Revcovi

REVCOVI- elapegademase injection
Chiesi USA, Inc.

1 INDICATIONS AND USAGE

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

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

Patients transitioning from Adagen to REVCOVI

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 REVCOVI is 0.2 mg/kg, intramuscularly, once a week.

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

REVCOVI dose in mg/kg = Adagen dose in U/kg 150

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 REVCOVI is 0.4 mg/kg based on ideal body weight or actual weight whichever is greater, 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.

2.2 Administration Instructions

REVCOVI 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

  • REVCOVI should not be diluted nor mixed with any other drug prior to administration.
  • Visually inspect REVCOVI for particulate matter and discoloration prior to administration. REVCOVI is a clear, colorless solution; discard if solution is discolored, cloudy or contains particulate matter.
  • Do not freeze or shake. REVCOVI should not be used if there are any indications that it may have been frozen. Once removed from refrigeration, allow REVCOVI to equilibrate to room temperature for 30 minutes.
  • REVCOVI 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.
  • REVCOVI should be administered immediately after syringe preparation.
  • Any remaining medication in the vial must be discarded immediately.

2.3 Therapeutic Monitoring Schedule

The treatment of ADA-SCID with REVCOVI 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 REVCOVI for the week.

ADA Activity

Once treatment with REVCOVI 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 REVCOVI, 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 REVCOVI 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 REVCOVI 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 REVCOVI are found to be the cause of a persistent fall in trough plasma ADA activity, then adjustment in the dosage of REVCOVI and other measures may be taken to induce tolerance and restore adequate ADA activity.

Erythrocyte dAXP

Two months after starting REVCOVI 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.

3 DOSAGE FORMS AND STRENGTHS

Injection: 2.4 mg/1.5 mL (1.6 mg/mL) clear and colorless solution of elapegademase-lvlr in a single-dose vial.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Injection Site Bleeding in Patients with Thrombocytopenia

Since REVCOVI 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.

REVCOVI 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 (14)]. 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 REVCOVI 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 REVCOVI 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 REVCOVI in patients with ADA-SCID. Four patients 3.4 months to 25 years of age, all Asian, were enrolled in the study and received REVCOVI. Three patients received REVCOVI for 21 weeks and one patient received REVCOVI 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).

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