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Elapegademase-lvlr Injection

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 9. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. DRUG INTERACTIONS

 

1. DESCRIPTION

Elapegademase-lvlr is a recombinant adenosine deaminase (rADA) based on bovine amino acid sequence, conjugated to monomethoxypolyethylene glycol (mPEG). rADA is manufactured in E.coli and is covalently conjugated to mPEG with a succinimidyl carbamate linker to produce methoxypolyethylene glycol recombinant adenosine deaminase (SC-PEG rADA). The approximate molecular weight of elapegademase-lvlr (SC-PEG rADA) is 113 KDa.

Elapegademase-lvlr injection is a sterile, preservative free, clear, colorless solution for intramuscular use supplied in single-dose vials. Each vial provides 1.5 mL of solution containing 2.4 mg elapegademase-lvlr (1.6 mg/mL), sodium chloride (12.75 mg), sodium phosphate dibasic heptahydrate (12.7 mg), sodium phosphate monobasic monohydrate (3.81 mg), and Water for Injection, USP. The pH is 6.9.

2. INDICATIONS AND USAGE

Elapegademase-lvlr is indicated for the treatment of adenosine deaminase severe combined immune deficiency (ADA-SCID) in pediatric and adult patients.

3. DOSAGE AND ADMINISTRATION

3.1 Recommended Dosage

Patients transitioning from Adagen to Elapegademase-lvlr

If a patient’s weekly Adagen dose is unknown, or a patient’s weekly Adagen dose is at or lower than 30 U/kg, the recommended minimum starting dose of elapegademase-lvlr is 0.2 mg/kg, intramuscularly, once a week.

If a patient’s weekly Adagen dose is above 30 U/kg, an equivalent weekly elapegademase-lvlr dose (mg/kg) should be calculated using the following conversion formula:

Subsequent doses may be increased by increments of 0.033 mg/kg weekly if trough ADA activity is under 30 mmol/hr/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 intramuscular (IM) administrations during a week.

Adagen-naïve patients

The starting weekly dose of elapegademase-lvlr is 0.4 mg/kg based on ideal body weight, divided into two doses (0.2 mg/kg twice a week), intramuscularly, for a minimum of 12 to 24 weeks until immune reconstitution is achieved. After that, the dose may be gradually adjusted down to maintain trough ADA activity over 30 mmol/hr/L, trough dAXP level under 0.02 mmol/L, and/or to maintain adequate immune reconstitution based on clinical assessment of the patient.

The optimal long-term dose and schedule of administration should be established by the treating physician for each patient individually and may be adjusted based on the laboratory values for trough ADA activity, trough dAXP level, and/or on the treating physician’s medical assessment of the patient’s clinical status.

3.2 Administration Instructions

Elapegademase-lvlr is for IM injection only. Follow sterile IM administration technique guidelines appropriate to the patient’s age and anatomy (i.e. choice of needle gauge and length, site of administration). Take precautions not to inject into or near an artery or nerve. Alternate the injection site periodically.

Preparation of Injection and Procedure Instructions

• Elapegademase-lvlr should not be diluted nor mixed with any other drug prior to administration.

• Visually inspect elapegademase-lvlr for particulate matter and discoloration prior to administration. Elapegademase-lvlr is a clear, colorless solution; discard if solution is discolored, cloudy or contains particulate matter.

• Do not freeze or shake. Elapegademase-lvlr should not be used if there are any indications that it may have been frozen. Once removed from refrigeration, allow elapegademase-lvlr to equilibrate to room temperature for 30 minutes.

• Elapegademase-lvlr is to be administered 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’s intramuscular administration.

• Elapegademase-lvlr should be administered immediately after syringe preparation.

• Any remaining medication in the vial must be discarded immediately.

3.3 Therapeutic Monitoring Schedule

The treatment of ADA-SCID with elapegademase-lvlr should be monitored by measuring trough plasma ADA activity, trough dAXP levels, and/or total lymphocyte counts. Monitoring should be more frequent if therapy was interrupted or if an enhanced rate of clearance of plasma ADA activity develops. Collect blood samples for the analysis of trough plasma ADA activity and trough dAXP level prior to the first administration of elapegademase-lvlr for the week.

ADA Activity

Once treatment with elapegademase-lvlr has been initiated, a target trough plasma ADA activity should be at least 30 mmol/hr/L. In order to determine an effective dose of elapegademase-lvlr, trough plasma ADA activity (pre-injection) should be determined every 2 weeks for Adagen-naïve patients and every 4 weeks for patients previously receiving Adagen therapy, during the first 8 - 12 weeks of treatment, and every 3 - 6 months thereafter.

A decrease of ADA activity below this level suggests noncompliance to treatment or a development of antibodies (anti-drug, anti-PEG, and neutralizing antibodies). Antibodies to elapegademase-lvlr should be suspected if a persistent fall in pre-injection levels of trough plasma ADA activity below 15 mmol/hr/L occurs. In such patients, testing for antibodies to elapegademase-lvlr should be performed.

If a persistent decline in trough plasma ADA activity occurs, immune function and clinical status should be monitored closely and precautions should be taken to minimize the risk of infection. If antibodies to elapegademase-lvlr are found to be the cause of a persistent fall in trough plasma ADA activity, then adjustment in the dosage of elapegademase-lvlr and other measures may be taken to induce tolerance and restore adequate ADA activity.

Erythrocyte dAXP

Two months after starting elapegademase-lvlr treatment, trough erythrocyte dAXP levels should be maintained below 0.02 mmol/L, and monitored at least twice a year.

Immune Function

The degree of immune function may vary from patient to patient. Each patient will require appropriate monitoring consistent with immunologic status. Total and subset lymphocytes should be monitored periodically as follows:

• Adagen-naïve patients: every 4 – 8 weeks for up to 1 year, and every 3 – 6 months thereafter

• Other patients: every 3 - 6 months

Immune function, including the ability to produce antibodies, generally improves after 2 - 6 months of therapy, and matures over a longer period. In general, there is a lag between the correction of the metabolic abnormalities and improved immune function. Improvement in the general clinical status of the patient may be gradual (as evidenced by improvement in various clinical parameters) but should be apparent by the end of the first year of therapy.

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

5.1 Injection Site Bleeding in Patients with Thrombocytopenia

Since elapegademase-lvlr is administered by IM injection, it should be used with caution in patients with thrombocytopenia and should not be used if thrombocytopenia is severe.

5.2 Delay in Improvement of Immune Function

Maintain precautions to protect immune deficient patients from infections until improvement in immune function has been achieved. The timing and degree of improvement in immune function may vary from patient to patient.

6. ADVERSE REACTIONS

6.1 Clinical Trials 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.

Elapegademase-lvlr was administered intramuscularly in two prospective, open-label, single-arm, multi-center studies to evaluate efficacy, safety, tolerability, and pharmacokinetics in patients with ADA-SCID: Study 1 was performed in the US and Study 2 was performed in Japan [see Clinical Studies]. Overall, 10 patients were treated and adverse reactions reported are summarized below.

Study 1

Study 1 is a one-way crossover study, conducted in the US, to evaluate the safety, efficacy, and pharmacokinetics of elapegademase-lvlr in patients with ADA-SCID who were receiving therapy with Adagen. Six patients, 8 to 37 years of age enrolled in the study. Patients’ exposure to elapegademase-lvlr ranged from 2 weeks to 146 weeks. No deaths were reported and one patient discontinued treatment due to injection site pain associated with an earlier drug product formulation that was consequently modified.

The most common adverse reactions were cough (3/6 patients) and vomiting (2/6 patients). Other adverse reactions that were reported in one patient each were: abdominal pain upper, arthralgia, asthenia, cerumen impaction, conjunctivitis, convulsion, dental caries, diarrhea, ear canal irritation, ear lobe infection, epistaxis, fatigue, fungal skin infection, gait disturbance, gastrointestinal infection, groin abscess, hematochezia, haemophilus infection (pulmonary), hemoptysis, influenza, injection site discomfort, laceration, lymphadenopathy, migraine, nasal edema, nausea, nephrolithiasis, oral candidiasis, oropharyngeal pain, otitis externa, productive cough, rash, stoma site infection, swelling face, tooth abscess, tooth extraction and upper respiratory tract infection, regardless of investigator causality assessment.

Study 2

Study 2 is a single-arm clinical study that was conducted to assess the safety, efficacy and pharmacokinetics of elapegademase-lvlr in patients with ADA-SCID. Four patients 3.4 months to 25 years of age, all Asian, were enrolled in the study and received elapegademase-lvlr. Three patients received elapegademase-lvlr for 21 weeks and one patient received elapegademase-lvlr for 15 weeks. One death due to CMV pneumonitis and respiratory failure was observed in an infant, who had also experienced pulmonary hemorrhage, respiratory failure and upper respiratory tract infection that represented serious adverse events. Neutropenia was a serious adverse reaction reported by one of the patients. There were 22 reported adverse events for four patients. Most common adverse events were respiratory infections (2/4 patients).

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity results from Study 1 and Study 2 suggest that patients who previously received Adagen may present an immunologic response to elapegademase-lvlr. Therefore, monitoring for changes in ADA levels during elapegademase-lvlr treatment is recommended. [see Dosage and Administration (3.3)]

The observed incidence of antibodies (including neutralizing antibodies) is dependent on assay sensitivity and specificity, assay methodology, and concomitant medications. Therefore, the comparison of the incidence of antibodies to elapegademase-lvlr with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience with ADAGEN

The following postmarketing adverse reactions were voluntarily reported for Adagen, the same class of enzyme replacement therapy used in the treatment of ADA-SCID, and may also be seen with elapegademase-lvlr treatment:

• Hematologic: hemolytic anemia, auto-immune hemolytic anemia, thrombocythemia, thrombocytopenia and autoimmune thrombocytopenia

• Dermatological: injection site erythema, urticaria

• Lymphomas

Since these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

7. DRUG INTERACTIONS

The drug interaction potential of elapegademase-lvlr is not known.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Adequate and well-controlled studies with elapegademase-lvlr have not been conducted in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted with elapegademase-lvlr. It is not known whether elapegademase-lvlr can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human

No pregnancy was reported for any patients receiving elapegademase-lvlr. There are two reports of confirmed cases of successful pregnancy and delivery in ADA-SCID patients treated with Adagen (the same class of enzyme replacement therapy used in the treatment of ADA-SCID). No teratogenic effects of Adagen were reported.

For patients treated with elapegademase-lvlr, more frequent monitoring of the health status for both the mother during pregnancy and the development of the offspring is recommended.

8.2 Lactation

Risk Summary

Human or animal lactation studies have not been conducted to assess the presence of elapegademase-lvlr in breast milk, the effects on the breastfed infant, or the effects on milk production for the mother.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for elapegademase-lvlr and any potential adverse effects on the breastfed infant from elapegademase-lvlr or from the underlying maternal condition.

8.4 Pediatric Use

The safety and efficacy of elapegademase-lvlr have been established in pediatric patients [see Clinical Studies].

8.5 Geriatric Use

Elapegademase-lvlr was not studied in patients 65 years and older.

9. OVERDOSAGE

There are no reports of administration of elapegademase-lvlr in excess of the prescribed doses. The highest weekly prescribed dose administered in the clinical studies was 0.4 mg/kg. In nonclinical studies, there was no evidence of toxicity related to study drug at doses up to 1.8-fold the clinical dose (based on mean human AUC normalized to the dose of elapegademase-lvlr administered per patient), except for a slight increase in activated partial thromboplastin time (APTT).

10. MECHANISM OF ACTION

SCID associated with a deficiency of ADA enzyme is a rare, inherited, and often fatal disease. 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 level of 2'-deoxyadenosine and adenosine is crucial for proper number and function of immune cells as well as decreasing the frequency of opportunistic infections. Elevated adenosine levels, as occurring in ADA deficiency, contribute to apoptosis and a block in the differentiation of thymocytes, causing severe T-lymphopenia.

Elapegademase-lvlr provides an exogenous source of ADA enzyme that is associated with a decrease in toxic adenosine and deoxyadenosine nucleotides levels as well as an increase in lymphocyte number [see Clinical Studies].

11. PHARMACODYNAMICS

The effect of elapegademase-lvlr on the QT interval is not known.

12. PHARMACOKINETICS

The pharmacokinetics (PK) of elapegademase-lvlr were evaluated based on steady state plasma ADA activity in six patients with ADA-SCID (five adults and one pediatric) from two studies (Study 1 and Study 2) who received weekly IM injections at doses ranging from 4.99 to 19.6 mg [see Clinical Studies]. The PK results are summarized in Table 1.

Table 1: Individual Estimates of Steady State Plasma Pharmacokinetic Parameters of Elapegademase-lvlr Following Weekly IM Administration in ADA-SCID Patients

a PK data calculated over the dosing interval after weekly IM administration of elapegademase-lvlr at a stable elapegademase-lvlr dose for at least five consecutive weeks

b Dose-normalized (DN) AUC0-168hr and Cmax estimates based on mg/kg/week dose of elapegademase-lvlr

c Non-dose normalized steady state Ctrough ADA activity in plasma at Day 7 prior to administration of next weekly dose

In Study 1, steady state ADA activity levels were reached following seven consecutive once weekly IM doses of elapegademase-lvlr. In addition, dAXP activity levels in all patients at the majority of all sampling timepoints in Study 1 were less than 0.02 mmol/L.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

REVCOVI (elapegademase-lvlr) injection, 2.4 mg/1.5 mL (1.6 mg/mL), is a sterile, preservative free, clear, colorless solution for intramuscular use available as one single-dose vial per carton (NDC 57665-002-01).

The vial stopper is not made with natural rubber latex.

Single-dose vial; do not re-use the vial. Discard unused portions.

Storage and Handling:

Store REVCOVI in the refrigerator between 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze or shake. REVCOVI should not be used if there are any indications that it may have been frozen.

Rx only

Rev 10/18