Supprelin LA - Drug Monograph

Introduction

Supprelin LA (histrelin acetate) is a gonadotropin-releasing hormone (GnRH) agonist implant approved for the treatment of central precocious puberty (CPP) in pediatric patients. This sustained-release subcutaneous implant provides continuous delivery of histrelin over 12 months, offering a convenient alternative to daily injections or monthly depot formulations for managing premature pubertal development.

Mechanism of Action

Histrelin is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH). Initially, it causes a transient increase in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion from the pituitary gland ("flare effect"). With continuous administration, histrelin produces a reversible suppression of pituitary gonadotropins through downregulation of GnRH receptors. This leads to decreased production of sex steroids (estradiol in females and testosterone in males), effectively halting the progression of precocious puberty.

Indications

• Treatment of central precocious puberty (CPP) in pediatric patients aged 2 years and older
• CPP is defined as the onset of pubertal signs before age 8 in girls and before age 9 in boys

Dosage and Administration

• Standard dosing: One 50 mg implant inserted subcutaneously in the inner upper arm
• Administration: Surgical insertion under local anesthesia by healthcare provider
• Duration: Each implant is designed to deliver histrelin continuously for 12 months
• Replacement: Requires surgical replacement every 12 months until appropriate time for puberty
• Special populations: No dosage adjustment required for renal or hepatic impairment

Pharmacokinetics

• Absorption: Continuous release from hydrogel polymer matrix at approximately 65 mcg/day
• Distribution: Distributed throughout body water; protein binding is minimal
• Metabolism: Undergoes proteolytic degradation in plasma and tissues
• Elimination: Primarily renal excretion as metabolites; elimination half-life approximately 1-2 hours
• Steady state: Achieved within 1 month of implantation

Contraindications

• Hypersensitivity to histrelin, GnRH analogs, or any component of the implant
• Women who are or may become pregnant (Category X)
• Breastfeeding mothers
• Undiagnosed vaginal bleeding

Warnings and Precautions

• Initial flare effect: May cause temporary worsening of pubertal signs during first weeks of treatment
• Implant site reactions: Monitor for infection, extrusion, or migration
• Surgical considerations: Requires proper insertion and removal techniques
• Bone density: Monitor bone mineral density in long-term therapy
• Ovarian cysts: May occur and usually resolve spontaneously
• Convulsions: Rare reports of seizures in patients with and without history of seizure disorder

Drug Interactions

• Drugs affecting GnRH analogs: Limited data, but theoretical interactions with drugs affecting pituitary function
• Corticosteroids: May alter pituitary response to GnRH analogs
• Sex steroids: Concurrent use may interfere with therapeutic effect
• Enzyme inducers: Potential for altered metabolism, though clinical significance unknown

Adverse Effects

• Implant site reactions (pain, erythema, swelling)
• Headache
• Weight gain
• Vaginal bleeding (spotting)
• Emotional lability
• Acne

• Hot flashes
• Nausea
• Breast tenderness
• Vaginitis
• Injection site reactions

• Anaphylactic reactions
• Implant migration
• Ovarian cysts
• Convulsions
• Hypertension

Monitoring Parameters

• Clinical assessment: Pubertal progression every 3-6 months (Tanner staging)
• Hormonal levels: LH, FSH, estradiol (females), or testosterone (males) at 1-2 months post-insertment and every 6 months
• Bone age: Annual radiographic assessment
• Growth parameters: Height, weight, and growth velocity every 3-6 months
• Implant site: Regular inspection for signs of infection, extrusion, or migration
• Bone mineral density: Consider baseline and periodic DEXA scans with long-term therapy

Patient Education

• Explain that initial worsening of symptoms may occur during the first few weeks
• Instruct on proper care of implant site and signs of infection to report
• Discuss expected therapeutic outcomes: halted pubertal progression, decreased growth velocity
• Inform about potential side effects and when to contact healthcare provider
• Emphasize importance of regular follow-up appointments and implant replacement every 12 months
• Discuss long-term implications for bone health and future fertility
• Provide guidance on appropriate expectations for pubertal development after therapy discontinuation

References

1. FDA Prescribing Information: Supprelin LA (histrelin acetate) implant 2. Eugster EA, Clarke W, Kletter GB, et al. Efficacy and safety of histrelin subcutaneous implant in children with central precocious puberty: a multicenter trial. J Clin Endocrinol Metab. 2007;92(5):1697-1704. 3. Silverman LA, Neely EK, Kletter GB, et al. Long-term continuous suppression with once-yearly histrelin subcutaneous implant for the treatment of central precocious puberty: a final report of a phase 3 multicenter trial. J Clin Endocrinol Metab. 2015;100(6):2384-2391. 4. Carel JC, Eugster EA, Rogol A, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics. 2009;123(4):e752-e762. 5. Lewis KA, Goldyn AK, West KW, Eugster EA. A single histrelin implant is effective for 2 years for treatment of central precocious puberty. J Pediatr. 2013;163(4):1214-1216.