Fitusiran (Monograph)

Brand name: Qfitlia
Drug class: Hemostatics

Introduction

Antithrombin-directed small interfering ribonucleic acid.

Uses for Fitusiran

Hemophilia A or B

Routine prophylaxis to prevent or reduce bleeding episodes in adult and pediatric patients ≥12 years of age with hemophilia A or hemophilia B with or without factor VIII or IX inhibitors.

Designated an orphan drug by FDA for this use.

The World Federation of Hemophilia (WFH) and Medical Scientific Advisory Council (MASAC) of the National Hemophilia Foundation published evidence-based guidelines on hemophilia management. These guidelines recommend prophylactic therapy with clotting factor concentrates or non-factor replacement therapies (e.g., emicizumab) as the standard of care for patients with severe hemophilia A or B without inhibitors. Bypassing agents (activated prothrombin complex concentrate [aPCC] or recombinant factor VIIa) and emicizumab have been used for prophylaxis in patients with hemophilia A or B with inhibitors. Fitusiran is not mentioned in these guidelines as the guidelines were published prior to drug approval.

Fitusiran Dosage and Administration

General

Pretreatment Screening

• Measure AT activity with an FDA-approved test ([Web]); do not initiate therapy if AT activity <60%.

• Assess liver function tests (ALT, AST, total bilirubin).

Patient Monitoring

• Assess liver function tests (ALT, AST, total bilirubin) monthly for at least 6 months after initiating fitusiran and after dose increases; assess periodically thereafter as clinically indicated.

• Measure AT activity at weeks 4 (month 1), 12 (month 3), 20 (month 5), and 24 (month 6) following initiation of therapy and after any dose modification. Once the target dosage has been identified based on an AT activity level of 15–35%, measure AT activity annually and when clinically indicated.

Dispensing and Administration Precautions

• Fitusiran should be used under the guidance of a healthcare professional experienced in the treatment of hemophilia or bleeding disorders.

Other General Considerations

• Continue prior clotting factor concentrate or bypassing agent prophylaxis for the first 7 days of fitusiran treatment, then discontinue. Manage breakthrough bleeding during this time with the patient's prior clotting factor concentrate or bypassing agent dosage regimen.

Administration

Sub-Q Administration

Administer by sub-Q injection only.

Available as a 50 mg/0.5 mL (100 mg/mL) single-dose prefilled pen or a 20 mg/0.2 mL (100 mg/mL) single-dose vial.

Use fitusiran under the guidance of a healthcare provider. May be self-administered or administered by a caregiver after appropriate training provided. For patients 12–17 years of age, administer by or under the supervision of an adult.

Administer sub-Q injection into the abdomen (at least 2 inches away from navel) or thigh or outer area of upper arm (if administered by a caregiver).

Do not inject into tender, bruised, scarred, or damaged skin or into a vein.

Warm to room temperature for 30 minutes before administration.

Use a sterile 1 mL Luer Lock syringe with a 27‑gauge ½‑inch needle to withdraw drug from vials.

Dosage

Pediatric Patients

Hemophilia A or B with or without Inhibitors

Sub-Q

Pediatric patients ≥12 years of age: 50 mg once every 2 months.

Measure AT activity to guide subsequent dosing (see Dosage Modification section below).

If a dose is missed, administer dose as soon as possible, then resume regular monthly or bimonthly schedule.

Adults

Hemophilia A or B with or without Inhibitors

Sub-Q

50 mg once every 2 months.

Measure AT activity to guide subsequent dosing (see Dosage Modification section below).

If a dose is missed, administer the dose as soon as possible, then resume regular monthly or bimonthly schedule.

Dosage Modification

Measure AT activity using an FDA-cleared test at weeks 4, 12, 20, and 24 following the initial dose and after any dosage modification; adjust the dose and/or dosing interval of fitusiran accordingly to maintain AT activity between 15–35% (see Table 1).

If AT activity <15%, reduce dosage. If antithrombin activity >35% after 6 months or if the patient has not achieved adequate bleed control, consider dosage increase.

The recommended AT monitoring schedule should be restarted after dosage reduction or escalation.

Once target dosage identified based on AT activity 15–35%, measure AT activity annually and when clinically indicated.

When therapy is discontinued, there is no need to continuing monitoring AT levels unless the patient is bleeding and treatment with clotting factor concentrates or bypassing agents is needed.

Breakthrough Bleed Management

If breakthrough bleeding requiring on-demand treatment with clotting factor concentrates or bypassing agents occurs during the first 7 days after the first fitusiran dose, manage using the patient's prior dosing regimen of the clotting factor concentrate or bypassing agent.

If breakthrough bleeding occurs after 7 days from the first fitusiran dose, manage using reduced dosages of clotting factor concentrates or bypassing agents to minimize risk of thrombotic events. Manufacturer provides guidelines for reduced dosing in Table 2. Initially, reduce the standard weight-based dose of these agents and double the dosing interval. Use clinical judgment to determine if higher doses, more frequent administration, or multiple repeat doses is needed.

Combination of clotting factor concentrates or bypassing agents with antifibrinolytic agents not studied.

Special Populations

Hepatic Impairment

Avoid use.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Fitusiran

Contraindications

• None

Warnings/Precautions

Warnings

Thrombotic events

Risk of thrombotic events (see Boxed Warning); risk is increased in patients with persistent antithrombin activity <15%, pro-thrombotic comorbidities, indwelling venous catheters, failure to follow perioperative bleed protocols, use of the unapproved 80 mg once monthly dose, or excessive use of clotting factor concentrates or bypassing agent for breakthrough bleeding.

Monitor and maintain antithrombin activity between 15–35% to reduce thrombotic risk. Monitor patients for signs and symptoms of thrombosis; interrupt fitusiran therapy if thrombosis occurs, and manage appropriately. Reassess risks and benefits before resuming fitusiran therapy.

Acute and Recurrent Gallbladder Disease

Risk of acute and recurrent gallbladder disease, including cholelithiasis and cholecystitis (see Boxed Warning).

Patients with gallbladder disease typically present with epigastric or generalized abdominal pain, indigestion, nausea, or vomiting.

Monitor for signs and symptoms; if disease suspected, obtain imaging and follow up. Consider interrupting or discontinuing therapy if gallbladder disease occurs.

Consider alternative therapy in patients with a history of symptomatic gallbladder disease.

Other Warnings and Precautions

Hepatotoxicity

Hepatotoxicity occurred with fitusiran in clinical studies, with higher rates seen with the unapproved 80 mg once monthly regimen compared to the AT-based regimen.

Avoid fitusiran in patients with hepatic impairment (i.e., Child-Pugh Class A, B, or C).

Obtain baseline liver tests (AST, ALT, and total bilirubin) and monitor monthly for at least 6 months after initiation and dose increases, then monitor as clinically indicated.

If new or worsening liver test abnormalities occur, evaluate, manage appropriately, and continue monitoring until tests normalize.

Interrupt therapy for ALT or AST >5 times the ULN; weigh benefits and risks before resuming therapy after normalization.

Interrupt therapy for severe elevations and reassess before resuming; permanently discontinue if elevations recur or if jaundice develops from hepatotoxicity.

Immunogenicity

In studies (up to 250 weeks' duration), some adults treated with fitusiran developed low‑titer, mostly transient antibodies that did not affect drug levels, activity, safety, or effectiveness.

Specific Populations

Pregnancy

No data in pregnant women to determine effects on fetal outcomes or reproductive capacity. Use only if potential benefits outweigh potential risks.

Lactation

Not known whether fitusiran is distributed into human milk or has any effects on the breastfed infant or milk production. Consider benefits of breastfeeding along with mother's need for fitusiran and potential adverse effects to the infant from the drug or underlying maternal condition.

Females and Males of Reproductive Potential

Use of fitusiran in females using hormonal contraceptives may increase thrombotic risk. An alternative non‑hormonal contraception is recommended before and during fitusiran therapy.

Pediatric Use

Safety and effectiveness established in patients ≥12 years of age based on well‑controlled studies in adults and adolescents.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether their response differs from younger patients.

Hepatic Impairment

No clinical studies conducted to evaluate effects of hepatic impairment on pharmacokinetics.

Increased serum transaminase elevations observed in clinical studies; avoid use in patients with established hepatic impairment (Child‑Pugh Class A, B, or C).

Renal Impairment

No clinical studies conducted to evaluate effects of renal impairment on pharmacokinetics. In a population pharmacokinetic analysis, mild renal impairment had no effect on exposure of fitusiran.

Common Adverse Effects

Most common adverse reactions (≥10%): viral infection, nasopharyngitis, bacterial infection.

Drug Interactions

No formal drug interaction studies to date.

Unlikely to cause or be affected by cytochrome P-450 or transporter‑mediated drug interactions at clinically relevant concentrations.

Clotting Factor Concentrates or Bypassing Agents

Fitusiran prophylaxis increases thrombin generation and further increases peak thrombin when used with clotting factor concentrates or bypassing agents.

Hormonal Contraceptives

Hormonal contraceptives may increase thrombotic risk. Estrogen‑based contraceptives increase thrombosis risk in women with inherited AT deficiency. Advise patients to use an alternative non‑hormonal contraception before and during therapy with fitusiran.

Fitusiran Pharmacokinetics

Absorption

Bioavailability

Demonstrates liver‑driven pharmacodynamics rather than plasma‑driven effects

Shows dose‑proportional plasma exposure with no accumulation after repeated monthly dosing

Plasma Concentrations

Median time to peak plasma concentration 2.8–3.8 hours

Special Populations

Only studied in male patients; race does not affect pharmacokinetics, and no studies evaluated hepatic or renal impairment

Mild or moderate renal impairment (eGFR >30 mL/minute per 1.73 m²) did not affect drug exposure during clinical trials

Distribution

Extent

Primarily to the liver

Protein Binding

96.6%

Elimination

Metabolism

Primary metabolized by the liver to endo‑ and exo‑nucleases into progressively shorter oligonucleotides

Not metabolized by CYP enzymes or transported by drug transporters

Elimination Route

Mean of 14.6% excreted unchanged in urine within 24 hours

Half-life

Mean terminal half-life 5.57–7.98 hours

Stability

Storage

Sub-Q

Prefilled Pen

Store in the refrigerator (2–8°C) in original carton to protect from light.

May be stored once at room temperature (15-30°C) for ≤3 months within the labeled expiration date; discard after 3 months or at expiration, whichever comes first.

Do not return to refrigeration after room temperature storage.

Vial

Store in the refrigerator (2–8°C) or at room temperature (15–30°C) in the original carton to protect from light.

Do not return to refrigeration after room temperature storage.

Do not shake, heat, freeze, or expose to direct sunlight.

Actions

• Antithrombin‑directed, double‑stranded, small interfering ribonucleic acid.

• Reduces AT production and increases thrombin generation to enhance clotting ability.

• Lower AT activity correlated with reduced bleeding rates, but persistent AT activity <15% increased thrombotic risk.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

• Advise the patient and/or caregiver to discontinue prophylactic use of clotting factor concentrates or bypassing agents no later than 7 days after starting fitusiran to reduce the risk of thrombotic events. Discuss the appropriate dosing and frequency of clotting factor concentrates or bypassing agents for breakthrough bleed management with the patient and/or caregiver prior to starting fitusiran prophylaxis.

• Advise the patient and/or caregiver of the risk of thrombotic events while receiving fitusiran. Inform the patient and/or caregiver of the need for periodic measurements of antithrombin activity that may result in changes to the fitusiran dose and/or frequency of administration to reduce the risk for thrombosis. Educate patients on the signs and symptoms of thrombotic events and to seek immediate medical attention if new symptoms of thrombotic events occur.

• Inform the patient and/or caregiver of the risk of acute and recurrent gallbladder disease while receiving fitusiran. Educate patients on the signs and symptoms of gallbladder disease and to seek medical attention if new symptoms of gallbladder disease occur.

• Inform the patient and/or caregiver of the risk of hepatotoxicity and that blood tests to monitor for this risk will be obtained before starting fitusiran and periodically during treatment. Inform patients to seek medical attention if symptoms of hepatotoxicity occur.

• Provide training to the patient and/or caregiver on proper sub-Q injection technique, including aseptic technique, and the preparation and administration of fitusiran prior to use.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Fitusiran is available through designated specialty pharmacies. Contact manufacturer or consult the Qfitlia^TM website ([Web]) for specific information.

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