Fitusiran (Monograph)

Brand name: Qfitlia
Drug class: Hemostatics

Introduction

Fitusiran is an antithrombin-directed small interfering ribonucleic acid.

Uses for Fitusiran

Fitusiran has the following uses:

Fitusiran is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients 12 years of age and older with hemophilia A or B with or without factor VIII or IX inhibitors.

Fitusiran Dosage and Administration

General

Fitusiran is available in the following dosage form(s) and strength(s):

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

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults and Pediatric Patients ≥12 Years of Age

• For subcutaneous use only.

• Intended for use under the guidance of a healthcare provider.

• Starting dose: 50 mg once every 2 months.

• Monitor antithrombin (AT) activity using an FDA-cleared test. Maintain AT activity between 15–35% by adjusting the dose and/or frequency of administration.

• After fitusiran 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 fitusiran.

• See Full Prescribing Information for dosing modification guidelines based on AT activity levels and additional instructions on preparation and administration of the drug.

Cautions for Fitusiran

Contraindications

• None

Warnings/Precautions

Thrombotic Events

Serious thrombotic events have been reported in fitusiran-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 fitusiran 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 fitusiran.

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 clotting factor concentrates (CFC) or bypassing agents (BPA) at a dose greater or more frequent than recommended may also increase thrombotic risk. 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. Monitor patients for signs and symptoms of thrombotic events. Interrupt fitusiran prophylaxis in patients with a thrombotic event and manage as clinically indicated.

Inform patients treated with fitusiran to monitor for and report signs and symptoms of thrombotic events. Consider the benefits and risks of resuming fitusiran prophylaxis following resolution of the thrombotic event.

Acute and Recurrent Gallbladder Disease

Treatment with fitusiran is associated with an increased occurrence of acute and recurrent gallbladder disease including cholelithiasis and cholecystitis. Fitusiran at a fixed dose (including 80 mg once monthly) is not approved or recommended for use. In the 270 patients in the fitusiran 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 fitusiran 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 fitusiran if gallbladder disease occurs.

Hepatotoxicity

In the two randomized studies testing fitusiran 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 fitusiran use. This patient had elevation of liver tests after a single 80 mg dose that continued to rise with repeated dosing of fitusiran 80 mg once monthly. This patient's liver tests recovered with drug discontinuation. Fitusiran 80 mg once monthly is not approved or recommended for use.

On the AT-DR, 3.4% of patients treated with fitusiran 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 fitusiran 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 fitusiran, monthly for at least the first 6 months of fitusiran 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 fitusiran treatment. Consider the benefits and risks of resuming fitusiran prophylaxis following resolution of transaminase elevations. If the decision is made to restart fitusiran, wait until liver tests have returned to baseline. If fitusiran 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 fitusiran.

Specific Populations

Pregnancy

There are no available data on fitusiran 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 fitusiran can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Fitusiran 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.

Lactation

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 fitusiran is safe for use during breastfeeding. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for fitusiran and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.

Females and Males of Reproductive Potential

Use of fitusiran 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 fitusiran.

Pediatric Use

The safety and effectiveness of fitusiran 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 fitusiran in pediatric patients with hemophilia A and B is supported by evidence from adequate and well-controlled studies in adult and pediatric patients. A total of 60 pediatric patients 12 to 17 years of age were treated with fitusiran in the clinical studies.

The safety and effectiveness of fitusiran have not been established in pediatric patients below 12 years of age.

Geriatric Use

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

Hepatic Impairment

Serum transaminase elevations have been observed in the clinical studies. Avoid use of fitusiran in patients with established hepatic impairment (Child-Pugh Class A, B and C).

Common Adverse Effects

Common adverse reactions (incidence >10%) are viral infection, nasopharyngitis, and bacterial infection.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Fitusiran prophylaxis leads to increased thrombin generation with additive increase in peak thrombin when used concomitantly with CFC or BPA.

Actions

Mechanism of Action

Fitusiran is a double-stranded small interfering ribonucleic acid (siRNA) that causes degradation of antithrombin (AT) messenger RNA (mRNA) through RNA interference, reducing plasma AT levels.

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 BPA or CFC no later than 7 days after starting fitusiran to reduce the risk of thrombotic events. Discuss the appropriate dosing and frequency of BPA or CFC 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 AT 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 subcutaneous injection technique, including aseptic technique, and the preparation and administration of fitusiran prior to use.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.

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