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Histrelin
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1 implant (50 mg of histrelin acetate to deliver 41 mg histrelin) inserted subcutaneously in the upper arm every 12 months; remove the implant after 12 months of therapy. At the time of implant removal, another implant may be inserted to continue therapy. In a multicenter, open-label, phase 3 clinical trial of patients with prostate cancer (n = 138), treatment with a single histrelin implant for at least 52 weeks decreased the mean serum testosterone concentration by approximately 1.4% at the end of week 1, by 76.3% at the end of week 2, by 96.1% at the end of week 4, and by 96.3% at week 52; mean serum testosterone levels were below the 50 ng/dL castrate threshold by the end of week 4. Serum testosterone was suppressed to below the castrate level in all evaluable patients on day 28 (n = 134); all patients who were missing values at day 28 were castrate by the time of their next visit at day 56. In a subset of 17 patients, mean serum testosterone concentrations increased by approximately 40.9% on day 2, and then decreased to below baseline by week 2, and to below the 50 ng/dL castrate threshold by week 4; serum testosterone concentrations remained below the castrate level in this subset for the entire treatment period. Serum prostate specific antigen (PSA), a secondary endpoint, decreased to within normal limits by week 24 in 93% of patients.[30369] A phase 2, dose-finding clinical trial found similar decreases in serum testosterone levels with the use of 1, 2, or 4 histrelin implants for the palliation of advanced prostate cancer; the insertion of more than 1 histrelin implant is not necessary.[30373]
NOTE: Histrelin has been designated an orphan drug by the FDA for this indication.
50 mg subcutaneously every 12 months. The implant provides a continuous release of histrelin 65 mcg/day for 12 months of hormonal therapy. Monitor hormonal and clinical parameters at month 1, every 6 months thereafter, and further as clinically appropriate to ensure adequate suppression. Remove and replace the implant after 12 months to continue therapy; the implant has been designed to continue to release histrelin for a few additional weeks in order to allow flexibility for medical appointments.[33431]
50 mg (1 implant) subcutaneously in the inner aspect of the upper arm every 12 months.[70632] [71198]
For use in pubertal suppression:
For use in previously suppressed individuals or in late pubertal individuals not previously suppressed:
No more than 1 Vantas subcutaneous implant insertion at any one time.
No more than 1 Vantas subcutaneous implant insertion at any one time.
No more than 1 Supprelin LA subcutaneous implant inserted at any one time, although most children with precocious puberty will discontinue histrelin therapy around adolescence.
Children 2 years and older: No more than 1 Supprelin LA subcutaneous implant inserted at any time.
Children younger than 2 years: Safety and efficacy have not been established.
Safety and efficacy have not been established.
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
CrCL 15 mL/min or higher: No dosage adjustments are needed.
CrCL less than 15 mL/min: Specific guidelines are not available; no dosage adjustments are recommended.[30369]
† Off-label indicationHistrelin acetate is a synthetic nonapeptide analog of gonadotropin releasing hormone (GnRH); the implant is a sterile, non-biodegradable, diffusion-controlled hydrogel polymer reservoir. Histrelin functions as a GnRH agonist, and is a potent inhibitor of gonadotropin secretion when given continuously at therapeutic doses. It is FDA approved for the palliative treatment of advanced prostate cancer and for the treatment of central precocious puberty. Initial transient increases of estradiol and/or testosterone may cause a temporary worsening of symptoms. However, testosterone concentrations in men being treated for advanced prostate cancer are reduced to castration levels within 2 to 4 weeks of starting therapy. In pediatric patients, LH levels decrease to prepubertal levels within 1 month of treatment, with a resultant decrease in the serum concentrations of sex steroids (i.e., estrogen or testosterone). Implant insertion is a surgical procedure.[30369][33431]
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
Insertion (Vantas and Supprelin LA):
Removal (Vantas and Supprelin LA):
The most common adverse reaction associated with histrelin therapy in men undergoing treatment for prostate cancer is hot flashes (65.5%). Of those men experiencing hot flashes while receiving histrelin therapy, 2.3% reported severe hot flashes, 25.4% reported moderate hot flashes, and 37.7% reported mild hot flashes. As a result of decreased testosterone, approximately 5.3% of men experience testicular atrophy during histrelin therapy; additional consequences of testosterone suppression reported in patients with advanced prostate cancer included impotence (erectile dysfunction) (3.5%), libido decrease (2.3%), and gynecomastia (4.1%). Flushing, diaphoresis, night sweats, breast pain, breast tenderness, and sexual dysfunction were also each reported in fewer than 2% of patients treated with histrelin (Vantas) in clinical trials.[30369] Gynecomastia and breast tenderness were each reported in one pediatric patient treated with histrelin (Supprelin LA) for central precocious puberty in 2 single-arm clinical trials. Histrelin, like other GnRH agonists, causes a transient increase in serum concentrations of the gonadotropins and the sex steroids (e.g., testosterone in males and females and estrogen in females) during the first few weeks of treatment. Patients may experience worsening of symptoms such as breast enlargement in girls with precocious puberty during this period. In children with central precocious puberty, suppression of gonadal steroids and manifestations of puberty decrease within 4 weeks of histrelin implant insertion.[33431]
Transient increases in serum testosterone causing worsening symptoms or new symptoms, known as tumor flare symptoms, may occur in patients receiving histrelin for the treatment of advanced prostate cancer during the first week of therapy. Symptoms may include bone pain, neuropathy (neuropathic pain), hematuria, or ureteral/bladder obstruction. Cases of spinal cord compression, which may result in paralysis, and ureteral obstruction, which may cause renal impairment, have been reported with GnRH agonists. Mild renal impairment (CrCL 30 to 59 mL/min) occurred in 2.9% of patients with advanced prostate cancer who received histrelin in 2 clinical trials (n = 171), which returned to a normal range by the next visit; 1.8% of patients developed moderate to severe renal impairment. In clinical trials of patients with advanced prostate cancer, decreased creatinine clearance, bone pain, back pain, aggravated back pain, aggravated hematuria, aggravated renal failure (unspecified), increased urinary frequency, urinary retention, and dysuria each were reported in less than 2% of patients who received histrelin.[30369] Transient increases in serum concentrations of estradiol in females and testosterone in both sexes may also occur during the first week of therapy for pediatric patients receiving histrelin for the treatment of central precocious puberty, during which new symptoms or worsening of symptoms may occur; however, within 4 weeks of initiation of therapy, suppression of gonadal steroids occurs and manifestations of puberty decrease.[33431]
Among 47 children with central precocious puberty who received histrelin, 1 patient reported menorrhagia and 1 reported dysmenorrhea; metrorrhagia was reported as possibly related in 2 patients. Histrelin, like other GnRH agonists, causes a transient increase in serum concentrations of the gonadotropins and the sex steroids (e.g., testosterone in males and females and estrogen in females) during the first few weeks of treatment. Patients may experience worsening of symptoms such as light vaginal bleeding in girls with precocious puberty during this period; suppression of gonadal steroids and manifestations of puberty decrease within 4 weeks of histrelin implant insertion.[33431]
Cases of pituitary apoplexy, a syndrome due to a sudden infarction or hemorrhage in the pituitary gland, have been reported after the administration of gonadotropin-releasing hormone (GnRH) agonists, most commonly in elderly males receiving GnRH agonists in the treatment of advanced prostate cancer, although it has been reported when used for other indications as well. 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 a sudden and severe headache, nausea, vomiting, visual changes including reduction in visual field (visual impairment) and ocular paresis, altered mental status, and sometimes cardiovascular collapse. Immediate medical management may be required.[31507] [31508] [30369] One pediatric patient treated with histrelin for central precocious puberty developed a benign pituitary tumor.[33431]
Injection site reaction involving the implant site (e.g., ecchymosis, erythema, pain, implant area protrusion, itching, soreness, swelling, and tingling) was the most commonly reported adverse reaction (51.1%) in 2 single-arm clinical trials of pediatric patients with central precocious puberty treated with histrelin (n = 47). In these trials, the following additional implant site reactions were reported separately: keloid scar (6.4%), scar (6.4%), suture-related complication (6.4%), application site pain (4.3%), and post-procedural pain (4.3%); wound infection, erythema, and pruritus were each reported in 1 patient.[33431] In a detailed evaluation for implant site reactions (n = 138), 13.8% of men with advanced prostate cancer experienced mild local or insertion site reactions including bruising (7.2%), pain/soreness/tenderness (3.6%), erythema (2.8%), and swelling (0.7%), mostly associated with initial insertion or removal and insertion of a new implant. The majority of these reactions began and resolved within the first 2 weeks following implant insertion, but persisted in 2.8% of patients; an additional 2.8% of patients developed application-site reactions after the first 2 weeks. Two patients had local infections/inflammations; one resolved after treatment with antibiotics and the other resolved without treatment. The incidence of local reactions after insertion of subsequent implants was comparable to those seen after initial insertion. In 2 clinical trials of patients with advanced prostate cancer (n = 171), implant site reaction occurred in 5.8%, while generalized pruritus, male genital pruritus, contusion, hypertrichosis, and hematoma were each reported in less than 2% of patients. In all clinical trials combined, an implant was not recovered in 8 patients. For 2 of these patients with advanced prostate cancer, serum testosterone rose above castrate level and the implant was neither palpable nor visualized with ultrasound; they were believed to have been extruded without the patient being aware. In the other 6 patients, serum testosterone remained below castrate level, but the implant was not palpable and no further diagnostic tests were conducted; one patient underwent an in-clinic surgical exploration that did not locate the implant.[30369] Rare events of spontaneous extrusion have also been observed in pediatric patients, and implant breakage was reported in postmarketing experience with pediatric patients. If the implant is not retrieved completely, the remaining pieces should be removed following the manufacturer's instructions.[33431]
Anaphylactoid reactions to synthetic GnRH or GnRH agonist analogs have been reported in the literature and are theoretically possible with the use of histrelin regardless of indication.[30370] [30371]
Long periods of medical castration in men will have effects on bone density such as osteoporosis. 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 such as histrelin.[30369] GnRH analog therapy can reduce bone mineral density in men as well as women. Reduced bone mineral density and osteopenia are also a concern if GnRH or LH-RH analogs are used in adolescent children. LH-RH analogs (aka GnRH analogs) have been used alone or added to growth hormone (rh-GH) therapy to moderately increase adult height in adolescents with normally timed puberty and idiopathic short status; the LH-RH analogs delay puberty and thus prolong the period of bone growth via delay of sex hormone-induced growth-plate senescence. In one study, the use of LH-RH agonist for 4 years, the typical duration needed to see an increase in adult height, was found to decrease bone mineral density in the lumbosacral region to more than 1 standard deviation below the population mean in 82% of adolescent patients receiving the LH-RH agonist. The authors concluded that LH-RH agonist therapy cannot be routinely recommended to augment height in short adolescents with normally timed puberty; for most adolescents the potential benefit of treatment would not outweigh the risks.[27524]
Emotional lability (e.g., crying, irritability, impatience, anger, and aggression) has been observed in postmarketing experience with patients treated with GnRH agonists, including histrelin. Depression, including rare reports of suicidal ideation and attempt, have also been reported with GnRH agonists, including histrelin, in children treated for central precocious puberty. Mood swings were also reported in 1 pediatric patient treated with histrelin for central precocious puberty. Many, but not all, of these patients had a history of psychiatric illness or other comorbidities with an increased risk of depression.[33431] [30369] In patients with advanced prostate cancer, insomnia occurred in 2.9% of patients in 2 clinical trials, while depression and irritability were each reported in less than 2%. Monitor for the development or worsening of psychiatric symptoms during treatment with histrelin.[30369]
In men, an increased risk of myocardial infarction, sudden cardiac death, and stroke has been reported in association with the use of GnRH analogs, although the risk appears low based on the reported odds ratios. Carefully evaluate cardiovascular risk factors and weigh the known benefits and risks of GnRH agonists such as histrelin when determining appropriate treatment for prostate cancer. Androgen deprivation therapy may also cause QT prolongation. In clinical trials, hypercholesterolemia, palpitations, ventricular extrasystoles, stent occlusion, exertional dyspnea, and peripheral edema/fluid retention were noted in less than 2% of patients treated with histrelin.[30369] The FDA evaluated data from published studies comparing outcomes in patients undergoing androgen deprivation therapy to treat prostate cancer versus patients not undergoing this treatment; most of the studies reported small, but statistically significant, increased risks of cardiovascular events in men receiving GnRH agonists. At this time, there are no known comparable studies evaluating the risk of cardiovascular disease in women or children taking GnRH agonists for other indications.[40127] [42122]
In clinical trials of men with advanced prostate cancer treated with histrelin, less than 2% of patients had a hepatic disorder or elevated hepatic enzymes (e.g., increased aspartate aminotransferase). During the postmarketing period, severe liver injury was reported in association with histrelin; the toxicity was reversible with the removal of the histrelin implant.[30369]
In men, hyperglycemia and an increased risk of developing diabetes mellitus have been reported in association with the use of GnRH analogs such as histrelin. In clinical trials of patients with advanced prostate cancer treated with histrelin, increased blood glucose was noted in less than 2% of patients.[30369] The FDA evaluated data from published studies comparing outcomes in patients undergoing androgen deprivation therapy to treat prostate cancer versus patients not undergoing this treatment; most of the studies reported small, but statistically significant, increased risks of diabetes in men receiving GnRH agonists. At this time, there are no known comparable studies evaluating the risk of diabetes in women or children taking GnRH agonists for other indications.[40127] [42122] Periodically monitor patients' blood glucose concentration and/or glycosylated hemoglobin; hyperglycemia may represent diabetes mellitus development or worsening of glycemic control in patients with the condition.[30369]
In 2 clinical trials of patients with advanced prostate cancer treated with histrelin, the following gastrointestinal adverse reactions were reported: constipation (3.5%), weight gain (2.3%), weight loss (less than 2%), abdominal pain (less than 2%), nausea (less than 2%), appetite stimulation (less than 2%), and food craving (less than 2%).[30369] Weight gain occurred in 1 pediatric patient treated with histrelin for central precocious puberty (n = 47).[33431]
One pediatric patient with Stargardt's Disease who received histrelin for the treatment of central precocious puberty experienced amblyopia.[33431]
Seizures have been reported in postmarketing experience with histrelin in patients with a history of epilepsy, cerebrovascular disorders, CNS anomalies or tumors, and in patients on concomitant mediations that have been associated with seizures; seizures have also been reported in patients without any risk factors.[33431] [30369] Pseudotumor cerebri (idiopathic intracranial hypertension) has been reported in pediatric patients during postmarketing experience.[33431] Dizziness, muscle twitching, and tremor were each reported in less than 2% of patients with advanced prostate cancer treated with histrelin in 2 clinical trials (n = 171).[30369]
An influenza-like illness possibly related to histrelin therapy was reported in one pediatric patient being treated for central precocious puberty in 2 single-arm clinical trials (n = 47).[33431]
Fatigue (9.9%) and headache (2.9%) were reported in 2 clinical trials of patients with advanced prostate cancer treated with histrelin (n = 171); additionally, arthralgia, feeling cold, lethargy, limb pain, malaise, myalgia, neck pain, generalized pain, renal calculus, and weakness were each reported in less than 2% of patients in these trials.[30369] In 2 single-arm trials of pediatric patients receiving histrelin for central precocious puberty (n = 47), headache, migraine, and feeling cold were each reported by 1 patient.[33431]
Epistaxis that was possibly related to histrelin therapy was reported in 1 pediatric patient being treated for central precocious puberty in 2 single-arm clinical trials (n = 47).[33431]
Anemia, hypercalcemia, increased blood lactate dehydrogenase, increased blood testosterone, and increased prostatic acid phosphatase were each reported in less than 2% of patients treated with histrelin in 2 clinical trials of patients with advanced prostate cancer (n = 171).[30369]
Histrelin is contraindicated in patients with hypersensitivity to histrelin, Gonadotropin-Releasing Hormone (GnRH), or with Gonadotropin-Releasing Hormone (GnRH) analogs hypersensitivity.[30370] [30371] [33431] [30369]
Due to transient increases in testosterone levels, histrelin (Vantas) may cause a sudden onset or worsening of prostate cancer (flare), such as bone pain, neuropathy, hematuria, or urinary tract obstruction or bladder obstruction. Patients with prostate cancer and urinary tract obstruction or metastatic vertebral lesions should be monitored carefully for signs of renal impairment or spinal cord compression, respectively, during initial histrelin treatment.[30369]
Therapy with histrelin results in suppression of the pituitary-gonadal system. Results of diagnostic tests for pituitary insufficiency and gonadotropic and gonadal functions conducted during and after histrelin therapy may be affected.
Histrelin should be used with caution in patients with pre-existing osteoporosis. GnRH analog therapy can reduce bone mineral density.[30369] Reduced bone mineral density and osteopenia are also a concern if GnRH or LH-RH analogs are used in adolescent children.[27524]
The use of GnRH analogs in men has been reported in association with hyperglycemia and an increased risk of developing diabetes mellitus. Carefully weigh the known benefits and risks of GnRH agonists such as histrelin when determining appropriate treatment for prostate cancer. Periodically monitor patients' blood glucose concentration and/or glycosylated hemoglobin; hyperglycemia may represent diabetes mellitus development or worsening of glycemic control in patients with the condition. Manage patients according to current clinical practice. There are no known comparable studies evaluating the risk of diabetes in women, children, or adolescents taking GnRH agonists for other indications.[30369] [40127] [42122]
Use histrelin with caution in patients with depression and emotional instability; monitor patients for worsening of psychiatric symptoms during treatment with histrelin. During postmarketing experience, emotional lability, such as crying, irritability, impatience, anger, and aggression were reported. Depression, including rare reports of suicidal ideation and attempt, were reported in children treated for central precocious puberty. Many, but not all, of these patients had a history of psychiatric illness or other comorbidities with an increased risk of depression.[33431]
Use histrelin with caution in patients with a preexisting seizure disorder. Seizures have been reported during postmarketing surveillance in patients with a history of epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and patients on concomitant medications that have been associated with seizures. Seizures have also been reported in patients without any risk factors.[33431]
The use of GnRH analogs in men has been reported in association with an increased risk of myocardial infarction, sudden cardiac death, and stroke although the risk appears to be low based on the reported odds ratios. Additionally, myocardial infarction and stroke may increase the risk of histrelin prolonging the QT interval. Carefully evaluate risk factors for cardiac disease and weigh the known benefits and risks of GnRH agonists such as histrelin when determining appropriate treatment for prostate cancer. Monitor patients for signs and symptoms suggestive of the development of cardiovascular disease and manage according to current clinical practice. There are no known comparable studies evaluating the risk of cardiovascular disease in women, children, or adolescents taking GnRH agonists for other indications.[28432] [28457] [30369] [40127] [42122] [56592] [65180]
Androgen deprivation therapy may prolong the QT/QTc interval. Use histrelin with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalance. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.[28432] [28457] [56592] [30369] [65180]
Therapy with histrelin results in suppression of the pituitary-gonadal system. Laboratory test interference may occur during and after histrelin therapy; specifically diagnostic tests of pituitary gonadotropic and gonadal functions.[30369]
Based on findings in animals and its mechanism of action, histrelin may cause infertility in males of reproductive potential.[30369]
Histrelin for precocious puberty (Supprelin LA) is contraindicated for use during pregnancy. The safety and efficacy of histraline for prostate cancer (Vantas) have not been established in females. Although there are no adequately controlled studies in pregnancy, histrelin can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Expected hormonal changes that occur with histrelin treatment increase the risk for pregnancy loss. Advise pregnant persons and females of reproductive potential of the risk to the fetus with Vantas use. Increased fetal mortality and post-implantation loss occurred when histrelin was administered to pregnant rats during organogenesis at exposures amounting to 0.2 to 3 times the human exposure based on body surface area. These doses also reduced maternal weight gain, stimulated ovarian follicular development, increased placental weight, and caused abnormal morphology and an increase in fetal size. In pregnant rabbits, administration of histrelin during organogenesis resulted in increased fetal mortality and abortion/early termination at the 2 highest doses and caused total litter loss at all doses (exposures of approximately 8 to 31 times human exposure at the recommended dose based on body surface area). Females may also be at increased risk for histrelin prolonging the QT interval.[28432] [28457] [30369] [33431] [56592] [65180]
Use histrelin with caution in breast-feeding patients. No data are available on the presence of histrelin in human milk; however, transfer into milk is unlikely due to its large molecular weight and structure.[70365] [30369]
Gonadotropin releasing hormone (GnRH) agonists, such as histrelin, have been associated with cases of pseudotumor cerebri (idiopathic intracranial hypertension) in pediatric patients. Monitor patients for signs and symptoms including headache, papilledema, blurred vision, diplopia, loss of vision, pain behind the eye or pain with eye movement, tinnitus, dizziness, and nausea.[33431]
Histrelin acetate is a gonadotropin releasing hormone (GnRH) agonist that is a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses. Following an initial stimulatory phase, the chronic, subcutaneous administration of histrelin acetate desensitizes responsiveness of the pituitary gonadotropin, which causes a reduction in testicular steroidogenesis. In humans, there is an initial increase in circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn transiently increases the production of gonadal steroids (e.g., estradiol and estrone in premenopausal females, and testosterone and dihydrotestosterone in males). However, with sustained administration, histrelin causes a reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropins, resulting in decreased levels of LH and FSH.[30369][33431]
Central Precocious Puberty: Long-term treatment with histrelin suppresses the LH response to GnRH, causing LH levels to decease to prepubertal levels within 1 month of treatment. As a result, serum concentrations of sex steroids (i.e., estrogen or testosterone) also decrease, ceasing progression of secondary sexual development in most patients. Additionally, linear growth velocity is slowed, which improves the chance of attaining predicted adult height.[33431]
Advanced Prostate Cancer: Testosterone is reduced to castration levels within 2 to 4 weeks after initiation of treatment.[30369]
Revision Date: 12/03/2024, 02:22:00 AMHistrelin is administered by a subcutaneous insertion of an implant containing histrelin acetate. The apparent volume of distribution (Vd) of histrelin following a subcutaneous bolus dose (500 mg) in healthy volunteers was 58.3 +/- 7.86 liters. In vitro, the mean fraction of unbound drug in plasma was 29.5% +/- 8.9%. Histrelin was metabolized by C-terminal dealkylation, resulting in one metabolite, in an in vitro drug metabolism study using human hepatocytes; peptide fragments resulting from hydrolysis are also likely metabolites. Following a subcutaneous bolus dose in healthy volunteers, the mean apparent clearance was 179 +/- 37.8 mL/min, and the mean terminal half-life was 3.92 +/- 1.01 hours. The mean apparent clearance following a 50 mg histrelin acetate implant in patients with prostate cancer (n = 17) was 174 +/- 56.5 mL/min. Drug excretion studies were not conducted with histrelin implants.[30369]
Affected cytochrome P450 isoenzymes: None
No pharmacokinetic-based drug interaction studies were conducted with histrelin implants.[30369][33431]
Histrelin acetate is not active when given orally.[30369]
Mean peak serum concentrations of histrelin were 1.1 +/- 0.375 ng/mL following subcutaneous insertion of one histrelin 50 mg implant in patients with advanced prostate cancer (n = 17), occurring at a median of 12 hours. Continuous subcutaneous release was evident, as serum levels were sustained throughout the 52-week dosing period; the mean serum histrelin concentration at the end of 52 weeks was 0.13 +/- 0.065 ng/mL. Observed serum concentrations over 8 weeks following insertion of a second implant after 52 weeks 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. The relative bioavailability for the histrelin 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 in prostate cancer patients were proportional to dose after insertion of 1, 2, 3, or 4 histrelin implants (n = 42).[30369]
The influence of hepatic insufficiency on histrelin pharmacokinetics and dosing has not been adequately studied.[30369]
Serum histrelin concentrations were approximately 50% higher in prostate cancer patients with mild to severe renal impairment (n = 42; CrCL, 15 to 60 mL/min) compared to patients with no renal impairment (n = 92) (0.392 ng/mL vs. 0.264 ng/mL); these changes in exposure are not considered clinically relevant.[30369]
The median maximum histrelin serum concentration was 0.43 ng/mL in a pharmacokinetic evaluation of pediatric patients receiving histrelin therapy for the treatment of central precocious puberty (n = 47); this concentration is expected to maintain gonadotropins at prepubertal levels. Median serum histrelin concentrations remained above the limit of quantification for the treatment period; histrelin acetate levels were sustained throughout the study period for most subjects. There was no apparent difference between subjects naive to a LHRH agonist treatment and subjects previously treated with a LHRH agonist.[33431]
Average serum histrelin concentrations were similar when compared for hispanic (n = 7), black (n = 30), and caucasian (n = 77) patients.[30369]
Histrelin for precocious puberty (Supprelin LA) is contraindicated for use during pregnancy. The safety and efficacy of histraline for prostate cancer (Vantas) have not been established in females. Although there are no adequately controlled studies in pregnancy, histrelin can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Expected hormonal changes that occur with histrelin treatment increase the risk for pregnancy loss. Advise pregnant persons and females of reproductive potential of the risk to the fetus with Vantas use. Increased fetal mortality and post-implantation loss occurred when histrelin was administered to pregnant rats during organogenesis at exposures amounting to 0.2 to 3 times the human exposure based on body surface area. These doses also reduced maternal weight gain, stimulated ovarian follicular development, increased placental weight, and caused abnormal morphology and an increase in fetal size. In pregnant rabbits, administration of histrelin during organogenesis resulted in increased fetal mortality and abortion/early termination at the 2 highest doses and caused total litter loss at all doses (exposures of approximately 8 to 31 times human exposure at the recommended dose based on body surface area). Females may also be at increased risk for histrelin prolonging the QT interval.[28432] [28457] [30369] [33431] [56592] [65180]
Use histrelin with caution in breast-feeding patients. No data are available on the presence of histrelin in human milk; however, transfer into milk is unlikely due to its large molecular weight and structure.[70365] [30369]
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