The recommended dose of Viadur is one implant for 12 months. Each implant contains 65 mg leuprolide. The implant is inserted subcutaneously in the inner aspect of the upper arm and provides continuous release of leuprolide for 12 months of hormonal therapy. Viadur must be removed after 12 months of therapy. At the time an implant is removed, another implant may be inserted to continue therapy.<br/>Insertion and Removal Procedures: Viadur is supplied in a box containing one sterile Viadur implant in a sealed vial, one Viadur sterile implanter, one sealed container of lidocaine HCl USP 2%, 10 mL, and one sterile Viadur Kit. The Viadur Kit is designed to provide a sterile field and supplies to facilitate the insertion and/or subsequent removal of the implant. In addition to the Viadur Kit, sterile gloves are required for the insertion procedure and subsequent removal of the implant.<br/>Insertion Procedure: Under aseptic conditions, an implanter is used to place the implant under the skin. The implant is inserted using the procedure outlined below.<br/>Removal Procedure: Viadur must be removed following 12 months of therapy. The position of the patient and the sterile technique are the same as for insertion. To remove Viadur use the Viadur Kit or the following sterile items:
Viadur (leuprolide acetate implant) is a sterile nonbiodegradable, osmotically driven miniaturized implant designed to deliver leuprolide acetate for 12 months at a controlled rate (Figure A). Viadur incorporates DUROS technology. The system contains 65 mg of leuprolide (free base). Leuprolide acetate is asynthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The implant is inserted subcutaneously in the inner aspect of the upper arm. After 12 months, the implant must be removed. At the time an implant is removed, another implant may be inserted to continue therapy. Viadur contains 72 mg of leuprolide acetate (equivalent to 65 mg leuprolide free base) dissolved in 104 mg dimethyl sulfoxide. The 4 mm by 45 mm titanium alloy reservoir houses a polyurethane rate-controlling membrane, an elastomeric piston, and a polyethylene diffusion moderator. The reservoir also contains the osmotic tablets, which are not released with the drug formulation. The osmotic tablets are composed of sodium chloride, sodium carboxymethyl cellulose, povidone, magnesium stearate, and sterile water for injection. Polyethylene glycol fills the space between the osmotic tablets and the reservoir. A minute amount of silicone medical fluid is used during manufacture as a lubricant. The weight of the implant is approximately 1.1g. The chemical name is 5-Oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt), with the following structural formula:
Leuprolide acetate, an LH-RH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Animal and human studies indicate that after an initial stimulation, chronic administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. In humans, administration of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to a transient increase in concentrations of gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of leuprolide acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to castrate levels. These decreases occur within 2 to 4 weeks after initiation of treatment. One Viadur Implant nominally delivers 120 micrograms of leuprolide acetate per day over 12 months. Leuprolide acetate is not active when given orally.<br/>PHARMACOKINETICS:<br/>Absorption: After insertion of Viadur, mean serum leuprolide concentrations were 16.9 ng/mL at 4 hours and 2.4 ng/mL at 24 hours. Thereafter, leuprolide was released at a constant rate. Mean serum leuprolide concentrations were maintained at 0.9 ng/mL (0.3 to 3.1 ng/mL; SD =��0.4) for 12 months. Upon removal and insertion of a new Viadur at 12 months, steady-state serum leuprolide concentrations were maintained.<br/>Distribution: The mean steady-state volume of distribution of leuprolide following 1 mg intravenous (IV) bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%.<br/>Metabolism: In healthy male volunteers administered a 1 mg IV bolus of leuprolide, the mean systemic clearance was 8.34 L/h, with a terminal elimination half-life of approximately 3 hours, based on a two-compartment model. A pentapeptide (M-1) is the major leuprolide metabolite upon administration with different leuprolide acetate formulations. No drug metabolism study was conducted with Viadur.<br/>Excretion: No drug excretion study was conducted with Viadur.<br/>Dose Proportionality: In a study comparing one Viadur implant to two Viadur implants, mean serum leuprolide concentrations were proportional to dose.<br/>Special Populations:
Viadur is supplied in a box containing 2 inner package trays. One tray contains a sterile Viadur implant in a sealed vial, a sterile Viadur implanter and a sealed container of lidocaine HCl USP 2%, 10 mL. The other tray constitutes a sterile Viadur Kit, which includes: 1 scalpel, 1 forceps, 1 syringe, povidone-iodine swabs, 1 package wound closure strips, 1-22 Ga x 1.5���needle, 1-25 Ga x 1.5���needle, 6 gauze sponges, 2 alcohol prep swabs, 1 package skin protectant, 1 bandage, 1 fenestrated drape, 1 marking pen, 1 ruler, and 1 mosquito clamp. A physician insert, patient information, and insertion and removal instructions are also provided in the box. (NDC 0026-9711-01) Rx Only Store at 25��C (77��F); excursions permitted to 15-30��C (59-86��F). [see USP Controlled Room Temperature] For more information call 1-800-288-8371 or visit www.VIADUR.com.
General: Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy . X-rays do not affect Viadur functionality. Viadur is radio-opaque and is well visualized on X-rays. The titanium alloy reservoir of Viadur is nonferromagnetic and is not affected by magnetic resonance imaging (MRI). Slight image distortion around Viadur may occur during MRI procedures.<br/>Information for Patients: An information leaflet for patients is included with the product.<br/>Laboratory tests: Response to Viadur should be monitored by measuring serum concentrations of testosterone and prostate-specific antigen periodically. 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.<br/>Drug Interactions: See PHARMACOKINETICS.<br/>Drug/Laboratory Test Interactions: Therapy with leuprolide results in suppression of the pituitary-gonadal system. Results of diagnostic tests of pituitary gonadotropic and gonadal functions conducted during and after leuprolide therapy may be affected.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Two-year carcinogenicity studies were conducted in rats and mice. In rats, dose-related increases of benign pituitary hyperplasia and benign pituitary adenomas were noted at 24 months when the drug was administered subcutaneously at high daily doses (4 to 24 mg/m, 50 to 300 times the daily human exposure based on body surface area). There were significant but not dose-related increases of pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice no pituitary abnormalities were observed at up to 180 mg/m(over 2000 times the daily human exposure based on body surface area) for 2 years. Mutagenicity studies were performed with leuprolide acetate using bacterial and mammalian systems. These studies provided no evidence of a mutagenic potential.<br/>Pregnancy, Teratogenic Effects: Pregnancy Category X .<br/>Pediatric Use: Viadur is contraindicated in pediatric patients and was not studied in children .
In clinical trials using daily subcutaneous leuprolide acetate in patients with prostate cancer, doses as high as 20 mg/day for up to 2 years caused no adverse effects differing from those observed with the 1 mg/day dose. The adverse event profiles were similar in patients receiving one or two Viadur implants.
The safety of Viadur was evaluated in 131 patients with prostate cancer treated for up to 24 months in two clinical trials. Viadur, like other LHRH analogs, caused a transient increase in serum testosterone concentrations during the first 2 weeks 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 . In the above-described clinical trials, the transient increase in serum testosterone concentrations was associated with an exacerbation of disease symptoms, manifested by pain or bladder outlet obstructive symptoms (urinary retention or frequency) in 6 (4.6%) patients. The majority of local reactions associated with initial insertion or removal and insertion of a new implant began and resolved within the first two weeks. Reactions persisted in 9.3% of patients. 10.3% of patients developed application-site reactions after the first two weeks following insertion. Local reactions after initial insertion of a single implant included bruising (34.6%) and burning (5.6%). Other, less frequently reported, reactions included pulling, pressure, itching, erythema, pain, edema, and bleeding. In these two clinical trials, four patients had local infection/inflammations that resolved after treatment with oral antibiotics. Local reactions following insertion of a subsequent implant were comparable to those seen after initial insertion. In the first 12 months after initial insertion of the implant(s), an implant extruded through the incision site in three of 131 patients . The following possibly or probably related systemic adverse events occurred during clinical trials within 24 months of treatment with Viadur, and were reported in���2% of patients (Table 1). In addition, the following possibly or probably related systemic adverse events were reported by<2% of patients using Viadur in clinical studies. General: General pain, chills, abdominal pain, malaise, dry mucous membranes Gastrointestinal: Constipation, nausea Hematologic: Iron deficiency anemia Metabolic: Edema, weight loss Musculoskeletal: Bone pain, arthritis Nervous: Dizziness, insomnia, paresthesia, amnesia, anxiety Skin: Pruritus, rash, hirsutism Urogenital: Urinary urgency, prostatic disorder, urinary tract infection, dysuria, urinary incontinence, urinary retention<br/>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 LH-RH agonist analog. In a clinical trial, 25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate for at least 6 months, underwent bone density studies as a result of pain. The leuprolide-treated group had lower bone density scores than the nontreated control group. It can be anticipated that long periods of medical castration in men will have effects on bone density.<br/>Postmarketing: Pituitary apoplexy: During post-marketing surveillance, rare 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 first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. Ninety-seven of the 131 patients in the two-year duration studies that supported approval of Viadur continued in an open-label, third-year extension study. One patient prematurely withdrew due to lack of efficacy that was attributed to a defective implant. Fifty of these patients continued in an open-label, fourth-year extension study.No spontaneous implant extrusions were reported in these extension studies. Since Viadur has been commercially available,<1% of patients implanted have been reported to have a spontaneous implant extrusion (with or without associated infection). Additional adverse events have been reported from US post-marketing experience with Viadur. Because these events 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. These events have been reported infrequently and include fatigue, hypertension, migration of implant, syncope, tremor, and vomiting.
Viadur, like other LH-RH agonists, causes a transient increase in serum concentrations of testosterone during the first week of treatment. Patients may experience worsening of symptoms or onset of new symptoms, including bone pain, neuropathy, hematuria, or ureteral or bladder outlet obstruction . Cases of ureteral obstruction and spinal cord compression, which may contribute to paralysis with or without fatal complications, have been reported with LH-RH agonists. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted.
Viadur is indicated in the palliative treatment of advanced prostate cancer.