Yartemlea

Description for Yartemlea

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.

INDICATIONS 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).

Dosage for Yartemlea

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.

Important Preparation and Administration Instructions

• Administer diluted YARTEMLEA as an intravenous infusion through a polyvinyl chloride (PVC) or PVC-lined infusion line with a 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 8 mg/mL to 8 mg/mL and administer by gravity infusion or via an infusion pump [see Dosage and Administration (2.3 and 2.5)].
• For pediatric patients weighing less than 10 kg, prepare YARTEMLEA in a polypropylene syringe, diluted to final concentration of 8 mg/mL and administer via a syringe pump [see Dosage and Administration (2.4 and 2.5)].

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
   1. Use aseptic technique to prepare YARTEMLEA.
   2. 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.
   3. Calculate the dose (mg) based on the patient’s body weight and the total volume (mL) of YARTEMLEA solution required.
   4. 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
   1. 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.
   2. Discard any unused portion left in the vial.
   3. Gently invert infusion bag 10 times to mix the diluted solution. Do not shake.
   4. 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.

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
   1. Use aseptic technique to prepare YARTEMLEA.
   2. Parenteral drug-product vial should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container YARTEMLEA is a clear to slightly opalescent, slightly yellow to yellow-brown solution. If discoloration or particles are observed in the vial, discard it.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.
   3. Calculate the dose (mg) based on the patient’s body weight and the total volume (mL) of YARTEMLEA solution required.
   4. 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. 1. Withdraw the required volume of YARTEMLEA solution from the vial using a polypropylene Discard any unused portion left in the vial.
   2. Dilute in 5% Dextrose Injection, USP to make a final concentration of 8 mg/mL with a total volume not to exceed 50 mL.
   3. Gently invert syringe 10 times to mix the diluted Do not shake.
   4. Following dilution of YARTEMLEA in the syringe, the solution may become opalescent, and small translucent-to-white particles may Discard prepared solution if particulate matter, other than translucent-to- white particles, is observed.
   5. Remove air bubbles from the syringe before administration.

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 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.

HOW SUPPLIED

Dosage Forms And Strengths

Injection: 370 mg/2 mL (185 mg/mL) as a clear to slightly opalescent, slightly yellow to yellow- brown solution in a single-dose vial.

How supplied/Storage And Handling

YARTEMLEA (narsoplimab-wuug) injection is a sterile, preservative-free, clear to slightly opalescent, slightly yellow to yellow-brown solution supplied as one 370 mg/2 mL (185 mg/mL) single-dose vial in a carton (NDC 62225-300-00).

Store YARTEMLEA vials refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of use. Do not freeze. Do not shake. Do not use beyond the expiration date stamped on the carton.

ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Serious Infections [see Warnings and Precautions (5.1)]

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 [see Clinical Studies (14)]. 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 > 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

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)
* Grouped terms

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.

Drug Interactions for Yartemlea

No information provided.

Warnings for Yartemlea

Included as part of the PRECAUTIONS section.

Precautions for Yartemlea

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.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Genotoxicity and animal carcinogenicity studies of narsoplimab-wuug have not been conducted.

A fertility study of narsoplimab-wuug in male and female mice produced no adverse effects on reproductive parameters, although a transient decrease in mean body-weight gain in females (premating) and a slight increase in mean percentage of sperm with abnormal morphology in males were observed in the highest dose groups. These effects were noted at exposures corresponding to 21-fold the exposure expected at the MRHD (based on AUC). In the absence of any functional effects on mating, fertility, or reproductive organ weight, these effects on sperm morphology were not considered adverse.

OVERDOSES

There is no known antidote for YARTEMLEA and YARTEMLEA is not dialyzable. If an overdose occurs, institute general supportive measures. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

Contraindications for Yartemlea

No information provided.

Clinical Pharmacology for Yartemlea

Mechanism Of Action

Narsoplimab-wuug inhibits MASP-2, the effector enzyme of the lectin pathway of the complement system, blocking lectin-dependent activation of complement component 3 (C3) and C4 without affecting the classical and alternative pathways of complement.

In hematopoietic stem cell transplant-associated thrombotic microangiopathy (TA-TMA), MASP-2 inhibition is thought to prevent lectin pathway-mediated cellular injury, including endothelial cell injury in small blood vessels.

Pharmacodynamics

The effect of YARTEMLEA on lectin pathway activity, assessed using inhibition of C4d deposition, was investigated in healthy subjects and patients with TA-TMA (TA-TMA Study). YARTEMLEA concentration levels achieved in patients with TA-TMA resulted in > 80% inhibition of lectin pathway activity. Based on pharmacokinetic/pharmacodynamic (PK/PD) modeling, a wash-out period of 6 weeks is sufficient to reduce YARTEMLEA concentrations to below pharmacologically active levels.

Pharmacokinetics

The PK profile of narsoplimab-wuug has been characterized in healthy subjects and in patients. PK of narsoplimab-wuug is less than dose-proportional for 2 and 4 mg/kg weekly IV dosing, with an accumulation ratio ranging from 1.02 to 1.75 at 4 mg/kg IV weekly dosing.

Narsoplimab-wuug steady state (measured at day 36) geometric mean C_max is 36.9 µg/mL, with geometric mean AUC0-tau of 2314 µg·h/mL following 4 mg/kg administered intravenously in healthy subjects. Narsoplimab-wuug steady state is reached after three once-weekly IV doses (day 15) of 4 mg/kg in healthy subjects.

Absorption

After intravenous administration, peak plasma concentrations of narsoplimab-wuug occur approximately at the end of each infusion.

Distribution

Narsoplimab-wuug is distributed in the blood and hydrophilic extravascular space with an average (CV%) volume of distribution of 10.9 L (65%) in patients.

Elimination

Total clearance of narsoplimab-wuug is concentration-dependent, with an estimated mean (CV%) value of 0.12 L/hour (68%) in patients. The mean (CV%) terminal elimination half-life was estimated to be 209 hours (73%) in patients.

Metabolism

Narsoplimab-wuug is expected to be metabolized into small peptides and amino acids by catabolic pathways.

Excretion

No biotransformation or excretion studies have been conducted.

Specific Populations

Body weight was a significant covariate affecting the PK of narsoplimab-wuug. No clinically significant differences in PK of narsoplimab-wuug were observed based on race or sex.

Immunogenicity

The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and the specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the narsoplimab-wuug studies described below with the incidence of ADA in other studies.

Anti-Drug Antibody Effects on Pharmacokinetics and Pharmacodynamics

In the 8-week treatment period in the TA-TMA Study, treatment-emergent antibodies to narsoplimab-wuug were detected in 3 of 28 patients (11%) with TA-TMA. One of the 3 patients (33%) developed neutralizing antibodies. There is no apparent correlation of antibody development to PK or PD response, and no alteration in clinical response or adverse events was observed.

Patient Information for Yartemlea

Serious infections: Inform patients and caregivers that treatment with complement inhibitors has been associated with an increased risk of serious infections. As YARTEMLEA is a complement inhibitor, advise patients and/or caregivers to immediately report any signs or symptoms suggestive of infections [see Warnings and Precautions (5.1)].

Manufactured by:
Omeros Corporation,
201 Elliott Avenue West,
Seattle, WA 98119
US license 2141

This product, or its use, may be covered by one or more US patents, including US Patent Nos. 9,011,860, 10,047,165, and 10,683,367, in addition to others, including patents pending.

YARTEMLEA is a trademark of Omeros Corporation.

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