Histrelin Acetate

Mechanism Of Action

Histrelin acetate is a gonadatropin releasing hormone (GnRH) agonist that acts as a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses. 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 testicular steroidogenesis.

In humans, administration of histrelin acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to a transient increase in concentration of gonadal steroids (testosterone and dihydrotestosterone in males); however, continuous administration of histrelin acetate results in decreased levels of LH and FSH due to a reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes. In males, testosterone is reduced to castration levels. These decreases occur within 2 to 4 weeks after initiation of treatment.

Histrelin acetate is not active when given orally.

Pharmacokinetics

Following subcutaneous insertion of one VANTAS implant in advanced prostate cancer patients (n = 17), peak serum concentrations of 1.10 ± 0.375 ng/mL (mean ± SD) occurred at a median of 12 hours. Continuous subcutaneous release was evident, as serum levels were sustained throughout the 52 week dosing period (see Figure 1). The mean serum histrelin concentration at the end of the 52 week treatment duration was 0.13 ± 0.065 ng/mL. When histrelin serum concentrations were measured following a second implant inserted after 52 weeks, the observed serum concentrations over 8 weeks following the second implant were comparable to the same period following the first implant. The average rate of subcutaneous drug release from 41 implants assayed for residual drug content was 56.7 ± 7.71 mcg/day, over the 52 week dosing period. The relative bioavailability for the VANTAS implant in prostate cancer patients with normal renal and hepatic function compared to a subcutaneous bolus dose in healthy male volunteers was 92%. Serum histrelin concentrations were proportional to dose after one, two or four 50 mg VANTAS implants (50, 100 or 200 mg as histrelin acetate) in 42 prostate cancer patients.

Figure 1: Mean Serum Histrelin Concentration versus Time Profile for 17 Patients Following Insertion of First and Second VANTAS Implants. (Note that only four patients underwent intensive pharmacokinetic sampling during the first 96 hours following the second implant.)

The apparent volume of distribution of histrelin following a subcutaneous bolus dose (500 mcg) in healthy volunteers was 58.4 ± 7.86 L. The fraction of drug unbound in plasma measured in vitro was 29.5% ± 8.9% (mean ± SD).

An in vitro drug metabolism study using human hepatocytes identified a single histrelin metabolite resulting from C-terminal dealkylation. Peptide fragments resulting from hydrolysis are also likely metabolites. Following a subcutaneous bolus dose in healthy volunteers the apparent clearance of histrelin was 179 ± 37.8 mL/min (mean ± SD) and the terminal half-life was 3.92 ± 1.01 hr (mean ± SD). The apparent clearance following a 50 mg (as histrelin acetate) VANTAS implant in 17 prostate cancer patients was 174 ± 56.5 mL/min (mean ± SD).

No drug excretion study was conducted with VANTAS implants.

Special Populations

Geriatrics: The majority (89.9%) of the 138 patients studied in the pivotal clinical trial were age 65 and over.

Pediatrics: VANTAS is not indicated for use in pediatric patients. [see Use In Specific Populations].

Race: When serum histrelin concentrations were compared for 7 Hispanic, 30 Black and 77 Caucasian patients, average serum histrelin concentrations were similar.

Renal Insufficiency: When average serum histrelin concentrations were compared between 42 prostate cancer patients with mild to severe renal impairment (CLcr: 15-60 mL/min) and 92 patients with no renal or hepatic impairment, levels were approximately 50% higher in those patients with renal impairment (0.392 ng/mL versus 0.264 ng/mL). These changes in exposure as a result of renal impairment are not considered to be clinically relevant. Therefore, no changes in drug dosing are warranted for these patient subpopulations.

Hepatic insufficiency: The influence of hepatic insufficiency on histrelin pharmacokinetics has not been adequately studied.

Drug-Drug Interactions

No pharmacokinetic-based drug-drug interaction studies were conducted with VANTAS.

Clinical Studies

In one open-label, multicenter, Phase 3 study (Study 1), 138 patients with prostate cancer were treated with a single VANTAS implant and were evaluated for at least 60 weeks. Of these, 37 patients had Jewett stage C disease, 29 had stage D disease, and the remaining 72 patients had an elevated or rising serum PSA after definitive therapy for localized disease. Serum testosterone levels were assessed as the primary efficacy endpoint to evaluate both achievement and maintenance of castrate testosterone suppression, with treatment success being defined as a serum testosterone level ≤ 50 ng/dL. At Week 52, the study included the option for removal and insertion of a new implant, with evaluation for an additional 52 weeks (the “extension phase”). A total of 120 patients completed the initial 52-week treatment period. Reasons for discontinuation were: death (n=6), disease progression (n=5), implant expulsion (n=3), hospice placement (n=2), and patient request/no specific reason given (n=2). Of the 120 patients who successfully completed 52 weeks of treatment, 111 were evaluable for efficacy. A total of 113 patients underwent removal of the first implant and insertion of a second implant for another year of therapy.

In a subset of 17 patients, serum testosterone concentrations were measured within the first week following initial implantation. In these 17 patients, mean serum testosterone concentrations increased from 376.4 ng/dL at Baseline to 530.5 ng/dL on Day 2, then decreased to below baseline by Week 2, and to below the 50 ng/dL castrate threshold by Week 4 (see Figure 2). Serum testosterone concentrations remained below the castrate level in this subset for the entire treatment period.

Figure 2: Mean Serum Total Testosterone Concentrations for all PK Patients, n=17. (Note that in this group, sampling began minutes after insertion of VANTAS.)

In the overall treatment group (n=138), mean serum testosterone was 388.3 ng/dL at Baseline. At the time of first assessment of testosterone (at the end of Week 1), the mean serum testosterone concentration was 382.8 ng/dL. At Week 2, mean serum testosterone was 92.2 ng/dL. At Week 4 it was 15 ng/dL. At Week 52, the final mean testosterone concentration was 14.3 ng/dL (see Figure 3).

Figure 3: Mean Serum Total Testosterone Concentrations (+SD) for All Patients (n=138) Who Received One VANTAS Implant. (Note that in this group, sampling began at the end of Week 1.)

Of 138 patients who received an implant, one discontinued prior to Day 28 when the implant was expelled on Day 15. Three others did not have an efficacy measurement for the Day 28 visit. Otherwise serum testosterone was suppressed to below the castrate level ( ≤ 50 ng/dL) in all 134 evaluable patients (100%) on Day 28. All three patients with missing values at Day 28 were castrate by the time of their next visit (Day 56).

Once serum testosterone concentrations at or below castrate level ( ≤ 50 ng/dL) were achieved, a total of 4 patients (3%) demonstrated breakthrough during the study. In one patient, a serum testosterone of 63 ng/dL was reported at Week 44. In another patient, a serum testosterone of 3340 ng/dL was reported at Week 40. This aberrant value was possibly related to lab error. In two patients, serum testosterone rose above castrate level and the implant could neither be palpated nor visualized with ultrasound. In the first patient, serum testosterone was 669 ng/dL at Week 8 and 311 ng/dL at Week 12. This patient reported strenuous exertion after insertion of the implant and a large scab formed at the insertion site. The implant may have been expelled without the patient's appreciation of the event. The other patient developed erythema at the insertion site at Week 22 and was treated with oral antibiotics. At Week 26, the implant was not palpable and was not visualized with ultrasound. At Week 34, the serum testosterone rose to 135 ng/dL. The implant may have been expelled without the patient's appreciation of the event. A new implant was inserted.

Of 120 patients who completed 52 weeks of treatment, a total of 115 patients had a serum testosterone measurement at Week 52. Of these, all had serum testosterone ≤ 50 ng/dL. In patients without a Week 52 value, castrate levels were achieved by Day 28, were maintained up to Week 52, and remained below the castrate threshold after Week 52.

In all 18 patients who prematurely discontinued prior to Week 52 – except one (implant expulsion on Day 15) – castrate levels of serum testosterone were achieved by Day 28 and were maintained up to and including the time of withdrawal.

A total of 113 patients had a new implant inserted for a second year of therapy following removal of the first implant. Of this group, 68 patients had measurement of serum testosterone on Day 2 or Day 3 and on Day 7 after insertion of the second implant in order to assess for the “acute-on-chronic” phenomenon. No acute increase in serum testosterone was seen in any patient in this group following insertion of the new implant.

Serum prostate specific antigen (PSA) was monitored as a secondary endpoint. Serum PSA decreased from baseline in all patients after they began treatment with VANTAS. Serum PSA decreased to within normal limits by Week 24 in 103 of 111 evaluable patients (93%).

Prior to conducting the pivotal study, a Phase 2, dose-ranging study was performed in 42 patients with advanced prostate cancer. Efficacy was assessed by serum testosterone levels as the primary efficacy endpoint. Patients received 1, 2 or 4 implants. The use of 2 or 4 implants did not confer any additional benefit in suppression of testosterone beyond that produced by the single implant.

Since histrelin is given as an implant by a healthcare professional, you will not be on a frequent dosing schedule.

The implant should not be left in your arm for longer than 12 months. Call your doctor when it is time for your implant to be removed.

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 VANTAS was evaluated in 171 patients with prostate cancer treated for up to 36 months in two clinical trials. The pivotal study (Study 1) consisted of 138 patients, while a separate supportive study (Study 2) consisted of 33 patients.

VANTAS, like other GnRH analogs, caused a transient increase in serum testosterone concentrations during the first week of treatment. Therefore, potential exacerbations of signs and symptoms of the disease during the first few weeks of treatment are of concern in patients with vertebral metastases and/or urinary obstruction or hematuria. If these conditions are aggravated, it may lead to neurological problems such as weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms [see WARNINGS AND PRECAUTIONS].

In the first 12 months after initial insertion of the implant(s), an implant extruded through the incision site in eight of 171 patients in the clinical trials (see the Recommended Procedure for correct implant placement).

In the pivotal study (Study 1) a detailed evaluation for implant site reactions was conducted. Out of the 138 patients in the study, 19 patients (13.8%) experienced local or insertion site reactions. All these local site reactions were reported as mild in severity. The majority were associated with initial insertion or removal and insertion of a new implant, and began and resolved within the first two weeks following implant insertion. Reactions persisted in 4 (2.8%) patients. An additional 4 (2.8%) patients developed application-site reactions after the first two weeks following insertion.

Local reactions after implant insertion included bruising (7.2% of patients) and pain/soreness/tenderness (3.6% of patients). Other, less frequently reported, reactions included erythema (2.8% of patients) and swelling (0.7% of patients). In this study, two patients had events described as local infections/inflammations, one that resolved after treatment with oral antibiotics and the other without treatment.

Local reactions following insertion of a subsequent implant were comparable to those seen after initial insertion.

The following possibly or probably related systemic adverse events occurred during clinical trials of up to 24 months of treatment with VANTAS, and were reported in ≥ 2% of patients (Table 1).

Table 1: Incidence (%) of Possibly or Probably Related Systemic Adverse Events Reported by ≥ 2% of Patients Treated with VANTAS for up to 24 Months

Hot flashes were the most common adverse event reported (65.5% of patients). In terms of severity, 2.3% of patients reported severe hot flashes, 25.4% of patients reported moderate hot flashes and 37.7% reported mild hot flashes. In addition, the following possibly or probably related systemic adverse events were reported by < 2% of patients using VANTAS in clinical studies.

• Blood and Lymphatic System Disorders: Anemia
• Cardiac Disorders: Palpitations, ventricular extrasystoles
• Gastrointestinal Disorders: Abdominal discomfort, nausea
• General Disorders: Feeling cold, lethargy, malaise, edema peripheral, pain, pain exacerbated, weakness, weight decreased
• Hepatobiliary Disorders: Hepatic disorder
• Injury, Poisoning and Procedural Complications: Stent occlusion
• Laboratory Investigations: Aspartate aminotransferase increased, blood glucose increased, blood lactate dehydrogenase increased, blood testosterone increased, creatinine clearance decreased, prostatic acid phosphatase increased
• Metabolism and Nutrition Disorders: Appetite increased, fluid retention, food craving, hypercalcaemia, hypercholesterolemia
• Musculoskeletal and Connective Tissue Disorders: Arthralgia, back pain, back pain aggravated, bone pain, muscle twitching, myalgia, neck pain, pain in limb
• Nervous System Disorders: Dizziness, tremor
• Psychiatric Disorders: Depression, irritability
• Renal and Urinary Disorders: Calculus renal, dysuria, hematuria aggravated, renal failure aggravated, urinary frequency, urinary frequency aggravated, urinary retention
• Reproductive System and Breast Disorders: Breast pain, breast tenderness, genital pruritus male, gynecomastia aggravated, sexual dysfunction
• Respiratory, Thoracic and Mediastinal Disorders: Dyspnea exertional
• Skin and Subcutaneous Tissue Disorders: Contusion, hypotrichosis, night sweats, pruritus, sweating increased
• Vascular Disorders: Flushing, hematoma
• Changes in Bone Density: Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with a GnRH agonist analog. It can be anticipated that long periods of medical castration in men will have effects on bone density.

Post-marketing

The following adverse reactions have been identified during post approval use of VANTAS. 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.

Cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed with a majority of pituitary apoplexy cases occurring within 2 weeks of the final dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, opthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.

Severe liver injury has been reported in association with VANTAS. The toxicity was reversible with the removal of the VANTAS implant.

Convulsions

Read the entire FDA prescribing information for Vantas (Histrelin Acetate)