Histrelin: A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Histrelin is a potent synthetic nonapeptide analogue of gonadotropin-releasing hormone (GnRH), classified as a GnRH agonist with pronounced antigonadotropin effects when administered continuously.[1] Its clinical utility is realized through a unique drug delivery system: a 12-month subcutaneous hydrogel implant that provides continuous, non-pulsatile release of the drug.[1] The pharmacological mechanism of histrelin is paradoxical; an initial, transient agonistic phase that stimulates gonadotropin and sex steroid release is followed by profound pituitary desensitization and receptor downregulation, leading to a sustained state of medical castration.[1]

This mechanism underpins its two primary, FDA-approved indications. Marketed as Supprelin LA, histrelin is a first-line therapy for the management of central precocious puberty (CPP) in children, where it effectively halts premature sexual development and can preserve adult height potential.[1] Under the brand name Vantas, it was indicated for the palliative treatment of advanced, hormone-sensitive prostate cancer in adult men by suppressing testosterone to castrate levels.[1] While Vantas was discontinued by its manufacturer in 2021 for reasons unrelated to its safety or efficacy, Supprelin LA remains a critical therapeutic option.[2]

The safety profile of histrelin is largely predictable and dominated by the physiological consequences of induced hypogonadism, such as hot flashes and decreased libido, as well as local reactions at the implant site.[2] More significant warnings include the potential for a transient "symptom flare" during therapy initiation, an increased risk of cardiovascular and metabolic complications in men, and rare but serious neuropsychiatric events in children.[8] The administration via a subcutaneous implant offers a major advantage in patient adherence but requires a minor surgical procedure for insertion and removal. Histrelin represents a powerful tool for endocrine manipulation, whose efficacy is inextricably linked to its unique formulation and whose safe use demands a thorough understanding of its biphasic pharmacology.

Identification and Physicochemical Properties

The precise identification of a pharmaceutical agent is fundamental to its safe and effective use. Histrelin is a well-characterized small molecule oligopeptide with a defined structure and a comprehensive set of chemical identifiers that distinguish it from other GnRH analogues.

Nomenclature and Chemical Identifiers

Histrelin is known by several chemical names, synonyms, and registry numbers that are used across scientific literature, regulatory filings, and clinical practice. Its primary designation is Histrelin, with the active pharmaceutical ingredient typically formulated as histrelin acetate.[1]

The International Union of Pure and Applied Chemistry (IUPAC) name for the free base is L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-1-benzyl-D-histidyl-L-leucyl-L-arginyl-L-proline ethylamide.[1] An alternative IUPAC name has also been recorded as 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-1-benzyl-D-histidyl-L-leucyl-N5-(diaminomethylene)-L-ornithyl-N-ethyl-L-prolinamide.[2] The drug is classified under the Anatomical Therapeutic Chemical (ATC) code L02AE05, which designates it as a GnRH analogue.[2] Synonyms used during its development and in chemical databases include ORF-17070, RWJ-17070, and-gonadotropin releasing hormone.[2]

Molecular Structure and Formula

Histrelin is a synthetic nonapeptide, meaning it is an oligopeptide composed of nine amino acid residues joined in a specific sequence.[1] The sequence is composed of pyroglutamyl, histidyl, tryptophyl, seryl, tyrosyl, 1-benzyl-D-histidyl, leucyl, arginyl, and N-ethylprolinamide residues.[1] This structure is an analogue of the native human GnRH decapeptide, modified to increase potency and duration of action. The specific sequence can be represented as {Pyr}-His-Trp-Ser-Tyr-D-His(Bzl)-Leu-Arg-Pro-NHEt.[11]

The molecular formula for the histrelin free base is $C_{66}H_{86}N_{18}O_{12}$, corresponding to a molar mass of 1323.528 g·mol⁻¹.[2] The clinically used form, histrelin acetate, is a diacetate salt. Its molecular formula is $C_{70}H_{94}N_{18}O_{16}$ (or $C_{66}H_{86}N_{18}O_{12} \cdot 2C_{2}H_{4}O_{2}$), with an average molecular weight of approximately 1443.7 g/mol.[3]

Physicochemical Characteristics

Histrelin is typically supplied as a powder for formulation.[11] It is a hygroscopic substance, meaning it readily absorbs moisture from the atmosphere, a property that necessitates careful storage and handling.[11] Its solubility is limited, being described as slightly soluble in aqueous acid, dimethyl sulfoxide (DMSO), and methanol.[11] For long-term stability in its raw powder form, storage at -20°C is recommended.[11]

Computational models predict several key physicochemical properties for the acetate salt. It has a predicted logP of -2.1, indicating high hydrophilicity. The molecule possesses numerous sites for hydrogen bonding, with 17 hydrogen bond acceptors and 16 donors, and a large polar surface area of 446.86 Ų. Its pKa values are predicted to be 9.49 (strongest acidic) and 11.59 (strongest basic).[15] Due to its large size and high number of rotatable bonds (34), histrelin violates standard drug-likeness criteria such as Lipinski's Rule of Five, which is common for peptide-based therapeutics.[15]

Table 1: Key Identifiers and Physicochemical Properties of Histrelin

Property	Value (Free Base)	Value (Acetate Salt)	Source(s)
DrugBank ID	DB06788	DBSALT001172	2
CAS Number	76712-82-8	220810-26-4	2
UNII	H50H3S3W74	QMG7HLD1ZE	2
ATC Code	L02AE05	L02AE05	2
IUPAC Name	L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-1-benzyl-D-histidyl-L-leucyl-L-arginyl-L-proline ethylamide	N/A	1
Sequence	{Pyr}-His-Trp-Ser-Tyr-D-His(Bzl)-Leu-Arg-Pro-NHEt	{Pyr}-His-Trp-Ser-Tyr-D-His(Bzl)-Leu-Arg-Pro-NHEt	11
Molecular Formula	$C_{66}H_{86}N_{18}O_{12}$	$C_{70}H_{94}N_{18}O_{16}$	2
Molecular Weight	1323.528 g·mol⁻¹	1443.632 g·mol⁻¹	2
Physical Form	Powder	Powder	11
Solubility	Slightly soluble in Aqueous Acid, DMSO, Methanol	N/A	11
Stability	Hygroscopic	N/A	11
logP (Predicted)	N/A	-2.1	15
pKa (Predicted)	N/A	Strongest Acidic: 9.49; Strongest Basic: 11.59	15

Pharmacology

The therapeutic effects of histrelin are derived from its potent and specific interaction with the gonadotropin-releasing hormone receptor. Its mechanism of action is biphasic and counterintuitive, leveraging a paradoxical response of the pituitary gland to continuous, non-pulsatile stimulation to achieve profound hormonal suppression.

Mechanism of Action

Histrelin is classified as a potent synthetic agonist of the gonadotropin-releasing hormone (GnRH) receptor, also known as the luteinizing hormone-releasing hormone (LHRH) receptor.[1] As a synthetic nonapeptide analogue of the endogenous GnRH decapeptide, it possesses structural modifications that confer a significantly higher binding affinity and greater potency than the natural hormone.[1] Its mechanism unfolds in two distinct and opposing phases, which are entirely dependent on the mode of administration.

Phase 1: Initial Agonistic Stimulation (The "Flare" Effect)

Upon initial administration, histrelin functions as a classical GnRH receptor agonist. It binds to and activates GnRH receptors located on the surface of gonadotrope cells in the anterior pituitary gland.[2] This binding mimics the physiological action of endogenous GnRH, triggering the synthesis and release of the two primary gonadotropins: luteinizing hormone (LH) and follicle-stimulating hormone (FSH).[1] The resulting sharp, transient increase in circulating LH and FSH levels is often referred to as a "flare." This gonadotropin surge directly stimulates the gonads (testes in males, ovaries in females), leading to a temporary increase in the production and secretion of gonadal steroids. In males, this manifests as a rise in serum testosterone and dihydrotestosterone; in females, it causes an increase in estradiol and estrone.[1] This initial stimulatory phase is not a side effect but an inherent and unavoidable consequence of the drug's agonistic nature. It carries significant clinical implications, as the transient hormonal surge can temporarily exacerbate the symptoms of the underlying hormone-dependent condition being treated, such as increased bone pain in prostate cancer or a brief progression of pubertal signs in children with CPP.[8]

Phase 2: Pituitary Desensitization and Downregulation

The therapeutic benefit of histrelin is derived not from its initial agonist activity but from the pituitary's subsequent response to continuous, non-pulsatile stimulation. Endogenous GnRH is released from the hypothalamus in a pulsatile fashion, which is critical for maintaining normal pituitary responsiveness. The histrelin implant, however, delivers the drug at a constant, steady rate.[1] This chronic and unremitting exposure to a potent agonist overwhelms the pituitary gonadotropes, leading to two key adaptive processes: receptor downregulation and cellular desensitization.[2] The GnRH receptors on the cell surface are internalized and degraded faster than they can be replaced, reducing the number of available receptors. Concurrently, the intracellular signaling pathways that link receptor activation to hormone secretion become uncoupled and refractory to further stimulation.

The combination of these processes renders the pituitary gland insensitive to both the exogenous histrelin and any endogenous GnRH. This functional uncoupling effectively shuts down the hypothalamic-pituitary-gonadal axis. The result is a profound and sustained decrease in the secretion of both LH and FSH.[1] With the loss of trophic support from pituitary gonadotropins, the gonads cease their steroidogenic activity. This leads to the ultimate therapeutic goal: the suppression of serum testosterone to castrate levels (defined as less than 50 ng/dL) in males and the reduction of serum estradiol to prepubertal levels in children with CPP.[1] This state of profound hypogonadism, or "medical castration," is maintained as long as continuous histrelin therapy is administered and is reversible upon cessation of the drug.[3]

Pharmacodynamic Effects

The pharmacodynamic effects of histrelin are the measurable hormonal and physiological changes that result from its mechanism of action. These effects follow a predictable timeline and are the basis for its clinical efficacy.

The transition from the initial stimulatory phase to the desired state of sustained hormonal suppression typically occurs within 2 to 4 weeks after the implant is inserted.[1] This timeframe is a critical period during which patients must be monitored for the clinical consequences of the initial hormone flare.

In the treatment of central precocious puberty, the pharmacodynamic goal is to return the child's hormonal milieu to a prepubertal state. Long-term treatment with the Supprelin LA implant effectively suppresses the LH response to GnRH stimulation. Within one month of treatment initiation, circulating LH levels decrease to prepubertal levels.[3] This, in turn, suppresses ovarian and testicular steroidogenesis. The clinical consequences of this hormonal suppression are the cessation of progressive secondary sexual development and a deceleration of the accelerated linear growth velocity and bone maturation characteristic of CPP. This slowing of skeletal maturation is crucial, as it can ultimately improve the patient's final adult height by allowing for a longer period of prepubertal growth.[3] During the first week of therapy, a transient increase in pubertal signs, such as light vaginal bleeding or breast development in girls, may be observed due to the initial flare effect.[9]

In the palliative treatment of advanced prostate cancer, the primary pharmacodynamic endpoint is the achievement of medical castration. The Vantas implant was designed to reduce serum testosterone concentrations to levels comparable to those achieved after surgical castration (i.e., <50 ng/dL).[1] This profound state of androgen deprivation is the principal mechanism for slowing the growth of hormone-sensitive prostate cancer cells, thereby providing palliative relief of symptoms.[16] This target is reliably achieved within 2 to 4 weeks of implantation and is sustained for the entire 12-month duration of the implant.[1]

Pharmacokinetics

The pharmacokinetic profile of histrelin is unique and is almost entirely dictated by the drug delivery system. The subcutaneous implant transforms a peptide with a very short intrinsic half-life into a long-acting therapy, providing stable, continuous drug exposure for one year. This formulation-driven pharmacokinetic behavior is the key to achieving the pituitary desensitization necessary for its therapeutic effect.

Absorption and Distribution

Histrelin is administered via a sterile, non-biodegradable, diffusion-controlled hydrogel polymer reservoir that is implanted subcutaneously.[1] This implant acts as a drug depot, releasing histrelin at a relatively constant, near zero-order rate. The two commercial formulations were designed with slightly different release rates: the Vantas implant released approximately 50 mcg of histrelin per day, while the Supprelin LA implant is designed to release approximately 65 mcg per day.[8]

This continuous release from the subcutaneous space leads to consistent systemic absorption. The systemic bioavailability of histrelin from the implant is high, estimated to be 92% in adults.[2] Following the insertion of the implant, peak serum concentrations ($C_{max}$) are reached at a median time ($T_{max}$) of approximately 12 hours.[9] A study evaluating the Vantas implant in prostate cancer patients found that it delivered constant serum histrelin levels, with a mean concentration of approximately 0.265 ng/mL over 52 weeks.[24]

Once in systemic circulation, histrelin distributes into the tissues. The apparent volume of distribution ($V_d$) in adults, following a bolus injection, is approximately 58.4 L.[9] The drug is moderately bound to plasma proteins, with a protein binding of approximately 70%.[2]

Metabolism and Elimination

As a synthetic peptide, histrelin is not a substrate for the hepatic cytochrome P450 enzyme system.[25] Instead, its metabolism is expected to occur via enzymatic degradation by proteases and peptidases that are widely distributed throughout the body.[3] The primary metabolic pathway is likely hydrolysis, which breaks the peptide bonds to form smaller, inactive peptide fragments. In vitro studies conducted with human hepatocytes have identified a single metabolite that results from C-terminal dealkylation, another common pathway for peptide metabolism.[9]

The intrinsic elimination of histrelin from the plasma is rapid. The terminal elimination half-life ($t_{1/2}$) is short, approximately 4.0 hours.[2] The total systemic clearance is approximately 174 mL/min.[22] The short half-life of the molecule itself stands in stark contrast to its 12-month duration of clinical effect. This disparity highlights that the drug's persistence in the body is governed by its slow, continuous release from the implant (absorption rate-limited kinetics), not by its rapid intrinsic elimination rate.

Pharmacokinetics in Special Populations

The pharmacokinetics of histrelin have been studied in patients with renal impairment. In a study of prostate cancer patients, those with mild to severe renal impairment (creatinine clearance: 15-60 mL/min) were found to have average serum histrelin concentrations that were approximately 50% higher than in patients with normal renal function.[3] Despite this increase in exposure, the difference was not considered to be clinically relevant, and therefore, no dosage adjustment is recommended for patients with renal impairment.[3] The influence of hepatic insufficiency on histrelin pharmacokinetics has not been adequately studied.[26]

Table 2: Summary of Histrelin Pharmacokinetic Parameters

Pharmacokinetic Parameter	Value	Source(s)
Delivery System	Subcutaneous hydrogel polymer implant	1
Release Rate	Supprelin LA: ~65 mcg/day Vantas: ~50 mcg/day	17
Bioavailability (Subcutaneous)	92% (in adults)	2
Time to Peak ($T_{max}$)	~12 hours	9
Volume of Distribution ($V_d$)	~58.4 L	9
Plasma Protein Binding	~70%	2
Terminal Half-Life ($t_{1/2}$)	~4.0 hours	2
Systemic Clearance	~174 mL/min	22
Metabolism Pathway	Proteolytic hydrolysis and C-terminal dealkylation	3
Duration of Action	12 months (implant-dependent)	9

Clinical Applications and Efficacy

The clinical utility of histrelin spans disparate patient populations at opposite ends of the human lifespan, from young children to elderly men. This broad applicability is not due to multiple mechanisms of action, but rather to the targeted application of a single, powerful therapeutic principle: the controlled and reversible induction of a hypogonadal state. By precisely suppressing the production of gonadal steroids, histrelin can be used to pause premature puberty, starve a hormone-dependent tumor, or align physical development with gender identity.

Approved Indication: Central Precocious Puberty (Supprelin LA)

Central precocious puberty (CPP) is a condition characterized by the premature activation of the hypothalamic-pituitary-gonadal axis, leading to the onset of secondary sexual characteristics before the age of 8 in girls and 9 in boys.[10] This early maturation is associated with accelerated linear growth and bone age advancement, which can paradoxically result in compromised final adult height due to premature fusion of the epiphyseal growth plates.[10] The diagnosis must be confirmed through biochemical testing, typically a GnRH agonist stimulation test showing a pubertal LH response, and radiographic assessment of advanced bone age.[31]

The therapeutic rationale for using a GnRH agonist like histrelin is to interrupt this premature activation. By inducing pituitary desensitization, histrelin suppresses gonadotropin release, reduces sex steroid levels to a prepubertal state, and thereby halts the progression of puberty.[3] This intervention allows for a more normal duration of childhood growth, with the goal of preserving or improving the patient's predicted adult height.[9] GnRH agonists are considered the first-line, standard-of-care treatment for CPP.[1]

The efficacy and safety of the Supprelin LA implant for this indication were established in two single-arm, open-label clinical studies involving a total of 47 children (44 females and 3 males) aged 4 to 11 years.[34] The pivotal Phase 3 study, designated 03-CPP-HIS-300, enrolled 36 children, including both treatment-naïve and those pre-treated with other GnRH agonists.[36]

• Efficacy Endpoints: The primary efficacy endpoint was the proportion of subjects whose peak LH concentration, following stimulation with a GnRH agonist, was suppressed to the prepubertal range (< 4 mIU/mL) at Month 1.[36] Secondary endpoints included the suppression of basal LH and FSH, suppression of gonadal sex steroids (estradiol in girls, testosterone in boys), and clinical assessments of pubertal progression (Tanner staging), growth velocity, and the ratio of bone age to chronological age.[34]
• Key Results: The trials demonstrated robust efficacy. By one month after implantation, all treatment-naïve subjects achieved the primary endpoint of peak-stimulated LH suppression. This suppression was maintained in all subjects (both naïve and pre-treated) at every subsequent measurement period through Month 12.[36] Correspondingly, serum estradiol and testosterone levels were suppressed to and maintained at prepubertal levels.[29] Clinical assessments confirmed these biochemical findings, showing stabilization or regression of the signs of puberty and a decrease in the rate of bone age advancement relative to chronological age.[34]

In clinical practice, treatment with Supprelin LA is typically continued until the child reaches a medically appropriate age for puberty to resume, which is generally around 11 years for females and 12 years for males.[10]

Approved Indication: Palliative Treatment of Advanced Prostate Cancer (Vantas)

Advanced prostate cancer is frequently a hormone-sensitive malignancy, meaning its growth and proliferation are driven by androgens, primarily testosterone.[4] Androgen deprivation therapy (ADT), which aims to reduce testosterone to very low levels, is a foundational strategy for the palliative management of this disease, helping to slow tumor progression and alleviate symptoms such as bone pain.[16]

Histrelin provides a form of medical castration, offering a non-invasive, reversible alternative to surgical orchiectomy. By suppressing pituitary LH secretion, the Vantas implant effectively shuts down testicular testosterone production.[1] Clinical studies demonstrated that the Vantas implant was highly effective in achieving and maintaining the primary therapeutic goal. In the pivotal trial, 100% of evaluable patients achieved suppression of serum testosterone to below the castrate threshold of 50 ng/dL by Day 28 of therapy.[24] This profound suppression was consistently maintained for the entire 52-week treatment period. Subsequent studies and clinical experience showed that this efficacy could be maintained for up to two years with the annual replacement of the implant.[8] Although the Vantas brand has been discontinued, the established efficacy of histrelin in this setting validates its mechanism as a potent tool for ADT.

Off-Label and Investigational Uses

Beyond its FDA-approved indications, the potent endocrine-modulating effects of histrelin have led to its use in other clinical contexts.

• Gender Dysphoria: Histrelin implants are frequently used off-label as a key component of gender-affirming care for transgender and gender-diverse adolescents.[2] When administered at the onset of puberty (Tanner stage 2), it effectively suppresses the development of endogenous secondary sexual characteristics. This provides the adolescent with critical time to explore their gender identity without the distress of irreversible physical changes that are incongruent with that identity. This "pubertal blockade" is a fully reversible intervention that serves as a bridge to subsequent gender-affirming hormone therapy if and when the patient and their care team decide to proceed.[2]
• Other Hormone-Dependent Conditions: The ability of histrelin to induce a hypoestrogenic state has led to its investigational use in a variety of gynecological conditions. These include endometriosis, uterine fibroids (leiomyomas), polycystic ovarian disease, and severe premenstrual syndrome, where suppression of the ovarian cycle can provide significant symptom relief.[2]

Dosing, Administration, and Formulations

The clinical use of histrelin is defined by its unique formulation as a long-acting subcutaneous implant. This delivery system is integral to its mechanism of action and offers significant advantages in terms of convenience and patient adherence over daily or monthly injections.

Commercial Formulations and Brand Information

Histrelin has been marketed in two distinct implant formulations, both containing 50 mg of histrelin acetate but designed with different daily release rates for their respective indications.[20]

• Supprelin LA: This is the currently available histrelin implant. It contains 50 mg of histrelin acetate and is designed to deliver approximately 65 mcg per day over a 12-month period. It is indicated exclusively for the treatment of CPP in children.[14]
• Vantas: This formulation also contained 50 mg of histrelin acetate but was designed to deliver a slightly lower dose of approximately 50 mcg per day over 12 months. It was indicated for the palliative treatment of advanced prostate cancer.[20] Endo Pharmaceuticals officially discontinued the Vantas implant in September 2021, and it is no longer commercially available.[2]

The implant itself is a sterile, non-biodegradable, diffusion-controlled device. It consists of a drug core containing 50 mg of histrelin acetate mixed with stearic acid, which is encapsulated within a cylindrical hydrogel polymer reservoir.[14] The implant is approximately 3.5 cm long and 3 mm in diameter. It is packaged hydrated in a glass vial containing 2 mL of sterile 1.8% sodium chloride solution to ensure it is primed for immediate drug release upon insertion.[14]

Dosing Regimens

The standard dosing regimen for both Supprelin LA and the former Vantas implant is straightforward: one 50 mg implant is inserted subcutaneously once every 12 months.[8] The implant is engineered to provide a continuous release of histrelin for the full 12-month period. The release profile includes a design feature that allows for a few additional weeks of drug delivery beyond the one-year mark. This provides a valuable window of flexibility for patients and clinicians in scheduling the appointment for implant removal and replacement, without risking a lapse in hormonal suppression.[8]

Implant Insertion and Removal Procedures

The placement and removal of the histrelin implant are minor surgical procedures that must be performed by a healthcare professional trained in the technique, using strict aseptic conditions to minimize the risk of infection.[6]

• Location: The recommended site for both insertion and removal is the inner aspect of the upper arm.[6]
• Insertion Procedure: The procedure begins with the administration of a local anesthetic to numb the insertion site.[17] The physician then makes a small incision (approximately 5 mm) in the skin. A specialized, sterile insertion tool, which comes pre-loaded or is loaded with the implant, is used to create a subcutaneous tunnel and deposit the implant just beneath the skin.[10] It is critical that the implant is placed superficially to facilitate later removal; deep insertion can significantly complicate the removal procedure.[42] After placement is confirmed by palpation, the small incision is closed with either dissolvable sutures or surgical strips.[19]
• Removal Procedure: After 12 months, the implant must be removed. This procedure also involves local anesthesia, a small incision made over one end of the implant, and careful dissection to free the implant from the surrounding tissue before it is extracted with forceps. If therapy is to continue, a new implant can be inserted through the same incision or at a new site.
• Post-Procedure Care: Following insertion, the patient is instructed to keep the arm clean and dry for at least 24 hours. Strenuous exercise or heavy lifting involving the treated arm should be avoided for approximately 7 days to allow the incision to heal properly.[19]
• Procedure-Related Complications: While generally safe, the procedures are not without risk. Potential complications include infection at the site, hematoma, and scarring. More specific to the device, difficulties in locating the implant at the time of removal have been reported, particularly if it was inserted too deeply.[27] Implant breakage during the removal procedure has also been observed, which may necessitate a more extensive dissection to ensure all fragments are recovered.[10] In a small number of cases across all clinical trials, the implant was not recovered.[27]

Safety and Tolerability Profile

The safety profile of histrelin is well-characterized and is largely predictable based on its potent pharmacological effects. Adverse reactions can be broadly categorized into three groups: those related to the physiological consequences of profound sex hormone suppression, local events related to the implant and its insertion/removal procedure, and a set of less common but potentially serious systemic effects.

Adverse Drug Reactions

The spectrum of adverse drug reactions associated with histrelin therapy is extensive, with frequencies varying by patient population (pediatric vs. adult) and indication.

Table 3: Adverse Reactions Associated with Histrelin Therapy by Frequency and System Organ Class

System Organ Class	Frequency	Adverse Reaction	Source(s)
General Disorders and Administration Site Conditions	Very Common (>10%)	Implant site reaction (pain, swelling, erythema, bruising, itching)	10
	Common (1-10%)	Fatigue, asthenia	18
Endocrine Disorders	Very Common (>10%)	Hot flashes (up to 66% in adults)	18
	Common (1-10%)	Testicular atrophy, gynecomastia, decreased libido, erectile dysfunction (in adults)	2
	Common (1-10%)	Initial transient worsening of pubertal signs (in children)	9
Nervous System Disorders	Common (1-10%)	Headache, dizziness	2
	Postmarketing	Seizures/convulsions, pseudotumor cerebri (idiopathic intracranial hypertension) in children	9
	Rare (<0.1%)	Pituitary apoplexy	9
Psychiatric Disorders	Postmarketing	Emotional lability (crying, irritability, anger, aggression), depression	9
Metabolism and Nutrition Disorders	Common (1-10%)	Weight gain/loss, elevated blood glucose	9
Cardiovascular Disorders	Common (1-10%)	Blushing	18
	Postmarketing	Increased risk of myocardial infarction, stroke, sudden cardiac death (in men)	8
Gastrointestinal Disorders	Common (1-10%)	Constipation	2
Renal and Urinary Disorders	Common (1-10%)	Renal impairment	2

• Local and Hypogonadal Effects: The most commonly reported adverse events are reactions at the implant site, occurring in approximately 51% of patients and including bruising, pain, swelling, and erythema.[10] These are typically mild and resolve within two weeks. The next most common category of side effects stems directly from the intended drug effect of hypogonadism. In adult men, hot flashes are exceedingly common (up to 66%), along with decreased libido, erectile dysfunction, testicular atrophy, and gynecomastia.[2] In children, the initial hormone flare can manifest as light vaginal bleeding or breast enlargement in girls during the first month of therapy.[18]
• Neuropsychiatric Effects: A significant safety concern, particularly in the pediatric population treated for CPP, is the emergence of psychiatric and neurological adverse events. Postmarketing reports have described emotional lability, including episodes of crying, irritability, impatience, anger, and aggression.[9] Depression, including rare reports of suicidal ideation, has also been associated with GnRH agonist use in this population.[22] Seizures have been observed in patients receiving histrelin, including in those with no prior history of epilepsy or other risk factors.[9] Furthermore, cases of pseudotumor cerebri (idiopathic intracranial hypertension) have been reported in children, presenting with symptoms like severe headache, papilledema, and blurred vision.[10]
• Metabolic and Cardiovascular Effects: In men receiving long-term GnRH agonist therapy for prostate cancer, there is an established increased risk of metabolic and cardiovascular complications. This includes the development of hyperglycemia and an increased risk of new-onset type 2 diabetes.[3] Epidemiological data have also shown an increased risk of serious cardiovascular events, including myocardial infarction, sudden cardiac death, and stroke.[8] Additionally, androgen deprivation therapy may prolong the QT/QTc interval on an electrocardiogram, increasing the risk of arrhythmias.[9]

Warnings and Precautions

The prescribing information for histrelin carries several important warnings and precautions that clinicians must consider.

• Initial Agonistic Action and Symptom Flare: There is a specific warning regarding the transient increase in serum testosterone (in men) or estradiol (in children) that occurs during the first few weeks of therapy.[6] In men with advanced prostate cancer, this can lead to a "tumor flare," manifesting as a temporary worsening of bone pain, or the development of new symptoms such as neuropathy, hematuria, or urinary tract obstruction. Patients with metastatic vertebral lesions or pre-existing urinary obstruction are at particular risk for developing spinal cord compression or acute renal impairment and must be monitored closely during this initial period.[8]
• Cardiovascular and Metabolic Disease: Clinicians are advised to evaluate patients, particularly men being treated for prostate cancer, for risk factors for cardiovascular disease and diabetes before initiating therapy. Blood glucose and/or HbA1c should be monitored periodically, and patients should be monitored for signs and symptoms of cardiovascular events.[3]
• Psychiatric and Neurological Monitoring: Patients, especially children and their caregivers, should be counseled about the potential for new or worsening psychiatric symptoms. Any signs of emotional lability, depression, or aggression should be reported. The risk of seizures and pseudotumor cerebri also necessitates vigilance for relevant signs and symptoms.[9]
• Pituitary Apoplexy: Although rare, cases of pituitary apoplexy—a clinical syndrome resulting from hemorrhage or infarction of the pituitary gland—have been reported following the administration of GnRH agonists. The onset can be rapid, and it often occurs in patients with a pre-existing, often undiagnosed, pituitary adenoma.[9]
• Implant-Related Issues: The labeling includes warnings about the surgical nature of the insertion and removal procedures and the potential for complications, including difficulty locating or removing the implant and the possibility of implant breakage.[10]

Contraindications and Use in Specific Populations

There are absolute contraindications to the use of histrelin.

• Hypersensitivity: The drug is contraindicated in patients with a known hypersensitivity to histrelin, any other component of the implant, or other GnRH or GnRH agonist analogues.[8] Anaphylactic reactions have been reported with this class of drugs.
• Pregnancy: Histrelin is classified as Pregnancy Category X and is strictly contraindicated in women who are or may become pregnant.[8] The hormonal changes induced by the drug can cause fetal harm and are expected to increase the risk of pregnancy loss or spontaneous abortion.[8]
• Pediatric Use: While Supprelin LA is specifically indicated for the treatment of CPP, its use is not recommended in children under the age of 2 years due to a lack of safety and efficacy data in this age group.[42] The Vantas formulation was not indicated for use in children.[47]

Regulatory History and Status

The regulatory journey of histrelin in the United States reflects the evolution of drug delivery technology, with an early injectable formulation giving way to the more convenient and effective long-acting implant system.

FDA Approval History

Histrelin was first approved for use in the United States in 1991, formulated as a daily subcutaneous injection for the treatment of CPP.[25] However, with the advent of longer-acting GnRH agonist formulations that offered more convenient dosing schedules, this daily injection was eventually discontinued.[29] The development of the hydrogel implant technology revitalized the drug's clinical utility.

• Vantas (NDA 21-732): The first histrelin implant, Vantas, was developed for the palliative treatment of advanced prostate cancer. Sponsored by Valera Pharmaceuticals, it received approval from the U.S. Food and Drug Administration (FDA) on October 12, 2004.[29] This approval marked the introduction of the first and only once-yearly implant for this indication, offering a significant advantage in convenience over monthly or quarterly injections of other GnRH agonists.
• Supprelin LA (NDA 22-058): Following the success of the Vantas implant, a modified version was developed specifically for the pediatric CPP population. This implant, Supprelin LA, was designed to release a higher daily dose of histrelin (65 mcg/day vs. 50 mcg/day for Vantas).[29] Sponsored by Indevus Pharmaceuticals, Inc., Supprelin LA was approved by the FDA on May 3, 2007.[2] The regulatory review for Supprelin LA was a 505(b)(1) application that leveraged much of the pre-clinical and device-related safety data from the previously approved Vantas application, supplemented by new clinical trials conducted specifically in children with CPP.[40]

Market Discontinuation of Vantas

Despite its established efficacy and unique delivery system, the Vantas implant is no longer available. Endo Pharmaceuticals, the company that later manufactured the product, officially discontinued Vantas in September 2021.[7] The other histrelin implant, Supprelin LA, remains on the market for its approved indication in CPP.[2]

The discontinuation of Vantas was not the result of any new findings related to the drug's safety or efficacy. No product recalls or specific warnings about Vantas precipitated its removal from the market. Instead, the withdrawal appears to be a consequence of broader corporate and market dynamics. During the period leading up to and following 2021, Endo Pharmaceuticals faced immense financial and legal pressure stemming from widespread litigation related to its marketing of opioid medications.[51] This turmoil culminated in the company filing for Chapter 11 bankruptcy in August 2022 and undergoing significant corporate restructuring, including the divestiture of assets and the discontinuation of certain products.[51] Within this context, the discontinuation of Vantas is best understood as a strategic business decision made by a company navigating a profound corporate crisis, rather than a reflection on the clinical value or risk-benefit profile of the product itself. This situation highlights how the availability of a clinically effective medication can be vulnerable to commercial forces independent of its therapeutic merit.

Conclusion and Expert Insights

Histrelin stands as a testament to the critical interplay between pharmacology and pharmaceutical formulation. As a potent GnRH agonist, its clinical value is fundamentally unlocked by its delivery via a long-acting, 12-month subcutaneous implant. This delivery system is not merely a matter of convenience; it is the essential element that transforms the drug's intrinsic, short-lived agonistic activity into a sustained, therapeutically beneficial state of profound and reversible hypogonadism.

A nuanced understanding of histrelin's biphasic mechanism of action is paramount for any clinician prescribing it. This paradoxical pharmacology is the key to interpreting both its therapeutic efficacy and its primary safety risks. The initial, transient agonistic phase is responsible for the clinically significant "symptom flare" that requires careful patient selection and vigilant monitoring during the first weeks of therapy. Conversely, the subsequent, sustained phase of pituitary desensitization and downregulation is responsible for achieving the desired state of medical castration, which forms the basis of its efficacy in both central precocious puberty and advanced prostate cancer.

The once-yearly administration of the Supprelin LA implant offers a substantial advantage in patient adherence and quality of life, particularly for children with CPP and their families, for whom frequent injections can be a significant burden. This benefit, however, is balanced by a considerable safety profile that extends beyond the predictable effects of hypogonadism. The documented risks of cardiovascular and metabolic disease in adult men, and the potential for serious neuropsychiatric adverse events like seizures and pseudotumor cerebri in children, mandate that histrelin be prescribed with a high degree of clinical expertise.

The market discontinuation of the Vantas implant serves as a salient reminder of the complex factors that govern drug availability. Its removal was not driven by clinical failure but by the broader corporate challenges faced by its manufacturer, leaving Supprelin LA as the sole commercially available histrelin implant. This status solidifies Supprelin LA's role as a critical and indispensable therapy for children with CPP. In conclusion, histrelin is a powerful and highly effective tool for endocrine manipulation, but its safe and successful application depends on a sophisticated appreciation of its unique pharmacokinetics, a proactive strategy to manage its initial flare effects, and diligent long-term monitoring for its systemic risks.

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