Regulatory Decision Summary for Eligard

This Supplement to a New Drug Submission (SNDS) was submitted to obtain market authorization to extend the use of Eligard (leuprolide acetate for injectable suspension) 45 mg (6-Month) in pediatric patients 2 years of age and older with Central Precocious Puberty (CPP).

Upon review, the proposed indication was approved.

The efficacy of Eligard (leuprolide acetate) 45 mg (6-month) was assessed in an uncontrolled, open-label, single-arm pivotal clinical trial (TOL2581A) involving 64 pediatric patients (62 females and 2 males) with Central Precocious Puberty (CPP) who had not previously received gonadotropin-releasing hormone (GnRH) agonist treatment. Enrolled patients received at least one dose of Eligard at a 24-week dosing interval and were monitored for 12 months. At the start of treatment, the mean age of patients was 7.5 years, ranging from 4 to 9 years. The primary efficacy endpoint was the proportion of patients with suppression of peak stimulated luteinizing hormone (LH) concentrations to below 4 IU/L at month 6. This endpoint was achieved in 87% of pediatric patients at month 6 (with a 95% confidence interval ranging from 76.2% to 94.3%), which was considered clinically important. Additionally, at month 12, 86% of patients had maintained LH levels below 4 IU/L.

Secondary endpoints provided additional supportive efficacy data. The suppression of estradiol and testosterone concentrations to prepubertal levels at the 6-month assessment was achieved in 97% and 100% of patients, respectively. Suppression of estradiol and testosterone was maintained at the 12-month assessment in 98% (55/56) of female and 50% (1/2) of male patients. Eligard 45 mg (6-month) arrested or reversed progression of clinical signs of puberty with reductions in growth velocity and bone age advancement. Over the course of the study, mean growth velocity decreased from 8.9 ± 13.1 cm/year at 1 month to 6.9 ± 3.1 cm/year at 6 months and to 6.4 ± 1.9 cm/year at 12 months.

Overall, these findings demonstrated the efficacy of Eligard 45 mg (6-month) in treating CPP.

The safety profile of Eligard 45 mg (6-month) in pediatric CPP patients was assessed in the pivotal study TOL2581A. The observed safety profile is consistent with that of currently marketed GnRH agonists. There were no adverse events that led to withdrawal from the study or discontinuation of study drug. Adverse events of any type were reported for 55 (85.9%) subjects. Serious adverse events were reported for one subject (1.6%).

Adverse reactions occurring in 5% or more of patients included injection site pain (31%), nasopharyngitis (22%), pyrexia (17%), headache (16%), cough (13%), abdominal pain (9%), injection site erythema (9%), nausea (8%), constipation (6%), vomiting (6%), upper respiratory tract infection (6%), bronchospasm (6%), productive cough (6%), hot flush (5%), bronchitis (5%), pharyngitis (5%), pharyngitis streptococcal (5%) and sinusitis (5%). Additionally, reported psychiatric adverse reactions included emotional disorder (2%) and irritability (2%).

In pivotal Study TOL2581A, no new safety signals were identified. The number of injection site reactions observed for Eligard was similar to what is described in the labeling for other currently marketed injectable GnRH agonists approved for CPP. There were two cases of rash, and one case each of urticaria and hypersensitivity in the safety population of Eligard but no cases of anaphylaxis. There were 4 reports of hot flushes in 3 subjects in pivotal Study TOL2581A which are consistent with other currently marketed GnRH agonists approved for CPP; and outside of hot flush that occurred within 2 weeks of drug administration, events of acute-on-chronic effect were not observed in Study TOL2581A. There was no evidence of seizures/convulsions in the Nervous System Disorder SOC, but patients with a history of seizure disorder or taking medications associated with seizures were excluded from the study. There were three adverse events in the Psychiatric Disorders SOC including irritability, emotional disorder and insomnia (each in one patient), but there was no evidence for suicidal ideation. There was no evidence of idiopathic intracranial hypertension in this study.

Post-marketing experience with other GnRH agonists in children with CPP has identified potential adverse reactions, including injection site reactions; hypersensitivity reactions (including anaphylaxis); transient increases in gonadal hormone production at the initiation of treatment and following subsequent doses (termed ‘acute-on-chronic’ effect; e.g., vaginal bleeding in girls), side effects related to HPG axis suppression during chronic therapy (e.g., vasomotor symptoms); seizures/convulsions; psychiatric adverse events (emotional lability/suicidal ideation) and idiopathic intracranial hypertension (pseudo tumor cerebri).

These potential and identified adverse reactions are addressed in the Product Monograph (PM). A Risk Management Plan has also been established to monitor known and potential safety issues and minimize associated risks.

In summary, based on the data from pivotal Study TOL2581A and available evidence, the observed benefit is clinically significant and outweighs the risks. Considering the evidence and clinical experience, it is concluded that the benefit-risk balance for Eligard 45 mg (6-month) is positive when prescribed within the recommended conditions of use outlined in the PM for CPP.

For further details about Eligard, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.