Table of Contents
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 6 DRUG INTERACTIONS 8 DOSAGE AND ADMINISTRATION 9 OVERDOSAGE 14 ACTION AND CLINICAL PHARMACOLOGY 14 STORAGE AND STABILITY 18 SPECIAL HANDLING INSTRUCTIONS 18 DOSAGE FORMS, COMPOSITION AND PACKAGING 18
PHARMACEUTICAL INFORMATION 20 CLINICAL TRIALS 22 DETAILED PHARMACOLOGY 25 TOXICOLOGY 26 REFERENCES 31
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Pr(r)
VANTAS
(histrelin acetate subdermal implant) 50 mg (delivers approximately 50 ug histrelin/day) | ||
|---|---|---|
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Subcutaneous | Subdermal implant 50 mg | For a complete listing see Dosage Forms, Composition and Packaging section. |
VANTAS(r) (histrelin acetate subdermal implant) 50 mg (delivers approximately 50 ug histrelin/day) is indicated for:
the palliative treatment of hormone-dependent advanced prostate cancer (Stage M1 [TNM] or Stage D2 [AUA]).
Geriatrics:
The majority (89.9%) of the 138 patients studied in phase III clinical trials were age 65 and older. (See CLINICAL TRIALS).
Pediatrics:
The safety and efficacy of VANTAS(r) in pediatric patients have not been established (see CONTRAINDICATIONS).
VANTAS(r) (histrelin acetate subdermal implant) 50 mg (delivers approximately 50
ug histrelin/day) is contraindicated in patients who are hypersensitive to gonadotropin releasing hormone (GnRH), GnRH agonist analogues, or to any ingredient in the formulation or component of the subdermal implant. Anaphylactic reactions to synthetic luteinizing hormone-releasing hormone (LHRH) or LHRH agonist analogues have been reported in the literature. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph. VANTAS(r) is contraindicated in pediatric patients. VANTAS(r) is contraindicated in women who are, or may become, pregnant while receiving the drug. VANTAS(r) can cause fetal harm when administered to a pregnant woman. The possibility exists that spontaneous abortion may occur. The use of VANTAS(r) in nursing mothers is not recommended.
General
VANTAS(r) (histrelin acetate subdermal implant) 50 mg (delivers approximately 50 ug histrelin/day), like other LHRH agonists, causes a transient increase in serum concentrations of testosterone during the first week of treatment. During this time, patients may experience worsening of symptoms or onset of new symptoms including bone pain, neuropathy, hematuria, or urethral or bladder outlet obstruction. Cases of urethral obstruction and spinal cord compression, which may contribute to paralysis with or without fatal complications, have been reported with LHRH agonists. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted. Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy.
Implant Insertion/Removal Procedure
Implant insertion is a surgical procedure and it is important that the insertion instructions are followed to avoid potential complications associated with the insertion of the implant and with implant expulsion. The insertion and removal of the implant should be under the supervision of a qualified physician. Detailed instructions on the insertion and removal procedures of the implant are provided in the DOSAGE and ADMINISTRATION section. In addition, patients should be instructed to refrain from wetting the arm for 24 hours and from heavy lifting or strenuous exertion of the inserted arm for 7 days after implant insertion. Infrequently, VANTAS(r) may be expelled from the body through the original incision site, rarely without the patient noticing. The patient should be instructed to monitor the incision site until it is healed. The patient should also return for routine checks of their condition
(r)
and to ensure that VANTAS is present and functioning in his body.
Carcinogenesis and Mutagenesis
Carcinogenicity studies were conducted in rats for 2 years at doses of 5, 25 or 150 ug/kg/day (up to 15 times the human dose) and in mice for 18 months at doses of 20, 200, or 2000 ug/kg/day (up to 200 times the human dose). As seen with other LH-RH agonists, histrelin acetate injection administration was associated with an increase in tumours of hormonally responsive tissues. There was a significant increase in pituitary adenomas in rats. There was an increase in pancreatic islet-cell adenomas in treated female rats and a non-dose-related increase in testicular Leydig-cell tumours (highest incidence in the low- dose group). In mice, there was significant increase in mammary-gland adenocarcinomas in all treated females. In addition, there were increases in stomach papillomas in male rats given high doses, and an increase in histiocytic sarcomas in female mice at the highest dose. Mutagenicity studies have not been performed with histrelin acetate. Saline extracts of implants with and without histrelin were negative in a battery of genotoxicity studies. Fertility studies have been conducted in rats and monkeys given subcutaneous daily doses of histrelin acetate up to 180 ug/kg for 6 months and full reversibility of fertility suppression was demonstrated. The development and reproductive performance of offspring from parents treated with histrelin acetate has not been investigated.
Changes in Bone Mineral Density
In patients with significant risk factors for decreased bone mineral content and/or bone mass such as chronic alcohol and/or tobacco use, presumed or strong family history of osteoporosis or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids, LHRH agonists may pose an additional risk. In these patients, risk versus benefit must be weighed carefully before therapy with VANTAS(r) is instituted.
Hepatic
The influence of hepatic insufficiency on histrelin pharmacokinetics has not been adequately studied.
Renal
Average serum histrelin concentrations were approximately 50% higher in prostate cancer patients with mild to severe renal impairment (CLcr: 15-60 mL/min), compared to those with no renal impairment. 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 patients.
Sexual Function/Reproduction
Fertility was assessed in rats and monkeys after 6 months of daily histrelin administration at doses of up to 180 ug/kg. At the end of dosing, there was atrophy of the genital organs in males and females of both species, the effect was reversible and fertility restored within 6 months of no treatment. (See TOXICOLOGY). The development and reproductive performance of offspring of histrelin-treated animals have not been assessed due to histrelin-induced reduced fertility and adverse events on maintenance of pregnancy.
Special Populations
Pregnant Women: VANTAS(r) is contraindicated in women who are, or may become, pregnant while receiving the drug. VANTAS(r) can cause fetal harm when administered to a pregnant woman. The possibility exists that spontaneous abortion may occur. (See CONTRAINDICATIONS). Animal Data: Major fetal abnormalities were observed in rabbits but not in rats after administration of histrelin acetate throughout gestation. There was dose-related increased fetal mortality in rats treated during organogenesis at 1, 3, 5, or 15 ug/kg/day and in rabbits at 20, 50, or 80 ug/kg/day. (See TOXICOLOGY). Nursing Women: The use of VANTAS(r) in nursing mothers is not recommended. (See CONTRAINDICATIONS). Pediatrics: The safety and efficacy of VANTAS(r) in pediatric patients have not been established. VANTAS(r) is contraindicated in pediatrics.
The majority (89.9%) of the 138 patients studied in phase III clinical trials were age 65 and older. (See
).
When serum histrelin concentrations were compared for 7 Hispanic, 30 Black, and 77 Caucasian patients, average serum histrelin concentrations were similar.
Monitoring and Laboratory Tests
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The response to VANTAS should be monitored periodically by measuring serum concentrations of testosterone and prostate-specific antigen (PSA) especially if the anticipated clinical or biochemical response to the treatment has not been achieved. Results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions. (See DRUG-LABORATORY INTERACTIONS).
Clinical Trial Adverse Drug Reactions
The safety of VANTAS(r) (histrelin acetate subdermal implant) 50 mg (delivers approximately 50 ug histrelin/day) was evaluated in 171 patients with prostate cancer treated for up to 36 months in two clinical trials. The pivotal study (Study 3) consisted of 138 patients, while a separate supportive study (Study 4) consisted of 33 patients. VANTAS(r), like other LHRH analogues, 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 8 of 171 patients in the clinical trials. (See DOSAGE AND ADMINISTRATION, Insertion and Removal Procedures for correct implant placement). In the pivotal study (Study 3) 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. Common local reactions after implant insertion included bruising (7.2%) and pain/soreness/tenderness (3.6%). Other, less frequently reported, reactions included erythema (2.8%) and swelling (0.7%). In this study, two patients had 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.
Common Adverse Events Judged Possibly or Probably Related
The following possibly or probably related systemic adverse events occurred during clinical trials of up to 24 months of treatment with VANTAS(r), 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(r) for up to 24 Months
| Body System | Adverse Event | Number (%) | |
| Vascular Disorders | Hot flashes * | 112 (65.5%) | |
| General Disorders | Fatigue | 17 | (9.9%) |
| Weight increased | 4 | (2.3%) | |
| Skin and Appendage Disorders | Implant site reaction | 10 | (5.8%) |
| Reproductive System and Breast Disorders Erectile dysfunction * | 6 | (3.5%) | |
| Gynecomastia * | 7 | (4.1%) | |
| Testicular atrophy * | 9 | (5.3%) | |
| Psychiatric Disorders | Insomnia | 5 | (2.9%) |
| Libido decreased * | 4 | (2.3%) | |
| Renal and Urinary Disorders | Renal impairment * * | 8 | (4.7%) |
| Gastrointestinal Disorders | Constipation | 6 | (3.5%) |
| Nervous System Disorders | Headache | 5 | (2.9%) |
Expected pharmacological consequences of testosterone suppression.
* * 5 of the 8 patients had a single occurrence of mild renal impairment (defined as creatinine clearance >= 30 to < 60 mL/min), which returned to a normal range by the next visit. 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, 24.5% 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(r) 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 renal clearance decreased, prostatic acid phosphatase increased
Metabolism and Nutrition Disorders
: Appetite increased, fluid retention, hypercalcemia, 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 an LHRH agonist analogue. It can be anticipated that long periods of medical castration in men will have effects on bone density.
Overview
No formal drug interaction studies with VANTAS(r) (histrelin acetate subdermal implant) 50 mg (delivers approximately 50 ug histrelin/ day) were performed. No data is available on the interaction with alcohol.
Drug-Drug Interactions
No drug interaction studies were conducted with VANTAS(r).
Drug-Food Interactions
No food interaction studies were conducted with VANTAS(r).
Drug-Herb Interactions
No herbal interaction studies were conducted with VANTAS(r).
Drug-Laboratory Interactions
Therapy with VANTAS(r) results in suppression of the pituitary-gonadal system. Results of diagnostic tests of pituitary gonadotropic and gonadal functions conducted during and after VANTAS(r) therapy may be affected.
Dosing Considerations
VANTAS(r) (histrelin acetate subdermal implant) 50 mg is designed to provide continuous subcutaneous release of histrelin acetate at a nominal rate of 50-60 micrograms per day over 12 months.
Recommended Dose and Dosage Adjustment
The recommended dose of VANTAS(r) is one implant for 12 months. Each implant contains 50 mg histrelin. The implant is inserted subcutaneously in the inner aspect of the upper arm and provides continuous release of histrelin for 12 months of hormonal therapy. VANTAS(r) must be removed after 12 months of therapy. At the time an implant is removed, another implant may be inserted to continue therapy. (See DOSAGE AND ADMINISTRATION).
Missed Dose
Not applicable.
Administration
VANTAS(r) implant is supplied in a sterile vial within an opaque plastic bag, which in turn is in a carton. The implant should be kept refrigerated (2-8degC) until the day of the procedure. The insertion tool, supplied with the implant, does not require refrigeration. All the supplies necessary to insert and/or remove the implant are readily available. It is important to use aseptic techniques to minimize any chance of infection. Sterile gloves are required for the insertion procedure and subsequent removal of the implant. The implant is inserted using the procedure outlined below:
The patient should be on his back, with the arm least used (e.g., left arm for a right-handed person) flexed so the physician has ready access to the inner aspect of the upper arm. Prop the arm with pillows so the patient can easily hold that position. The optimum site for insertion is approximately half way between the shoulder and the elbow and in the crease between the bicep and triceps.
Load the insertion tool prior to prepping the insertion field and insertion site. Remove the insertion tool from its sterile bag. The tool is shipped with the cannula fully extended. Verify this by inspecting the position of the green retraction button. The button should be all the way forward, towards the cannula, away from the handle. Remove the metal band from the vial, remove the rubber stopper, and use the mosquito clamp to grasp either tip of the implant. Avoid grabbing or clamping the middle of the implant to prevent distortion of the implant. Insert the implant into the cannula of the insertion tool. The implant will rest in the cannula so that just the tip is visible at the bottom of the bevel.
Swab the insertion area with the betadine swabs, then lay the fenestrated drape over the insertion site (for clarity of illustration, the accompanying photos do not show the drape).
Determine that the patient has no lidocaine/epinephrine allergies. Inject a few mL's of the anesthetic, starting at the planned incision site, then infiltrating up to the length of the implant, 32 mm, in a fan-like fashion.
Using the scalpel, make a 2-3 mm incision immediately subcutaneous and perpendicular to the shoulder.
Grasp the insertion tool by its handle, as shown. Insert the tip of the insertion tool into the incision with the bevel up and advance the tool subcutaneously along the path of the anesthetic, up to the inscribed line on the cannula. To ensure subcutaneous placement, the implanter should visibly raise the skin at all times during insertion. Be sure that the implanter doesn't enter the muscle tissue. Hold the insertion tool in place as you move your thumb to the green retraction button. Press the button down to release the locking mechanism, then draw the button back to the back stop, all the while holding the tool in place. The cannula will withdraw from the incision, leaving the implant in the dermis. Withdraw the implanter from the incision. Release of the implant can be checked by palpation. NOTE: Do not try to push the tool in deeper once the retraction process has started to avoid severing the implant. If you wish to re-start the process, withdraw the tool, grasp the implant by the tip to extract it, reset the retraction button to its most forward position, reload the implant, and start again. After placement, sterile gauze may be used to apply pressure briefly to the insertion site to ensure hemostasis.
To close the incision, use one or two sutures (optional), knots facing inside the incision. Apply a light coating of antibiotic ointment directly onto the incision. Close with two surgical strips. Apply one or two of the 10 cm gauze pads over the incision and secure with elastoplast.
Please give the patient the Part III, Consumer Information material. Instruct the patient to refrain from wetting the arm with the implant for 24 hours. The pressure bandage can be removed at that time. The patient should not remove the surgical strips; rather, the strips should be allowed to fall off on their own after several days. Patients should refrain from heavy lifting and strenuous physical activity of the inserted arm for 7 days to allow the incision to fully close.
VANTAS(r) must be removed after 12 months of therapy. The techniques and instruments required are the same as for implantation. Assemble all the necessary implements prior to the procedure.
The implant may be located by palpating the area near the incision from the prior year. Generally, the implant is readily palpated. Press the distal end of the implant to determine the proximal tip's location relative to the old incision. In the event the implant is difficult to locate, ultrasound can be used. If ultrasound fails to locate the implant, other imaging techniques such as CT or MRI may be used to locate it.
Patient position and site preparation are the same as for the initial insertion. Swab the area above and around the implant with the betadine swabs. Drape the area with a fenestrated drape.
After determining the absence of known allergies to the anesthetic agent, press down on the implant tip furthest from the old incision to determine the location of the tip closest to the incision. Inject a small amount of lidocaine/epinephrine at the tip near the incision, then advance the needle along the length, but beneath the implant, steadily injecting a small amount of anesthetic along the way. The anesthetic will raise up the implant within the dermis. If you are inserting a new implant, you have the option of either placing the new one in the same "pocket" as the removed one, or using the same incision, insert the new implant in the opposite direction. If placing the implant in the opposite direction, apply anesthetic along the length of the path for the new implant prior to removal.
Using the #11 scalpel, make a 2-3 mm incision near the tip and about 1-2 mm deep. Generally, the tip of the implant will be visible through a thin pseudo capsule of tissue. If not, push down on the distal tip of the implant and massage it forward towards the incision. Carefully "nick" the pseudo capsule to reveal the polymer tip. Grasp the tip with the mosquito clamp and extract t the implant. Dispose of the implant in a proper manner, treating it like any other bio-waste.
The new implant may be placed through the same incision site. Alternatively, the contralateral arm may be used.
Provide the patient the Part III, Consumer Information material.
There have been no reports of overdose in VANTAS(r) (histrelin acetate subdermal implant) 50 mg (delivers approximately 50 ug histrelin/ day) clinical trials and the adverse event profile was similar in patients receiving one, two or four VANTAS(r) implants. High doses of histrelin acetate injection in animal studies were generally associated only with effects attributed to the expected pharmacology. The method of drug delivery makes accidental or intentional overdosage unlikely.
Mechanism of Action
VANTAS(r) (histrelin acetate subdermal implant) 50 mg (delivers approximately 50 ug histrelin/day), an LHRH agonist, is a potent inhibitor of gonadotropin secretion when given continuously. 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 luteinizing hormone (LH) and follicle-stimulating hormone (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 results in decreased levels of LH and FSH. In males, serum testosterone is reduced to castrate levels within 2 to 4 weeks after initiation of treatment. Histrelin acetate is not active when given orally.
Pharmacodynamics
The relationship between serum testosterone concentration and serum histrelin concentration in 119 prostate cancer patients was characterized by a clockwise hysteresis, indicating an indirect pharmacodynamic relationship. This indirect relationship is consistent with the mechanism of action: following an initial stimulatory phase, chronic subcutaneous administration of histrelin acetate desensitizes responsiveness of the pituitary, which in turn causes reductions in ovarian and testicular steroidogenesis, including production of testosterone.
Pharmacokinetics
The pharmacokinetics of histrelin has been determined in healthy adult male volunteers and adult male patients with advanced prostate cancer. The healthy male volunteers received histrelin acetate in a single 500 ug aqueous solution dose by subcutaneous administration. The prostate cancer patients received either a single or multiple 50 mg histrelin acetate subdermal implant by subcutaneous route. The mean serum histrelin concentrations (measured by radioimmunoassay (RIA)) following the two modes of administration are shown for 52 weeks, in the figure below, and for 1 week (168 hr) in the inset below. When serum histrelin concentrations were measured following a second implant (inserted after 52 weeks) similar concentrations were observed over an 8-week period compared to the initial implant. Serum histrelin concentrations were proportional to dose after one, two or four 50 mg histrelin acetate subdermal implants (50, 100 or 200 mg) in 42 prostate cancer patients.
50 mg Histrelin acetate Implant 500 ug SC bolus
Histrelin Serum Conc (ng/mL)
Histrelin Serum Conc (ng/mL)
0.1
0 24 48 72 96 120 144 168
Time (hr)
0.1
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Time (wk)
Following a 500 ug subcutaneous bolus dose of histrelin acetate, peak serum histrelin concentrations occurred between 0.75 and 2 hr post dosing, with a peak of 13.5 +-
ng/mL (mean +- SD). Peak serum histrelin concentrations were achieved more slowly with the histrelin acetate subdermal implant (median of 12 hr post implant insertion). Peak concentrations averaged 1.10 +- 0.375 ng/mL (mean +- SD). Continuous subcutaneous release was evident throughout the 52-week dosing period, as serum histrelin levels were sustained throughout, in contrast to the rapid decline in serum histrelin concentrations following a subcutaneous bolus dose (see Figure 1 above). The average rate of subcutaneous drug release from 41 histrelin subdermal implants assayed for residual drug content was 56.7 +- 7.71 ug/day over the 52-week dosing period. This compares well to the average in vitro release rate of 56-57 ug/day. A bioavailability of 92% was estimated for the histrelin acetate subdermal implant in prostate cancer patients, with normal renal and hepatic function, relative to a subcutaneous bolus dose in healthy male volunteers.
Distribution: The apparent volume of distribution of histrelin, following a subcutaneous bolus dose, in healthy male volunteers was 58.4 +- 7.86 L. The fraction of drug unbound in plasma measured in vitro was 29.5% +- 8.9% (mean +- SD). Metabolism: An in vitro drug metabolism study using human hepatocytes identified a single 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 of histrelin, following a 50 mg histrelin acetate implant in 17 prostate cancer patients with intensive pharmacokinetic sampling was 174 +- 56.5 mL/min (mean +- SD).
No drug excretion study was conducted with the 50 mg histrelin acetate implant.
Special Populations and Conditions
Pediatrics: The safety and efficacy of VANTAS(r) in pediatric patients have not been established. VANTAS(r) is contraindicated in pediatrics.
The majority (89.9%) of the 138 patients studied in clinical trials were age 65 and over.
Gender: VANTAS(r) is not indicated for females.
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 patients.
The influence of hepatic insufficiency on histrelin pharmacokinetics has not been adequately studied.
No data is available.
Histrelin Subdermal Implant: VANTAS(r) (histrelin acetate subdermal implant) 50 mg (delivers approximately 50 ug histrelin/day) is supplied in a sterile vial, packaged within an opaque plastic bag, which in turn is packaged in a carton. An insertion tool is also provided. Upon receipt of VANTAS(r) and the insertion tool, remove the carton containing the implant and store it under refrigeration (2 to 8degC) until the day of the insertion procedure. Protect from exposure to light. Do not freeze. The insertion tool does not require refrigeration. Keep in a safe place out of reach of children.
During insertion and removal of VANTAS(r) (histrelin acetate subdermal implant) 50 mg (delivers approximately 50 ug histrelin/day), it is important to use aseptic techniques to minimize any chance of infection. Use sterile gloves throughout the procedure.
VANTAS(r) (histrelin acetate subdermal implant) 50 mg (delivers approximately 50 ug histrelin/day) consists of a cylindrically shaped reservoir made of a hydrophilic polymer (hydrogel), containing the peptide within its core. The implant is packaged hydrated in a clear glass vial containing approximately 2.0 mL of 1.8% NaCl solution, so that it is primed for immediate release of the drug upon insertion. The sterile insertion tool (Trocar) is comprised of a multi-piece plastic tool, an 8 gauge bevelled stainless steel cannula, 7.5 cm in exposed length, marked at the 4.9 cm point. Trocar is to be used with VANTAS(r) for single use only.
: Subdermal implant 50 mg
: Sodium chloride solution 1.8% and stearic acid
:
The subdermal implant is placed in a 3.5 mL Type I clear glass vial containing 2 mL of approximately 1.8% sodium chloride solution, closed with a pre-treated grey Teflon coated stopper and sealed with an aluminum crimp seal. The glass vial containing the hydrated implant is supplied in an opaque plastic bag, which in turned is individually packaged in a carton.
The insertion tool is enclosed in a sterile bag and packaged individually in a carton. Supplied as a single box containing one sterile subdermal implant vial and one sterile insertion tool.