NARSOPLIMAB: 12 Adverse Event Reports & Safety Profile

Narsoplimab-wuug, a mannan-binding lectin-associated serine protease 2 (MASP-2) inhibitor, is a recombinant human immunoglobulin G4 (IgG4) monoclonal antibody produced in Chinese Hamster Ovary cells. The approximate molecular weight is 143 kDa. YARTEMLEA (narsoplimab-wuug) injection is a sterile, preservative-free, clear to slightly opalescent, slightly yellow to yellow-brown solution for intravenous infusion.

Each

2-mL single-dose glass vial contains 370 mg of narsoplimab-wuug, arginine hydrochloride (84.3 mg), citric acid monohydrate (1.42 mg), polysorbate 80 (0.2 mg), sodium citrate (8.6 mg), and Water for Injection, USP. Sodium hydroxide and hydrochloric acid were added to adjust the pH to 5.8.

AND USAGE YARTEMLEA is indicated for the treatment of adult and pediatric patients 2 years of age and older with hematopoietic stem cell transplant-associated thrombotic microangiopathy (TA-TMA). YARTEMLEA is a MASP-2 inhibitor indicated for the treatment of adult and pediatric patients 2 years of age and older with hematopoietic stem cell transplant-associated thrombotic microangiopathy (TA-TMA). ( 1 )

AND ADMINISTRATION Weight (kg)

Recommended Dosage

Greater than or equal to 50 kg 370 mg given as an intravenous infusion over 30 minutes once weekly. Increase frequency to twice weekly if there is inadequate improvement in TA-TMA signs and symptoms. ( 2.1 ) Less than 50 kg 4 mg/kg given as an intravenous infusion over 30 minutes once weekly. Increase frequency to twice weekly if there is inadequate improvement in TA-TMA signs and symptoms. ( 2.1 )

See Full Prescribing

Information for instructions on preparation and administration. ( 2.2 , 2.3 , 2.4 , 2.5 )

2.1 Recommended Dosage The recommended dosage of YARTEMLEA is provided in Table 1 .

Table

1: Recommended Dosage of YARTEMLEA in Adult and Pediatric Patients Two Years of Age and Older with TA-TMA Weight (kg)

Recommended Dosage

Greater than or equal to 50 kg 370 mg given as an intravenous infusion over 30 minutes once weekly. Increase frequency to twice weekly if there is inadequate improvement in TA-TMA signs and symptoms. Less than 50 kg 4 mg/kg given as an intravenous infusion over 30 minutes once weekly. Increase frequency to twice weekly if there is inadequate improvement in TA-TMA signs and symptoms. If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time.

2.2 Important Preparation and Administration Instructions Administer diluted YARTEMLEA as an intravenous infusion through a polyvinyl chloride (PVC) or PVC-lined infusion line with a 0.2-micron polyethersulfone (PES) in-line filter and a polyurethane catheter. For adults and pediatric patients weighing 10 kg or more , prepare YARTEMLEA in an intravenous bag, diluted to final concentration of 0.8 mg/mL to 8 mg/mL and administer by gravity infusion or via an infusion pump <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 and 2.5 )]</span> . For pediatric patients weighing less than 10 kg , prepare YARTEMLEA in a polypropylene syringe, diluted to final concentration of 0.8 mg/mL and administer via a syringe pump <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 and 2.5 )]</span> .

2.3 Preparation Instructions into an Intravenous Bag This section describes preparation of YARTEMLEA for adults and pediatric patients weighing 10 kg or more in an intravenous bag. 1.

Preparation

Use aseptic technique to prepare YARTEMLEA. Parenteral drug-product vial should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. YARTEMLEA is a clear to slightly opalescent, slightly yellow to yellow-brown solution. If discoloration or particles are observed in the vial, discard it. Calculate the dose (mg) based on the patient's body weight and the total volume (mL) of YARTEMLEA solution required. Remove the YARTEMLEA vial from the refrigerator and allow the vial to come to room temperature (18°C to 25°C [64°F to 77°F]) for 30 minutes. Vial must be used to prepare the appropriate dosing solution within 4 hours following removal from refrigerated storage. 2. Dilution for Intravenous Bag Infusion Withdraw the required volume of YARTEMLEA solution from the vial using a polypropylene syringe and dilute in a polyvinyl chloride (PVC) infusion bag of 5% Dextrose Injection, USP to make a final concentration of 0.8 mg/mL to 8 mg/mL with a total volume not to exceed 50 mL. Discard any unused portion left in the vial. Gently invert infusion bag 10 times to mix the diluted solution. Do not shake. Following dilution of YARTEMLEA in the infusion bag, the solution may become opalescent, and small translucent-to-white particles may appear. Discard prepared solution if particulate matter, other than translucent-to-white particles, is observed.

2.4 Preparation Instructions into an Intravenous Syringe This section describes preparation of YARTEMLEA for pediatric patients weighing less than 10 kg in a syringe. 1.

Preparation

Use aseptic technique to prepare YARTEMLEA. Parenteral drug-product vial should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. YARTEMLEA is a clear to slightly opalescent, slightly yellow to yellow-brown solution. If discoloration or particles are observed in the vial, discard it. Calculate the dose (mg) based on the patient's body weight and the total volume (mL) of YARTEMLEA solution required. Remove the YARTEMLEA vial from the refrigerator and allow the vial to come to room temperature (18°C to 25°C [64°F to 77°F]) for 30 minutes. Vial must be used to prepare the appropriate dosing solution within 4 hours following removal from refrigerated storage. 2. Dilution for Intravenous Syringe Infusion Withdraw the required volume of YARTEMLEA solution from the vial using a polypropylene syringe. Discard any unused portion left in the vial. Dilute in 5% Dextrose Injection, USP to make a final concentration of 0.8 mg/mL with a total volume not to exceed 50 mL. Gently invert syringe 10 times to mix the diluted solution. Do not shake. Following dilution of YARTEMLEA in the syringe, the solution may become opalescent, and small translucent-to-white particles may appear. Discard prepared solution if particulate matter, other than translucent-to-white particles, is observed. Remove air bubbles from the syringe before administration.

2.5 Storage and Administration Storage of Diluted Product If the prepared diluted solution is not used immediately, store the diluted YARTEMLEA solution at room temperature at 18°C to 25°C (64°F to 77°F) for up to 4 additional hours. Discard unused YARTEMLEA solution if not used within 4 hours from the time of dilution to the end of the infusion.

Administration

Administer YARTEMLEA diluted solution intravenously by gravity infusion or via infusion pump (for solution prepared in an intravenous bag) or via syringe pump (for solution prepared in a syringe) over 30 minutes through a PVC or PVC-lined infusion line with a 0.2-micron polyethersulfone (PES) in-line filter and a polyurethane catheter. Flush the intravenous line at the end of the infusion with sufficient volume of 5% Dextrose Injection, USP to clear the line of YARTEMLEA infusion solution. Do not co-administer other drugs through the same intravenous line.

None None ( 4 )

REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Infections [see Warnings and Precautions ( 5.1 )] Most common adverse reactions (incidence > 20% and independent of causality) are viral infections, sepsis, hemorrhage, diarrhea, vomiting, nausea, neutropenia, pyrexia, fatigue and hypokalemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Omeros Corporation at 1-844-YARTEM1 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trial 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 safety data described in this section reflect exposure to YARTEMLEA in the TA-TMA Study in which 28 adult patients received YARTEMLEA. In total, 24 patients received YARTEMLEA at a dose of 4 mg/kg intravenously once weekly for 4 or 8 weeks and 4 patients received 370 mg intravenously weekly for 8 weeks <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> . The median duration of treatment with YARTEMLEA was 8 weeks (range: 2 to 16.4 weeks). Serious adverse reactions were reported in 61% of patients receiving YARTEMLEA. Serious adverse reactions in &gt; 5% of patients who received YARTEMLEA included acute kidney injury, confusional state, acute respiratory failure, neutropenic sepsis, septic shock, pulmonary edema, and vomiting. Fatal adverse reactions occurred in 7% of patients, including neutropenic sepsis and septic shock. Adverse reactions leading to dosage interruptions occurred in 7% of patients who received YARTEMLEA and included Escherichia sepsis, pyrexia, pulmonary alveolar hemorrhage, and acute myocardial infarction. The most common adverse reactions (≥ 20%) were viral infections, sepsis, hemorrhage, diarrhea, vomiting, nausea, neutropenia, pyrexia, fatigue, and hypokalemia.

Table

2 summarizes the adverse reactions, without regard to causality or relatedness to YARTEMLEA, in the TA-TMA Study.

Table

2: Adverse Reactions (≥ 15%) in Patients Receiving YARTEMLEA in the TA-TMA Study * Grouped terms Adverse Reaction All Grades n (%) N = 28 Grade ≥ 3 n (%) N = 28 Hemorrhage* 12 (43) 2 (7)

Diarrhea

10 (36) 2 (7) Infection, viral* 10 (36) 2 (7) Neutropenia* 10 (36) 10 (36)

Pyrexia

10 (36) 1 (4)

Vomiting

9 (32) 2 (7) Fatigue* 8 (29) 1 (4) Hypokalemia* 7 (25) 3 (11)

Nausea

7 (25) 1 (4) Sepsis* 7 (25) 6 (21) Pneumonia* 5 (18) 4 (14) Hypotension* 5 (18) 3 (11) Abdominal pain* 5 (18) 1 (4) Anemia* 5 (18) 3 (11) Back pain 5 (18) 0 (0) An additional 221 adult and pediatric patients with TA-TMA were treated with YARTEMLEA in a global expanded access program (EAP) that included patients for whom YARTEMLEA was their initial treatment following diagnosis of TA-TMA as well as patients who had previously failed or stopped other treatments. The median number of YARTEMLEA doses received by the 221 patients in the EAP was 8 and the median duration of therapy was 5.5 weeks. No new clinically significant safety signals were identified in patients treated in the EAP.

AND PRECAUTIONS Serious infections: Monitor patients for signs/symptoms and treat appropriately. ( 5.1 )

5.1 Serious Infections Serious and life-threatening infections have occurred in patients treated with YARTEMLEA. Serious infections, independent of causality, were reported in 36% (10/28) of patients with TA-TMA receiving YARTEMLEA in clinical trials. These infections included sepsis, viral infections, pneumonia, bacteremia, fungal infection, gastroenteritis, respiratory tract infection and urosepsis. If YARTEMLEA is administered to patients with active infections, monitor closely for signs and symptoms of worsening infection and treat promptly.