Elapegademase is a recombinant adenosine deaminase indicated for the treatment of adenosine deaminase severe combined immune deficiency (ADA-SCID) in adult and pediatric patients. It is a conjugate of multiple strands of monomethoxypolyethylene glycol attached to ADA derived from bovine intestine. SCID associated with ADA deficiency is a rare, inherited disorder that is often fatal. Patients with this disorder experience an accumulation of adenosine and 2'-deoxyadenosine, which causes metabolic abnormalities that are directly toxic to lymphocytes. Patients with SCID have extreme susceptibility to infection, which can lead to death in infancy if immunologic reconstitution cannot be achieved. The majority of patients affected also have significant lymphopenia. The frequency of SCID has been estimated to range from 1 in 50,000 to 1 in 500,00 births. SCID can only be cured by bone marrow transplantation. Elapegademase is a specific ADA enzyme replacement and will not benefit patients with immunodeficiency due to other causes. Adherence to a strict treatment schedule of elapegademase therapy, including careful monitoring of trough plasma ADA activity, trough deoxyadenosine nucleotide (dAXP), and/or total lymphocyte counts, has been shown to increase plasma or serum ADA activity and lymphocyte counts and eliminate the toxic metabolites caused by ADA deficiency. Immune function, including the ability to produce antibodies, generally improves after 2 to 6 months of therapy and may continue to improve over a longer period.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Elapegademase should be clear and colorless.
Intramuscular Administration
-Do not shake or freeze. Do not use elapegademase if there are any indications that it may have been frozen. Once removed from refrigeration, allow elapegademase to equilibrate to room temperature for 30 minutes.
-Do not dilute nor mix with any other drug prior to administration.
-Administer elapegademase using polypropylene syringes. Draw the solution from the vial with a 25 gauge needle or larger.
-Change the needle to a size and gauge appropriate for the patient. Use caution to not inject into or near an artery or nerve. Alternate the injection site periodically.
-Administer intramuscularly immediately after syringe preparation. Discard unused elapegademase.
During clinical trial evaluation of elapegademase, rash, injection site discomfort, and laceration were reported in 1 patient each. During postmarketing pegademase bovine use, injection site erythema and urticaria were reported. Since pegademase bovine belongs to the same class of enzyme replacement therapy as elapegademase, similar reactions are expected.
Vomiting was the most common gastrointestinal (GI) adverse reaction associated with elapegademase therapy during clinical trials and was reported in 2 out of 6 patients. Abdominal pain, diarrhea, nausea, and nephrolithiasis were reported in 1 patient each.
During clinical trial evaluation of elapegademase, arthralgia was reported in 1 patient.
Centrally-mediated adverse reactions that occurred in 1 patient each during clinical trials of elapegademase include asthenia, fatigue, migraine, seizures, and gait disturbance.
Cough, reported in 3 out of 6 patients, and respiratory infection, reported in 2 out of 4 patients, were the most common adverse reactions reported during clinical trials of elapegademase. A variety of infections were reported during clinical trials in 1 patient each and include ear lobe infection, fungal skin infection, gastrointestinal infection, groin abscess, haemophilus pulmonary infection, oral candidiasis, upper respiratory tract infection, influenza, otitis externa, productive cough, stoma site infection, and tooth abscess. One infant died secondary to CMV pneumonitis and respiratory failure; he had also experienced pulmonary hemorrhage and upper respiratory tract infection. Neutropenia was a serious reaction reported by 1 patient. Other adverse reactions that occurred in 1 patient each during clinical trials include lymphadenopathy, conjunctivitis, dental caries, ear canal irritation, nasal edema, oropharyngeal pain, swelling face, tooth extraction, and cerumen impaction.
Epistaxis, hematochezia, and hemoptysis were reported in 1 patient each during clinical trials of elapegademase.
As with all therapeutic proteins, there is a potential for immunogenicity. Immunogenicity results from clinical trials suggest that patients who previously received pegademase bovine may present an immunologic response to elapegademase. Antibody formation to elapegademase may develop resulting in more rapid adenosine deaminase (ADA) clearance. If a persistent decline in trough plasma ADA concentrations to less than 15 mmol/hour/L occurs, antibody formation should be suspected, and testing for antibodies to elapegademase should be performed. If antibodies to elapegademase are found to be the cause of a persistent fall in trough plasma ADA activity, then adjust the elapegademase dose and take other measures to induce tolerance and restore adequate ADA activity.
During postmarketing pegademase bovine use, new primary malignancy (lymphomas) has been reported. Since pegademase bovine belongs to the same class of enzyme replacement therapy as elapegademase, similar reactions are expected.
During postmarketing pegademase bovine use, hemolytic anemia, autoimmune hemolytic anemia, thrombocytosis, thrombocytopenia, and autoimmune thrombocytopenia have been reported. Since pegademase bovine belongs to the same class of enzyme replacement therapy as elapegademase, similar reactions are expected.
Because elapegademase is administered via intramuscular injection, use with caution in patients with coagulopathy or thrombocytopenia. Elapegademase use is not recommended if thrombocytopenia is severe.
Until immune function improvement has been documented, continue appropriate precautions to protect patients from infection. If during the course of elapegademase therapy, there is a failure to maintain adequate plasma adenosine deaminase (ADA) concentrations for any reason, care must be taken to minimize the risk of infection until ADA concentrations are within target range. Antibodies to elapegademase may develop resulting in more rapid ADA clearance. If a persistent decline in trough plasma ADA concentrations occurs secondary to antibody development, dosage adjustment and other measures may be taken to induce tolerance and restore adequate ADA activity.
There are no available data on elapegademase use during pregnancy to inform a drug-associated risk of pregnancy-related outcomes. Animal studies have not been conducted using elapegademase. There were 2 reports of confirmed cases of successful pregnancy and delivery in adenosine deaminase severe combined immune deficiency (ADA-SCID) patients treated with pegademase bovine; no teratogenic effects were reported. For pregnant patients receiving elapegademase, more frequent monitoring of the health status for both the mother during pregnancy and the development of the offspring is recommended.
There are no data on the presence of elapegademase in human milk, the effects on a breast-fed infant, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
For the treatment of severe combined immunodeficiency disease (SCID) due to adenosine deaminase (ADA) deficiency:
-for patients not currently receiving pegademase bovine:
Intramuscular dosage:
Adults: 0.4 mg/kg/week IM (based on ideal body weight or actual weight whichever is greater), divided into 2 doses (0.2 mg/kg/dose IM twice weekly), for a minimum of 12 to 24 weeks until immune reconstitution is achieved. Once achieved, gradually adjust dose down to maintain trough ADA activity over 30 mmol/hour/L, trough deoxyadenosine nucleotide (dAXP) concentration under 0.02 mmol/L, and/or to maintain adequate immune reconstitution based on clinical assessment of the patient.
Infants, Children, and Adolescents: 0.4 mg/kg/week IM (based on ideal body weight or actual weight whichever is greater), divided into 2 doses (0.2 mg/kg/dose IM twice weekly), for a minimum of 12 to 24 weeks until immune reconstitution is achieved. Once achieved, gradually adjust dose down to maintain trough ADA activity over 30 mmol/hour/L, trough deoxyadenosine nucleotide (dAXP) concentration under 0.02 mmol/L, and/or to maintain adequate immune reconstitution based on clinical assessment of the patient.
Neonates: 0.4 mg/kg/week IM (based on ideal body weight or actual weight whichever is greater), divided into 2 doses (0.2 mg/kg/dose IM twice weekly), for a minimum of 12 to 24 weeks until immune reconstitution is achieved. Once achieved, gradually adjust dose down to maintain trough ADA activity over 30 mmol/hour/L, trough deoxyadenosine nucleotide (dAXP) concentration under 0.02 mmol/L, and/or to maintain adequate immune reconstitution based on clinical assessment of the patient.
-for patients transitioning from pegademase bovine to elapegademase:
Intramuscular dosage:
Adults: 0.2 mg/kg/dose IM every 7 days if patient's weekly pegademase bovine dose is 30 units/kg or less or it is unknown. If patient's weekly pegademase bovine dose is above 30 units/kg, calculate an equivalent weekly elapegademase dose using this formula: elapegademase dose (mg/kg) = pegademase bovine dose (units/kg)/150. Subsequent doses may be increased by increments of 0.033 mg/kg/dose weekly if trough ADA activity is under 30 mmol/hour/L, trough deoxyadenosine nucleotides (dAXP) are above 0.02 mmol/L, and/or the immune reconstitution is inadequate based on the clinical assessment of the patient. The total weekly dose may be divided into multiple IM administrations during a week.
Infants, Children, and Adolescents: 0.2 mg/kg/dose IM every 7 days if patient's weekly pegademase bovine dose is 30 units/kg or less or it is unknown. If patient's weekly pegademase bovine dose is above 30 units/kg, calculate an equivalent weekly elapegademase dose using this formula: elapegademase dose (mg/kg) = pegademase bovine dose (units/kg)/150. Subsequent doses may be increased by increments of 0.033 mg/kg/dose weekly if trough ADA activity is under 30 mmol/hour/L, trough deoxyadenosine nucleotides (dAXP) are above 0.02 mmol/L, and/or the immune reconstitution is inadequate based on the clinical assessment of the patient. The total weekly dose may be divided into multiple IM administrations during a week.
Neonates: 0.2 mg/kg/dose IM every 7 days if patient's weekly pegademase bovine dose is 30 units/kg or less or it is unknown. If patient's weekly pegademase bovine dose is above 30 units/kg, calculate an equivalent weekly elapegademase dose using this formula: elapegademase dose (mg/kg) = pegademase bovine dose (units/kg)/150. Subsequent doses may be increased by increments of 0.033 mg/kg/dose weekly if trough ADA activity is under 30 mmol/hour/L, trough deoxyadenosine nucleotides (dAXP) are above 0.02 mmol/L, and/or the immune reconstitution is inadequate based on the clinical assessment of the patient. The total weekly dose may be divided into multiple IM administrations during a week.
Therapeutic Drug Monitoring:
-Determine the optimal dosage regimen by monitoring tough plasma adenosine deaminase (ADA) activity, trough deoxyadenosine nucleotide (dAXP) concentrations, and/or total lymphocyte counts.
-Measure plasma ADA activity and trough dAXP concentrations prior to therapy initiation.
-Maintain the trough plasma ADA activity at 30 mmol/hour/L or more. Of note, antibody to elapegademase may develop resulting in more rapid ADA clearance. If a persistent decline in trough plasma ADA activity to less than 15 mmol/hour/L occurs, antibody development should be suspected. A dosage adjustment may be necessary.
-In order to determine an effective dose of elapegademase, measure trough plasma ADA activity every 2 weeks for pegademase bovine-naive patients and every 4 weeks for patients previously receiving pegademase bovine therapy, during the first 8 to 12 weeks of treatment, and every 3 to 6 months thereafter.
-Maintain the trough dAXP concentration below 0.02 mmol/L, and monitor at least twice a year.
-Monitor total and subset lymphocytes periodically every 4 to 8 weeks for up to 1 year, and every 3 to 6 months thereafter for pegademase bovine-naive patients. For other patients, monitor every 3 to 6 months.
-Implement more frequent monitoring any time a change in dose is made, therapy is interrupted, or an enhanced rate of plasma ADA clearance develops.
Maximum Dosage Limits:
-Adults
Varies depending on trough ADA activity, trough dAXP concentration, and immune reconstitution.
-Geriatric
Varies depending on trough ADA activity, trough dAXP concentration, and immune reconstitution.
-Adolescents
Varies depending on trough ADA activity, trough dAXP concentration, and immune reconstitution.
-Children
Varies depending on trough ADA activity, trough dAXP concentration, and immune reconstitution.
-Infants
Varies depending on trough ADA activity, trough dAXP concentration, and immune reconstitution.
-Neonates
Varies depending on trough ADA activity, trough dAXP concentration, and immune reconstitution.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Elapegademase products.
Elapegademase provides exogenous replacement therapy for patients with severe combined immunodeficiency disease (SCID) associated with adenosine deaminase (ADA) deficiency. ADA enzyme is involved in purine metabolism, catalyzing the irreversible hydrolytic deamination of adenosine or deoxyadenosine to inosine or deoxyinosine, respectively, as well as several naturally occurring methylated adenosine compounds. Maintaining a low concentration of 2'-deoxyadenosine and adenosine is crucial for proper number and function of immune cells as well as decreasing the frequency of opportunistic infections. In the absence of ADA, there is an accumulation of adenosine and 2'-deoxyadenosine. The accumulation of these purine substrates contributes to apoptosis and a block in the differentiation of thymocytes, causing severe T-lymphopenia. Elapegademase is specific ADA enzyme replacement that is associated with a decrease in toxic adenosine and deoxyadenosine nucleotide concentrations as well as an increase in lymphocyte number.
Elapegademase is administered via intramuscular injection.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Intramuscular Route
The pharmacokinetics of elapegademase have been studied in 6 patients with adenosine deaminase severe combined immune deficiency (ADA-SCID) ranging in age from 16 to 37 years who received weekly IM injections at doses ranging from 4.99 to 19.5 mg. In these patients, the Tmax (hour) ranged from 27.2 to 72, dose-normalized AUC (hour x mmol/hour/L)/(mg/kg) ranged from 19,013 to 42,400, dose-normalized Cmax (mmol/hour/L)/(mg/kg) ranged from 150 to 292, and Ctrough (mmol/hour/L) ranged from 20.2 to 46.2. Steady state concentrations of ADA were reached after 7 consecutive once weekly IM doses of elapegademase. Additionally, deoxyadenosine nucleotide (dAXP) activity levels in all patients at the majority of sampling timepoints were less than 0.02 mmol/L.