Regulatory Decision Summary for Peyona

Apnea of prematurity (AOP) is a disorder of preterm infants, i.e. those born before a gestational age (GA) of 37 weeks, consisting of clinically significant apnea episodes. Clinically significant is defined as apnea of a duration of 20 seconds or longer, or shorter episodes if accompanied by hypoxemia (cyanosis or pallor) or bradycardia (heart rate < 100 beats per minute). Untreated, AOP may lead to irreversible hypoxic neurological damage and, in the most severe cases, death.

For several decades caffeine citrate has been used as the standard pharmacological therapy for AOP.Caffeine, as a methylxanthine, is believed to exert its therapeutic effect in AOP by stimulating respiratory neural output via competitive inhibition of adenosine at cell surface receptors, blocking adenosines neuronal suppressive activity.

In this New Drug Submission (NDS), the sponsor provided evidence from the medical literature to demonstrate the safety and effectiveness of a caffeine citrate solution (Cafcit®), which has been established to be quantitatively and qualitatively identical to Peyona.

The submitted evidence for the safety and efficacy of Cafcit® consisted of the published report of a pivotal randomized multicenter placebo-controlled trial, supplemented by the published U.S. FDA review of the study, which led to market authorization of Cafcit® in the U.S.. Supportive clinical data were also provided in the form of several publications describing the results of the Caffeine for Apnea of Prematurity (CAP) Trial. This was supplemented by a systematic literature review, in accord with the Health Canada Submission Relying on Third Party Data (SRTD) guidance, in the form of a Cochrane review of treatment of apnea in preterm infants with methylxanthines, including caffeine.

In the pivotal clinical trial, 47 neonates were randomized to receive caffeine citrate (Cafcit®; 20mg/kg loading dose administered under the supervision of NICU neonatologists, followed by a daily maintenance dose of 5 mg/kg) and 35 were randomized to receive placebo. At randomization, the neonates were ≥ 28 weeks post conception and 24 hours or more after birth, and had experienced six or more apnea episodes within 24 hours. Occurrence of apnea episodes was monitored for up to 10 days.

Administration of caffeine citrate resulted in reduction in frequency of apneic episodes by 50 percent or greater over 8 or more days, compared to baseline, in 68.9% of infants in the caffeine citrate arm versus 43.2% in the placebo arm (p = 0.018). Several other analyses were reported. Of the 60 patients who had a reduction in apnea rate ≥ 50% from baseline at least once during the study, 20 patients in the caffeine group (55%) versus 7 in the placebo group (29%) maintained this effect until the end of the study. A total of 10 patients in the caffeine group (22%) had no apnea events for 8 days or more, versus 0 patients in the placebo group.

The second, supportive, double- blind randomized placebo-controlled CAP trial provided evidence of the efficacy of caffeine citrate when administered to neonates with AOP as measured by improvements in endpoints of bronchopulmonary dysplasia and improved rate of survival without neurodevelopmental disability.

In addition to the pharmacovigilance data from several decades of use of caffeine citrate internationally, the post-market safety data reviewed in the submission includes the published results of the European Medicines Agency (EMA) Peyona Post-Approval Safety Study (PASS). Potentially serious adverse events (AEs) reported with caffeine citrate include seizures, necrotizing enterocolitis (NEC), cardiovascular events, and hypersensitivity/infusion reactions. As a methylxanthine, caffeine is a central nervous system stimulant, and therefore seizures are a potential AE. Warnings regarding risk of seizures are included in the proposed Canadian Product Monograph (PM), in the SERIOUS WARNINGS AND PRECAUTIONS BOX, WARNINGS AND PRECAUTIONS, and OVERDOSAGE sections. In the blinded phase of the pivotal trial, 2 cases of NEC were reported in the caffeine citrate treatment group and 1 case in the placebo group, and in 3 infants on caffeine citrate in the open-label extension phase; these results are described in the Peyona Product Monograph (PM). Monitoring and analyses however have failed to provide evidence of a causal relationship between caffeine citrate administration and NEC in this population, who are already at high-risk for this condition. This is reflected in the PM, and the SERIOUS WARNINGS AND PRECAUTIONS BOX includes NEC, as well as cardiovascular and metabolic adverse events, and warns regarding an increased risk of caffeine accumulation in patients with renal impairment. Other AEs associated with administration of caffeine citrate which are listed in the PM include tachycardia, hypoglycaemia, hyperglycemia, thyroid test abnormalities, jitteriness, gastroesophageal reflux, constipation, deafness and phlebitis.

The benefit-risk assessment of Peyona is considered favorable for the short-term treatment of primary apnea of premature newborns, when treatment is initiated under the supervision of a physician experienced in neonatal intensive care and Peyona is used solely in Neonatal Intensive Care Units.