Histrelin (Supprelin LA, Vantas)
Histrelin Acetate (5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-N-tau-benzyl-D-histidyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide diacetate)
FDA-approved synthetic nonapeptide GnRH agonist delivered as a 50 mg subcutaneous hydrogel implant (Supprelin LA for central precocious puberty, Vantas for advanced prostate cancer), providing 12 months of continuous gonadotropin suppression (PMID 17327379, PMID 16515997).
Last updated: 2026-03-10
Safety Summary
In the CPP clinical trials (n=47), the most common adverse reactions involved the implant site: bruising (51%), pain (40%), soreness (32%), erythema (23%), swelling (17%) (FDA Supprelin LA label). Serious adverse reactions in the 12-month study included seizure in one patient and pituitary tumor (benign) in another. In the long-term extension, serious adverse reactions included depression (n=1), aggression (n=2), and one death from acute bronchopneumonia and Dravet syndrome (not drug-related). In prostate cancer patients (n=171 up to 24 months), hot flashes were the most common event (65.5%), followed by fatigue (9.9%), implant site reaction (5.8%), testicular atrophy (5.3%), gynecomastia (4.1%), erectile dysfunction (3.5%), constipation (3.5%), headache (2.9%), insomnia (2.9%), decreased libido (2.3%), renal impairment (4.7%), and weight increase (2.3%) (Vantas Canadian label). Post-marketing reports for GnRH agonists include pseudotumor cerebri, psychiatric events, convulsions, and severe cutaneous adverse reactions (FDA label 2025). Across indications, local procedural problems and expected endocrine effects dominate the safety profile.
Known Side Effects
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Who Should NOT Use This
Histrelin can cause fetal harm. Expected hormonal changes increase risk of pregnancy loss. Animal studies showed teratogenicity and fetotoxicity at clinically relevant exposures (FDA Supprelin LA and Vantas labels).
Anaphylactic reactions to synthetic GnRH agonist analogs have been reported (Vantas FDA label).
Not known whether histrelin is excreted in human milk. Decision should weigh importance of drug to mother versus risk to nursing infant (Vantas FDA label).
Initial testosterone flare may exacerbate these conditions. Anti-androgen should be co-administered during initial weeks (Vantas FDA label, PMID 30131604).
Increased risk of hyperglycemia/diabetes and cardiovascular disease reported in men receiving GnRH agonists (Vantas FDA label).
Convulsions have been reported in patients receiving GnRH agonists, with and without a history of seizures (FDA Supprelin LA label 2025).
Psychiatric events including depression, emotional lability, irritability, restlessness, anger, and aggression reported with GnRH agonists. Closer monitoring is prudent in vulnerable patients (FDA Supprelin LA label 2025).
Talk to Your Doctor
Before considering Histrelin (Supprelin LA, Vantas), discuss it with your healthcare provider. Ask about potential interactions with your current medications, whether it is appropriate for your health conditions, and what monitoring may be needed.
Sources: [1-9]
Evidence Assessment
Tier 1: FDA-approved for two indications. Supprelin LA (NDA 022058) approved May 2007 for central precocious puberty based on a Phase 3 multicenter trial in 36 children (PMID 17327379) with long-term extension data up to 6 years (PMID 25803268). Vantas (NDA 021732) approved October 2004 for advanced prostate cancer based on a Phase 3 trial in 138 men (PMID 16515997). The original daily injection formulation (NDA 019836) was approved December 1991 as a New Molecular Entity with Priority Review. Multiple post-marketing studies and real-world evidence support efficacy and safety (PMID 34147047, PMID 24295437). Standard of care for CPP treatment and prostate cancer androgen deprivation therapy.
1Efficacy and safety of histrelin subdermal implant in children with central precocious puberty: a multicenter trialPMID 17327379
Eugster EA et al. - The Journal of Clinical Endocrinology and Metabolism (2007) - Phase 3 open-label prospective multicenter trial - 36
By 1 month, peak LH fell from 28.2+/-19.97 to 0.8+/-0.39 mIU/mL in naive subjects (P<0.0001) and from 2.1+/-2.15 to 0.5+/-0.32 in previously treated (P=0.0056). Estradiol suppressed from 24.5+/-22.27 to 5.9+/-2.37 pg/mL in naive girls (P=0.0016). Suppression maintained throughout 12 months. No significant adverse events.
Limitations: Small sample size (N=36). Open-label, no control group. Single-arm study design.
2Long-Term Continuous Suppression With Once-Yearly Histrelin Subcutaneous Implants for the Treatment of Central Precocious Puberty: A Final Report of a Phase 3 Multicenter TrialPMID 25803268
Silverman LA et al. - The Journal of Clinical Endocrinology and Metabolism (2015) - Phase 3 long-term extension study (up to 6 years) - 36
Sustained gonadotropin suppression maintained up to 6 years. Bone age to chronological age ratio decreased from 1.417 to 1.18 at 48 months (P<0.01). Predicted adult height in girls increased from 151.9 to 166.5 cm at month 60 (P<0.05), with 10.7 cm height gain in treatment-naive children. No adverse effect on growth or HPG axis recovery.
Limitations: Extension of small initial cohort. Not all subjects continued full 6 years. Open-label. Manufacturer-funded (Endo Pharmaceuticals).
3Efficacy and safety of histrelin subdermal implant in patients with advanced prostate cancerPMID 16515997
Schlegel PN - The Journal of Urology (2006) - Phase 3 open-label multicenter trial - 138
100% of 134 patients achieved chemical castration (testosterone <=50 ng/dL) by week 4. Suppression maintained in >99% through 52 weeks. PSA decreased 90% from baseline (83.6 ng/mL) by week 16 (P=0.0001). 79% achieved complete PSA response by week 60. No testosterone or LH surge with reimplantation.
Limitations: Open-label, no active comparator. Fixed-dose design.
4Random unstimulated pediatric luteinizing hormone levels are not reliable in the assessment of pubertal suppression during histrelin implant therapyNCT00779103PMID 24295437
Neely EK et al. - International Journal of Pediatric Endocrinology (2013) - Post-hoc analysis of Phase 3 trial data - 36
All 36 children maintained peak LH <4 mIU/mL (mean 0.62+/-0.43) throughout therapy, confirming suppression. However, random unstimulated LH exceeded pubertal threshold (>0.3 mIU/mL) in 48.4% of tests and in 88.9% of subjects at some point. Random LH mean was 0.35+/-0.25 mIU/mL. Conclusion: random LH is unsuitable for monitoring histrelin therapy; stimulation testing required.
Limitations: Post-hoc analysis of existing trial data. Single LH assay platform. Manufacturer-funded.
5Clinical characteristics and treatment patterns with histrelin acetate subcutaneous implants vs. leuprolide injections in children with precocious puberty: a real-world study using a US claims databasePMID 34147047
Silverman LA et al. - Journal of Pediatric Endocrinology and Metabolism (2021) - Retrospective real-world claims database study - 4217
Mean treatment duration significantly longer for histrelin (26.7+/-14.8 months vs 14.1+/-12.1 months, P<0.0001). More patients switched from leuprolide to histrelin (12.3%) than vice versa (3.6%, P<0.0001). Median annual costs slightly lower for histrelin ($23,071 vs $27,021, P<0.0001).
Limitations: Retrospective claims data. Cannot assess clinical outcomes (hormonal suppression, height). Administrative coding limitations. Sponsored by Endo Pharmaceuticals.
6Histrelin. A review of its pharmacological properties and therapeutic role in central precocious pubertyPMID 7684676
Barradell LB, McTavish D - Drugs (1993) - Comprehensive review
Histrelin 8-10 mcg/kg/day SC desensitizes anterior pituitary within 3 months, ablating pubertal gonadotrophin response. Decelerates skeletal maturation, allowing more statural growth. Most common adverse event: injection site reactions (45%). Effects reversible -- puberty resumed in 44/45 patients within 12 months of stopping therapy.
Limitations: Review from 1993. Based on small clinical trials. Pre-implant era data (daily injection formulation).
7Extended Use of Histrelin Implant in Pediatric PatientsPMID 37342480
Multiple authors (two-center collaboration) - Transgender Health (likely) / Pediatric endocrinology journal (2023) - Retrospective two-center cohort study - 49
Among 50 implants retained >=17 months in 49 pediatric patients (42 TG/NB, 7 CPP), 42/50 maintained clinical/biochemical suppression. Mean single-implant use was 37.5+/-13.6 months. Escape occurred in 8/50 (16%) at mean 30.4 months (range 15-65). Only 3/50 had clinical escape. Removal complications in 3/23 (13%) including breakage and difficult removal. Four patients used Vantas (50 mcg/day) with comparable 12-month efficacy to Supprelin LA (65 mcg/day).
Limitations: Retrospective design. Nonstandardized assays and visit timing. No GnRH stimulation testing. COVID-19 limited follow-up in some subjects. Potential selection bias.
8Prolonged Pubertal Suppression due to Retained Histrelin Implant in Three Children with Central Precocious PubertyPMID 40015262
Marpuri I, Geffner ME, Chao LC - Hormone Research in Paediatrics (2025) - Case series - 3
Three females with CPP experienced implant breakage during extraction. In 2 cases, retained fragments suppressed pubertal hormones for 5 years. In the third, histrelin left in place due to loss of follow-up caused amenorrhea for 6 years. All resumed menstruation after surgical removal of fragments.
Limitations: Case series, N=3. No systematic study of fragment bioactivity.
9Androgen-targeted therapy in men with prostate cancer: evolving practice and future considerationsPMID 30131604
Crawford ED et al. - Prostate Cancer and Prostatic Diseases (review) (2018) - Comprehensive review of ADT options
Reviews all forms of ADT including LHRH agonists (leuprolide, triptorelin, goserelin, histrelin), antagonists (degarelix), and androgen pathway inhibitors. Confirms anti-androgens are usually used concomitantly with LHRH agonists to reduce flare impact or achieve complete androgen blockade. Notes histrelin 12-month implant is available but not widely used.
Limitations: Narrative review, not systematic. Industry authors.