REVCOVI Solution for injection Ref.[10276] Active ingredients: Elapegademase

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.

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).

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 REVCOVI. Therefore, monitoring for changes in ADA levels during REVCOVI treatment is recommended [see Dosage and Administration (2.3)].

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 REVCOVI with the incidence of antibodies to other products may be misleading.

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 REVCOVI 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.

The drug interaction potential of REVCOVI is not known.

Risk Summary

Adequate and well-controlled studies with REVCOVI have not been conducted in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted with REVCOVI. It is not known whether REVCOVI 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 REVCOVI. 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 REVCOVI, more frequent monitoring of the health status for both the mother during pregnancy and the development of the offspring is recommended.

Risk Summary

Human or animal lactation studies have not been conducted to assess the presence of REVCOVI 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 REVCOVI and any potential adverse effects on the breastfed infant from REVCOVI or from the underlying maternal condition.

The safety and efficacy of REVCOVI have been established in pediatric patients [see Clinical Studies (14)].

REVCOVI was not studied in patients 65 years and older.