Histrelin Acetate

SUPPRELIN LA (histrelin acetate) subcutaneous implant is indicated for the treatment of children with central precocious puberty (CPP). Children with CPP (neurogenic or idiopathic) have an early onset of secondary sexual characteristics (earlier than 8 years of age in females and 9 years of age in males). They also show a significantly advanced bone age that can result in diminished adult height attainment. Prior to initiation of treatment a clinical diagnosis of CPP should be confirmed by measurement of blood concentrations of total sex steroids, luteinizing hormone (LH) and follicle stimulating hormone (FSH) following stimulation with a GnRH analog, and assessment of bone age versus chronological age. Baseline evaluations should include height and weight measurements, diagnostic imaging of the brain (to rule out intracranial tumor), pelvic/testicular/adrenal ultrasound (to rule out steroid secreting tumors), human chorionic gonadotropin levels (to rule out a chorionic gonadotropin secreting tumor), and adrenal steroids to exclude congenital adrenal hyperplasia. SUPPRELIN LA is a gonadotropin releasing hormone (GnRH) agonist indicated for the treatment of children with central precocious puberty (CPP) ( 1 ).

SUPPRELIN LA is a sterile, nonbiodegradable, diffusion-controlled, hydrogel polymer reservoir drug delivery system designed to deliver histrelin acetate continuously for 12 months after subcutaneous implantation. The sterile implant contains 50 mg histrelin acetate and delivers approximately 65 mcg histrelin acetate per day over 12 months. SUPPRELIN LA is available as a 50 mg histrelin acetate subcutaneous implant which delivers approximately 65 mcg histrelin acetate per day over 12 months ( 3 ).

SUPPRELIN LA is contraindicated in: Patients who are hypersensitive to gonadotropin releasing hormone (GnRH) or GnRH agonist analogs Pregnancy [see Use in Specific Populations ( 8.1 )] . History of hypersensitivity to gonadotropin releasing hormone (GnRH) or GnRH analogs ( 4 ). Pregnancy ( 4 ).

Initial Agnostic Action: Initial transient increases of estradiol and/or testosterone may cause a temporary worsening of symptoms ( 5.1 ). Implant Breakage: Have been observed during implant removal. Monitor luteinizing hormone, follicle stimulating hormone or testosterone for suppression of CPP ( 5.2 , 5.6 ) Psychiatric Events: Have been reported in patients taking GnRH agonists. Events include emotional lability, such as crying, irritability, impatience, anger, and aggression. Monitor for development or worsening of psychiatric symptoms. ( 5.3 ) Convulsions: Have been observed in patients receiving GnRH agonists with or without a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and in patients on concomitant medications that have been associated with convulsions. ( 5.4 ) Severe Cutaneous Adverse Reactions: Have been reported in patients receiving GnRH agonists. Interrupt SUPPRELIN LA if signs or symptoms of severe cutaneous adverse reactions develop. Permanently discontinue SUPPRELIN LA if a severe cutaneous adverse reaction is confirmed. ( 5.5 ) Pseudotumor Cerebri (Idiopathic Intracranial Hypertension): Have been reported in pediatric patients receiving GnRH agonists. Monitor patients for headache, papilledema, and blurred vision. ( 5.6 )

5.1 Initial Agonistic Action SUPPRELIN LA, like other GnRH agonists, initially causes a transient increase in serum concentrations of estradiol in females and testosterone in both sexes during the first week of treatment. Patients may experience worsening of symptoms or onset of new symptoms during this period. However, within 4 weeks of histrelin therapy, suppression of gonadal steroids occurs and manifestations of puberty decrease.

5.2 Implant Breakage Implant insertion is a surgical procedure and it is important that the insertion instructions are followed to avoid potential complications. The insertion and removal of the implant should be done aseptically. Proper surgical technique is critical in minimizing adverse events related to the insertion and the removal of the histrelin implant. On occasion, localizing and/or removal of implant products have been difficult and imaging techniques were used, including ultrasound, CT, or MRI (note: the histrelin implant is not radiopaque). In some cases the implant broke during removal and multiple pieces were recovered. Confirm that the entire implant has been removed. If the implant was not retrieved completely, the remaining pieces should be removed following the instructions in the Suggested Removal Procedure section [see Dosage and Administration ( 2.2 )]. Rare events of spontaneous extrusion of the implant have been observed in clinical trials. During SUPPRELIN LA treatment, patients should be evaluated for evidence of clinical and biochemical suppression of CPP manifestations (see Section 5.6 , Monitoring and Laboratory tests). Detailed instructions on the insertion and removal procedures of the implant are provided above [see Dosage and Administration ( 2.2 )] .

5.3 Psychiatric Events Psychiatric events have been reported in patients taking GnRH agonists, including SUPPRELIN LA. Postmarketing reports with this class of drugs include symptoms of emotional lability, such as crying, irritability, impatience, anger, and aggression. Monitor for development or worsening of psychiatric symptoms during treatment with SUPPRELIN LA [see Adverse Reactions ( 6 )] .

5.4 Convulsions Postmarketing reports of convulsions have been observed in patients receiving GnRH agonists, including SUPPRELIN LA. Reports with GnRH agonists have included patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and patients on concomitant medications that have been associated with convulsions such as bupropion and SSRIs. Convulsions have also been reported in patients in the absence of any of the conditions mentioned above.

5.5 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions have been reported in patients receiving GnRH agonists [see Adverse Reactions ( 6.3 )] . These reactions include Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), including cases with visceral involvement and/or requiring skin grafts. Monitor patients for signs and symptoms of severe cutaneous adverse reactions such as fever, flu-like symptoms, mucosal lesions, progressive skin rash or lymphadenopathy. Advise patients and caregivers of the signs and symptoms of severe cutaneous adverse reactions. If a severe cutaneous adverse reaction is suspected, interrupt SUPPRELIN LA. Consult a healthcare provider with expertise in the diagnosis and management of severe cutaneous adverse reactions. If a diagnosis of severe cutaneous adverse reaction is confirmed permanently discontinue SUPPRELIN LA.

5.6 Pseudotumor Cerebri (Idiopathic Intracranial Hypertension) Pseudotumor cerebri (idiopathic intracranial hypertension) have been reported in pediatric patients receiving GnRH agonists. Monitor patients for signs and symptoms of pseudotumor cerebri, including headache, papilledema, blurred vision, diplopia, loss of vision, pain behind the eye or pain with eye movement, tinnitus, dizziness, and nausea.

5.7 Monitoring and Laboratory Tests LH, FSH and estradiol or testosterone should be monitored at 1 month post implantation then every 6 months thereafter. Additionally, height (for calculation of height velocity) and bone age should be assessed every 6-12 months.

The following serious adverse reactions are described here and elsewhere in the label: Initial Agonist Action [see Warnings and Precautions ( 5.1 )] Implant Breakage [see Warnings and Precautions ( 5.2 )] Psychiatric Events [see Warnings and Precautions ( 5.3 )] Convulsions [see Warnings and Precautions ( 5.4 )] Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.5 )] Pseudotumor Cerebri (Idiopathic Intracranial Hypertension) [see Warnings and Precautions ( 5.6 )] The most common adverse reaction is implant site reaction (51.1%), including complications related to the insertion or removal of the implant ( 6 ). Adverse events related to suppression of endogenous sex steroid secretion may occur ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Endo at 1-800-462-3636 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Overall Adverse Reaction Profile The most common adverse reactions with SUPPRELIN LA involved the implant site. Local reactions after implant insertion include bruising, pain, soreness, erythema and swelling. During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the natural stimulatory effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed [see Warnings and Precautions ( 5.1 )] .

6.2 Adverse Reactions in Clinical Trials Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of SUPPRELIN LA in children with CPP was evaluated in two single-arm clinical trials conducted in a total of 47 patients (44 females and 3 males) over a period of time ranging from 9 to 18 months. The most commonly reported adverse reaction was implant site reaction, which was reported by 24 of 47 (51.1%) patients. Implant site reaction includes discomfort, bruising, soreness, pain, tingling, itching, implant area protrusion and swelling. Two subjects experienced a serious adverse reaction: 1 subject who coincidentally had Stargardt’s Disease experienced amblyopia and 1 subject had a benign pituitary tumor (pituitary adenoma). One subject discontinued the study due to an adverse reaction of infection at the implant site. There were no clinically meaningful findings in standard clinical hematology and chemistry tests and/or in vital signs. The incidence of implantation adverse events reported by more than 2 patients are summarized in Table 1. Table 1: Incidence of implantation adverse reactions reported by ≥ 2 patients treated with SUPPRELIN LA in both clinical trials Adverse Reactions N=47 N (%) Implant site reaction 24 (51.1) Keloid scar 3 (6.4) Scar 3 (6.4) Suture related complication 3 (6.4) Application site pain 2 (4.3) Post procedural pain 2 (4.3) The following adverse reactions were reported as possibly related or related in 1 patient each: wound infection, breast tenderness, dysmenorrhea, epistaxis, erythema, feeling cold, gynecomastia, headache, menorrhagia, migraine, mood swings, pituitary tumor benign, pruritus, weight increased, disease progression and influenza-like illness. The adverse reaction metrorrhagia was reported as possibly related or related in 2 patients.

6.3 Post-marketing Experience The following adverse reactions have been identified during post approval use of SUPPRELIN LA or GnRH agonists. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. General Disorders and Administration Site Conditions : implant breakage Psychiatric Disorders : Emotional lability, such as crying, irritability, impatience, anger, and aggression. Depression, including rare reports of suicidal ideation and attempt. Many, but not all, of these patients had a history of psychiatric illness or other comorbidities with an increased risk of depression. Nervous System Disorders : seizures. Pseudotumor cerebri (idiopathic intracranial hypertension) have been observed with GnRH agonists. Skin Reactions: erythema multiforme, bullous dermatitis, dermatitis exfoliative, drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome and toxic epidermal necrolysis, and acute generalized exanthematous pustulosis.

Overview: No formal drug-drug, drug-food, or drug-herb interaction studies were performed with SUPPRELIN LA. Drug-Laboratory Interactions: Therapy with SUPPRELIN LA results in suppression of the pituitary-gonadal system. Results of diagnostic tests of pituitary gonadotropic and gonadal functions conducted during and after SUPPRELIN LA therapy may be affected. SUPPRELIN LA decreased mean serum insulin like growth factor 1 (IGF 1) levels by approximately 11% in one study (Study 1). SUPPRELIN LA increased the serum concentration of dehydroepiandrosterone (DHEA) in 8 of 36 patients in another study (Study 2).

Use of SUPPRELIN LA in children less than 2 years of age is not recommended ( 8.4 ).

8.1 Pregnancy Risk Summary SUPPRELIN LA is contraindicated during pregnancy [see Contraindications ( 4 )] since expected hormonal changes that occur with SUPPRELIN LA treatment increase the risk for pregnancy loss. The limited data with histrelin use in pregnant women are insufficient to determine a drug-associated risk for major birth defects or adverse developmental outcomes. Consistent with mechanism of action for SUPPRELIN LA [see Clinical Pharmacology ( 12.1 )], animal reproduction studies showed an increase in fetal loss at clinically relevant exposures. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Histrelin acetate administered to pregnant rats during the period of organogenesis increased fetal mortality and post-implantation loss at doses of 1, 3, 5 or 15 mcg/kg/day, approximating clinical exposure based on body surface area. These dosages also reduced maternal body weight gain, stimulated ovarian follicular development, increased placental weight and caused abnormal morphology and an increase in fetal size. Histrelin acetate administered to pregnant rabbits during the period of organogenesis increased fetal mortality and abortion/early termination at the two highest doses and caused total litter loss at all doses of 20, 50 or 80 mcg/kg/day (approximately 3- to 12-times clinical exposures based on body surface area).

8.2 Lactation Risk Summary There are no data on the presence of SUPPRELIN LA in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Absorption and systemic activity are not expected from potential exposure to the peptide, histrelin, in the breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SUPPRELIN LA and any potential adverse effects on the breastfed child from SUPPRELIN LA or from the underlying maternal condition.

8.4 Pediatric Use Safety and effectiveness in pediatric patients below the age of 2 years have not been established. The use of SUPPRELIN LA in children under 2 years is not recommended.

SUPPRELIN LA is a GnRH agonist and an inhibitor of gonadotropin secretion when given continuously. It delivers approximately 65 mcg histrelin acetate per day. Both animal and human studies indicate that following an initial stimulatory phase, chronic, subcutaneous administration of histrelin acetate desensitizes responsiveness of the pituitary gonadotropin which, in turn causes a reduction in ovarian and testicular steroidogenesis. In humans, administration of histrelin acetate results in an initial increase in circulating levels of LH and FSH, leading to a transient increase in concentration of gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of histrelin acetate causes a reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes. These inhibitory effects result in decreased levels of LH and FSH.