have been conducted to evaluate the potential of QFITLIA to interact with other co-administered drugs which are either substrates, inhibitors or inducers of CYP isozymes, or are substrates or inhibitors of drug transporters. In Vitro Studies Results from in vitro The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of QFITLIA or of other fitusiran products. During QFITLIA treatment (up to 250 weeks) in four studies, 10 out of 290 adults with hemophilia (3. 4%) developed ADAs. All patients had low ADA titers, and the majority of patients had transient ADAs. There was no identified clinically significant effect of ADAs on PK, PD, safety, or effectiveness of QFITLIA.

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.

INSTRUCTIONS FOR USE
QFITLIAtrademark ( ) (fitusiran) injection, for subcutaneous use Single-Dose Vial (20 mg/0. 2 mL) This Instructions for Use contains information on how to inject QFITLIA from a vial. Read this Instructions for Use before using QFITLIA. Do not inject yourself or someone else until you have been shown how to inject QFITLIA from a vial. QFITLIA is only for use in adults and children 12 years of age and older. This QFITLIA vial is for single-use only. It contains 20 mg of QFITLIA for injection under the skin (subcutaneous injection). Important information to know before injecting QFITLIA Read all of the instructions carefully before using QFITLIA. Ask your healthcare provider how often you will need to inject the medicine. Check your prescription label to make sure you draw up the correct medicine dose prescribed by your healthcare provider. Throw away (dispose of) the used vial, syringe and needle right away after use. Only use the vial one time. After you inject your dose, throw away (dispose of) any unused QFITLIA left in the vial. Do not save any unused QFITLIA in the vial for later use. QFITLIA is for subcutaneous use only. Do not Storing QFITLIA vial Store QFITLIA vial either in the refrigerator between 36°F to 46°F (2°C to 8°C) or at room temperature between 59°F to 86°F (15°C to 30°C) in the original carton to protect from light. Do not Do not Do not Do not Do not Keep QFITLIA vial and all medicines out of the reach of children. Get ready to inject A1) Gather the supplies. Find a clean, flat work surface. Make sure you have the following supplies: A2) Check the vial. Do not Check the label on the vial to be sure that you have the correct prescribed medicine and dose. Check expiration date (EXP:). Do not A3) Check the medicine. Look at the medicine in the vial to make sure it is clear and colorless to pale yellow. Do not A4) If the QFITLIA vial was stored in the refrigerator, warm up for 30 minutes. Set the QFITLIA vial on a clean, flat surface and let it warm up at room temperature between 59°F to 86°F (15°C to 30°C) for at least 30 Do not A5) Wash your hands well with soap and water. A6) Remove the protective cap from the QFITLIA vial. A7) Wipe the rubber stopper of the vial with an alcohol wipe and allow it to dry. Choose and prepare the injection site B1) Choose the injection site. Thigh Stomach A caregiver can also inject in the outer area of your upper arm Do not Do not Do not B2) Prepare the injection site. Clean the injection site with an alcohol wipe. Let the skin dry before injecting. Prepare the injection C1) Attach the needle to the syringe and remove the needle cap. Attach the needle to the syringe. Hold the syringe body and pull the needle cap straight off the syringe. Do not Do not C2) Withdraw the solution. Withdraw slightly more than your prescribed dose into the syringe. Push the needle through the center of the rubber vial stopper. Leave the needle in the vial and turn both the syringe and vial upside down (vial on top). Hold the syringe and vial firmly in one hand. Make sure the tip of the needle is in the QFITLIA solution. With your other hand, pull back on the plunger rod to withdraw slightly more than your prescribed dose into the syringe. Withdraw slightly more than 0. 2 mL for a 20 mg dose. 1 mL for a 10 mg dose. C3) Check for air bubbles. Keep the needle in the vial and make sure both syringe and vial are upside down (vial on top). If air bubbles are in the syringe, hold the syringe straight up and tap the side of the syringe until the bubbles float to the top. Push the plunger rod up to push the bubbles out of the syringe. C4) Adjust plunger to your prescribed dose. Push the plunger rod to push solution back into the vial until you have the prescribed dose in the syringe. Push plunger rod to 0. If the medicine in the syringe is less than your prescribed dose, repeat steps C2, C3 and C4 until you have your correct dose. Remove the needle from the vial. Inject QFITLIA D1) Pinch a fold of skin and insert the needle. Gently pinch a fold of skin at the cleaned injection site. Insert the needle into the skin fold at a 45° to 90° angle. D2) Inject QFITLIA. Relax the skin pinch. Slowly push the plunger rod all the way to the bottom of the syringe body and inject all of the QFITLIA solution. D3) Gently pull out the needle and syringe from the injection site. Do not Do not If you see any blood at the site, lightly dab it with a cotton ball or gauze pad. If your injection site becomes red or sore, call your healthcare provider right away. Throw away (dispose of) used vial, needle and syringe E1) Do not Keep your sharps disposal container out of the reach of children. If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic, can be closed with a tightfitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used QFITLIA needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA''s website at: http://www. gov/safesharpsdisposal Do not Do not Manufactured by: QFITLIA is a trademark of GENZYME CORPORATION For patent information: https://www. us/en/products-and-resources/patents For more information go to www. com or call 1-800-745-4447. This Instructions for Use has been approved by the US Food and Drug Administration. Image Image Image Image Image Image Image Image Image Image Image Image.">DOSAGE AND ADMINISTRATION
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 15en dash35% by adjusting the dose and/or frequency of administration ( 2. 2 See Full Prescribing Information for important preparation and administration instructions ( 2. 4 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. Monitor AT activity using an FDA-cleared test. Information on FDA-cleared tests for AT activity is available at http://www. gov/CompanionDiagnostics. Measure AT activity prior to initiation of QFITLIA. Do not initiate QFITLIA dosing if AT activity is <60%. 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 15en dash35% [see Boxed Warning Dosage and Administration (2. 2) Warnings and Precautions (5. 1) 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 15en dash35%, 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. 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 Factor IX aPCC rFVIIa aPCC = activated prothrombin complex concentrate, EHL = extended half-life, rFVIIa = activated recombinant FVII, SHL = standard half-life. Recommended dose 10 IU/kg Use clinical judgement for situations requiring higher doses, more frequent administration, or multiple repeat doses. 20 IU/kg 20 IU/kg 30 U/kg <=45 mug/kg Repeat dosing Should not repeat in <24 hours Should not repeat in <24 hours Should not repeat in <5en dash7 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. 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.
INSTRUCTIONS FOR USE
QFITLIA ( ) (fitusiran) injection, for subcutaneous use Single-Dose Prefilled Pen (50 mg/0. 5 mL) This Instructions for Use contains information on how to inject QFITLIA. Read this Instructions for Use before using the QFITLIA Prefilled Pen. Do not inject yourself or someone else until you have been shown how to inject QFITLIA Prefilled Pen. QFITLIA Prefilled Pen is only for use in adults and children 12 years of age and older. This QFITLIA Prefilled Pen is a single-dose device. It contains 50 mg of QFITLIA for injection under the skin (subcutaneous injection). The parts of the QFITLIA Prefilled Pen are shown below: Important information to know before injecting QFITLIA Read all of the instructions carefully before using the QFITLIA Prefilled Pen. Ask your healthcare provider how often you will need to inject the medicine. Throw away (dispose of) the used QFITLIA Prefilled Pen right away after use. Do not QFITLIA Prefilled Pen is for subcutaneous use only. Do not Storing QFITLIA Prefilled Pen Store QFITLIA Prefilled Pen in the refrigerator between 36°F to 46°F (2°C to 8°C) in the original carton to protect from light. QFITLIA Prefilled Pen may be stored at room temperature between 59°F to 86°F (15°C to 30°C) for a single period of up to 3 months within the expiration date printed on the label. Do not Do not Do not Do not Do not Keep QFITLIA Prefilled Pen and all medicines out of the reach of children. Get ready to inject A1) Gather supplies Find a clean, flat work surface. Make sure you have the following supplies: A2) Check the QFITLIA Prefilled Pen Note: Do not Do not Do not A3) Look at the label Check the label to be sure that you have the correct prescribed medicine and dose. Check the expiration date. Do not A4) Check the medicine Look at the medicine through the Window, it should be clear and colorless to pale yellow. Note: Do not A5) If QFITLIA Prefilled Pen was stored in the refrigerator, warm up for 30 minutes. Lay the QFITLIA Prefilled Pen on a clean, flat surface and let it warm up at room temperature between 59°F to 86°F (15°C to 30°C) for at least 30 Do not B. Choose and prepare your injection site B1) Wash your hands well with soap and water B2) Choose an injection site Thigh Stomach A caregiver can also inject in the outer area of your upper arm Do not For subcutaneous use only. Do not Do not B3) Prepare the injection site Clean the injection site with an alcohol wipe. Let the skin dry before injecting. Give the injection C1) Remove Blue Cap Remove the Blue Cap by pulling it straight off as shown. Do not Do not Do not Do not Note: C2) Place QFITLIA Prefilled Pen on injection site Hold the QFITLIA Prefilled Pen as shown so you can see the Window. Place the Orange Needle Cover on the skin at a 90-degree angle. C3) Press down firmly arrow Watch Window turn fully yellow Press down and hold the QFITLIA Prefilled Pen firmly against the skin until you cannot see the Orange Needle Cover There will be a "click" and The Window will start to turn yellow. Keep pressing the QFITLIA Prefilled Pen against the skin and watch the Window. The Window will turn completely yellow, and You may hear a 2nd "click. " C4) Remove After you have completed your injection pull straight up to remove QFITLIA Prefilled Pen from the skin. The Orange Needle Cover will cover the needle. If you see any blood at the site, lightly dab a cotton ball or gauze pad. Do not If the Window does not turn completely yellow Do not D. Throw away (dispose of) used QFITLIA Prefilled Pen Do not Keep your sharps disposal container out of the reach of children. How to dispose of (throw away) QFITLIA Prefilled Pen Put your used QFITLIA Prefilled Pen and Blue Cap in an FDA-cleared sharps disposal container right away after use. Do not If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic, can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used QFITLIA Prefilled Pens. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA''s website at: http://www. gov/safesharpsdisposal Do not Do not Manufactured by: QFITLIA is a trademark of GENZYME CORPORATION For patent information: https://www. us/en/products-and-resources/patents For more information go to www. com or call 1-800-745-4447. This Instructions for Use has been approved by the US Food and Drug Administration. Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image.
INSTRUCTIONS FOR USE
QFITLIAtrademark ( ) (fitusiran) injection, for subcutaneous use Single-Dose Vial (20 mg/0. 2 mL) This Instructions for Use contains information on how to inject QFITLIA from a vial. Read this Instructions for Use before using QFITLIA. Do not inject yourself or someone else until you have been shown how to inject QFITLIA from a vial. QFITLIA is only for use in adults and children 12 years of age and older. This QFITLIA vial is for single-use only. It contains 20 mg of QFITLIA for injection under the skin (subcutaneous injection). Important information to know before injecting QFITLIA Read all of the instructions carefully before using QFITLIA. Ask your healthcare provider how often you will need to inject the medicine. Check your prescription label to make sure you draw up the correct medicine dose prescribed by your healthcare provider. Throw away (dispose of) the used vial, syringe and needle right away after use. Only use the vial one time. After you inject your dose, throw away (dispose of) any unused QFITLIA left in the vial. Do not save any unused QFITLIA in the vial for later use. QFITLIA is for subcutaneous use only. Do not Storing QFITLIA vial Store QFITLIA vial either in the refrigerator between 36°F to 46°F (2°C to 8°C) or at room temperature between 59°F to 86°F (15°C to 30°C) in the original carton to protect from light. Do not Do not Do not Do not Do not Keep QFITLIA vial and all medicines out of the reach of children. Get ready to inject A1) Gather the supplies. Find a clean, flat work surface. Make sure you have the following supplies: A2) Check the vial. Do not Check the label on the vial to be sure that you have the correct prescribed medicine and dose. Check expiration date (EXP:). Do not A3) Check the medicine. Look at the medicine in the vial to make sure it is clear and colorless to pale yellow. Do not A4) If the QFITLIA vial was stored in the refrigerator, warm up for 30 minutes. Set the QFITLIA vial on a clean, flat surface and let it warm up at room temperature between 59°F to 86°F (15°C to 30°C) for at least 30 Do not A5) Wash your hands well with soap and water. A6) Remove the protective cap from the QFITLIA vial. A7) Wipe the rubber stopper of the vial with an alcohol wipe and allow it to dry. Choose and prepare the injection site B1) Choose the injection site. Thigh Stomach A caregiver can also inject in the outer area of your upper arm Do not Do not Do not B2) Prepare the injection site. Clean the injection site with an alcohol wipe. Let the skin dry before injecting. Prepare the injection C1) Attach the needle to the syringe and remove the needle cap. Attach the needle to the syringe. Hold the syringe body and pull the needle cap straight off the syringe. Do not Do not C2) Withdraw the solution. Withdraw slightly more than your prescribed dose into the syringe. Push the needle through the center of the rubber vial stopper. Leave the needle in the vial and turn both the syringe and vial upside down (vial on top). Hold the syringe and vial firmly in one hand. Make sure the tip of the needle is in the QFITLIA solution. With your other hand, pull back on the plunger rod to withdraw slightly more than your prescribed dose into the syringe. Withdraw slightly more than 0. 2 mL for a 20 mg dose. 1 mL for a 10 mg dose. C3) Check for air bubbles. Keep the needle in the vial and make sure both syringe and vial are upside down (vial on top). If air bubbles are in the syringe, hold the syringe straight up and tap the side of the syringe until the bubbles float to the top. Push the plunger rod up to push the bubbles out of the syringe. C4) Adjust plunger to your prescribed dose. Push the plunger rod to push solution back into the vial until you have the prescribed dose in the syringe. Push plunger rod to 0. If the medicine in the syringe is less than your prescribed dose, repeat steps C2, C3 and C4 until you have your correct dose. Remove the needle from the vial. Inject QFITLIA D1) Pinch a fold of skin and insert the needle. Gently pinch a fold of skin at the cleaned injection site. Insert the needle into the skin fold at a 45° to 90° angle. D2) Inject QFITLIA. Relax the skin pinch. Slowly push the plunger rod all the way to the bottom of the syringe body and inject all of the QFITLIA solution. D3) Gently pull out the needle and syringe from the injection site. Do not Do not If you see any blood at the site, lightly dab it with a cotton ball or gauze pad. If your injection site becomes red or sore, call your healthcare provider right away. Throw away (dispose of) used vial, needle and syringe E1) Do not Keep your sharps disposal container out of the reach of children. If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic, can be closed with a tightfitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used QFITLIA needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA''s website at: http://www. gov/safesharpsdisposal Do not Do not Manufactured by: QFITLIA is a trademark of GENZYME CORPORATION For patent information: https://www. us/en/products-and-resources/patents For more information go to www. com or call 1-800-745-4447. This Instructions for Use has been approved by the US Food and Drug Administration. Image Image Image Image Image Image Image Image Image Image Image Image.

The following clinically significant adverse reactions are described elsewhere in the labeling: Thrombotic Events [see Boxed Warning Warnings and Precautions (5. 1) Acute and Recurrent Gallbladder Disease [see Boxed Warning 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. gov/medwatch. 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 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.

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. gov/medwatch. 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. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2en dash4% and 15en dash20%, respectively. 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. 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. 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) Clinical Studies (14) The safety and effectiveness of QFITLIA have not been established in pediatric patients below 12 years of age. 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. Serum transaminase elevations have been observed in the clinical studies [see Warnings and Precautions (5.

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) Warnings and Precautions (5.1)

NONCLINICAL TOXICOLOGY
In a 2-year carcinogenicity study in Sprague Dawley rats, fitusiran was not carcinogenic up to the highest dose tested following subcutaneous administration at doses of 0.03, 0.1 or 0.3 mg/kg/week in males and 0.1, 0.3, or 1 mg/kg/week in females. All doses in males and females were below the maximum recommended human dose (MRHD) of 50 mg per month based on body surface area (BSA) comparisons due to the sensitivity of wild type animals to the pharmacological effects of fitusiran. Fitusiran was not carcinogenic in Tg-rasH2 mice following subcutaneous administration at doses of 0.05, 0.15, or 0.5 mg/kg/week in males and 0.025, 0.08, or 0.25 mg/kg/week in females for 26 weeks. Fitusiran was not mutagenic or clastogenic in a battery of genetic toxicity studies (i.e., in vitro in vitro in vivo In a chronic repeat dose toxicology study in Sprague Dawley rats, fitusiran-treated males received subcutaneous doses of 0.25, 0.5, or 1 mg/kg/week for 16 weeks then were cohabitated with fitusiran-naïve females. No adverse effects on male fertility endpoints were observed. All doses used in males were below the MRHD based on BSA comparisons due to the sensitivity of wild type animals to the pharmacological effects of fitusiran.
CLINICAL STUDIES
The efficacy and safety of QFITLIA in adult and pediatric patients aged 12 years and older with hemophilia A or B with or without inhibitors were established in two clinical studies: Hemophilia A or B with Inhibitory Antibodies: ATLAS-INH (NCT03417102) Hemophilia A or B without Inhibitory Antibodies: ATLAS-A/B (NCT03417245) Patients in the above parent studies rolled over into the long-term extension study ATLAS-OLE (NCT03754790). The clinical studies ATLAS-INH and ATLAS-A/B tested an 80 mg monthly fixed dose of QFITLIA. Because of thrombotic events with this dose, the QFITLIA AT-DR targeting AT activity of 15en dash35% was implemented in ATLAS-OLE. The AT-DR was initiated when studies ATLAS-INH and ATLAS-A/B were nearly completed, therefore, the efficacy of QFITLIA AT-DR treatment was assessed by comparing the QFITLIA AT-DR treatment data from the long-term extension study ATLAS-OLE to the control data from studies ATLAS-INH and ATLAS-A/B. The efficacy analyses were conducted according to the intent to treat (ITT) principle preserving the randomization in the parent studies. ATLAS-INH ATLAS-INH was a randomized, multicenter, open-label clinical study in 57 adult and pediatric males (aged >=12 years) with hemophilia A or B with inhibitory antibodies to factor VIII (FVIII) or factor IX (FIX), who previously received on-demand (episodic) treatment with BPAs for bleeding. Eligible patients were randomized in a 2:1 ratio to receive QFITLIA prophylaxis at a fixed dose 80 mg SC monthly (N=38) or BPA on-demand for treatment of breakthrough bleeding episodes (N=19) for 9 months. The 80 mg dose of QFITLIA is not approved because of an increased risk of serious thrombotic events, gallbladder events (including the need for cholecystectomy) and hepatotoxicity [see Boxed Warning 5. 3 Of the 57 enrolled patients all had inhibitors; 45 patients had Hemophilia A and 12 had Hemophilia B. All patients in the study were male. The mean age of patients was 28. 4 years, and 10 (17. 5%) patients were 12en dash17 years of age. A total of 68. 4% of patients were Asian, 28. 1% were White, 1. 8% were other, and 1. 8% were multiple races; 5. 3% patients identified as Hispanic or Latino and 94. 7% identified as not Hispanic or Latino. Generally, the demographic and patient characteristics at baseline were comparable between the patients with hemophilia A and B. ATLAS A/B ATLAS A/B was a randomized, multicenter, open-label clinical study in 120 adult and pediatric males (aged >=12 years) with hemophilia A or B without inhibitory antibodies to FVIII or FIX, who previously received on-demand (episodic) treatment with CFC for bleeding. Eligible patients were randomized in a 2:1 ratio to receive QFITLIA prophylaxis at a fixed dose of 80 mg SC monthly (N=80) or CFCs on-demand to treat breakthrough bleeding episodes (N=40) for 9 months. The 80 mg dose of QFITLIA is not approved because of an increased risk of serious thrombotic events, gallbladder events (including the need for cholecystectomy) and hepatotoxicity [see Boxed Warning Warnings and Precautions (5. 3) Of the 120 enrolled patients none had inhibitors; 93 patients had Hemophilia A and 27 had Hemophilia B. The mean age of patients was 33. 8 years, and 14 (11. 7%) patients were 12en dash17 years of age. A total of 59. 2% of patients were Asian, 37. 5% were White, 1. 7% were Black or African American, and 1. 7% were multiple races; 3. 3% of patients identified as Hispanic or Latino, 90. 8% identified as not Hispanic or Latino, and 5. 8% had ethnicity information unreported. ATLAS-OLE A total of 227 patients rolled over from two clinical studies (ATLAS-INH and ATLAS-A/B) and ATLAS-PPX, a crossover study in patients previously on CFC or BPA prophylaxis, and were treated with QFITLIA in ATLAS-OLE. This multicenter open-label extension study evaluated the long-term safety and efficacy of QFITLIA in adult and pediatric males aged >=12 years with hemophilia A or B, with or without inhibitory antibodies to FVIII or FIX. Eligible patients initially received QFITLIA 80 mg SC once monthly. The study was amended to evaluate the efficacy and safety of the AT-DR. A total of 213 patients were subsequently transitioned to AT-DR targeting AT activity of 15en dash35%. In the AT-DR, the QFITLIA starting dose was 50 mg every two months, and dosing was individually adjusted based on AT activity level using the INNOVANCE Antithrombin assay. The dose could be increased to 50 mg every month or 80 mg every month or decreased to 20 mg every two months or 20 mg every month. QFITLIA was discontinued if AT activity was <15% at the lowest dose. No patients required escalation to 80 mg every month to achieve the target AT range. The dose required to maintain AT activity 15en dash35% in patients who initiated dosing on 50 mg every two months was: 50 mg every two months (35. 8% of patients), 50 mg every month (15. 7% of patients), 20 mg every two months (30. 9% of patients), or 20 mg every month (2. 9% of patients). A total of 14. 7% of patients discontinued QFITLIA due to more than one AT activity <15%. Patients with known co-existing coagulation disorders other than hemophilia A or B, increased risk of thrombosis as assessed by history of arterial or venous thromboembolism, significant valvular disease or atrial fibrillation, or co-existing thrombophilic disorder (e. , Factor V Leiden mutation), AT activity <60% at screening, platelet count <=100,000/muL, eGFR <=45 mL/min (using the MDRD), or clinically significant liver disease were not eligible for enrollment. The efficacy of QFITLIA AT-DR in ATLAS-OLE was evaluated for a duration of 7 months (primary efficacy period) following a 6-month dose adjustment period. The median observed annualized bleeding rate (IQR) for treated bleeds was 3. 5) overall, 1. 6) in inhibitor patients and 3. 2) in non-inhibitor patients. QFITLIA Prophylaxis Compared to On-Demand BPA or CFC The efficacy results of QFITLIA prophylaxis using AT-DR in ATLAS-OLE compared to on-demand BPA or CFC control data from studies ATLAS-INH and ATLAS-A/B with respect to rate of treated bleeds, treated spontaneous bleeds, and treated joint bleeds are shown in Table 5 (patients with inhibitors) and Table 6 (patients without inhibitors) below. Table 5: Annualized Bleed Rate for Treated Bleeds with QFITLIA Prophylaxis versus On-Demand BPA in Patients >=12 Years of Age with Inhibitors Endpoint QFITLIA AT-DR On-Demand BPA ABR = annualized bleed rate; AT-DR = AT-Dosing Regimen; BPA = bypassing agents; CI = confidence interval. All Treated Bleeds ABR (95% CI) Based on negative binomial regression model. 0) % reduction 73% Treated Spontaneous Bleeds ABR (95% CI) 3. 6) % reduction 82% Treated Joint Bleeds ABR (95% CI) 4. 1) % reduction 73% Table 6: Annualized Bleed Rate for Treated Bleeds with QFITLIA Prophylaxis versus On-Demand CFC in Patients >=12 Years of Age without Inhibitors Endpoint QFITLIA AT-DR On-Demand CFC ABR = annualized bleed rate; AT-DR = AT-Dosing Regimen; CFC = clotting factor concentrate; CI = confidence interval. 2) % reduction 71% Treated Spontaneous Bleeds ABR (95% CI) 5. 6) % reduction 74% Treated Joint Bleeds ABR (95% CI) 6. 9) % reduction 71%.

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