Viadur

CLINICAL PHARMACOLOGY

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.

PHARMACOKINETICS

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.

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%.¹

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.¹

A pentapeptide (M-1) is the major leuprolide metabolite upon administration with different leuprolide acetate formulations. No drug metabolism study was conducted with Viadur^®.

Excretion

No drug excretion study was conducted with Viadur^®.

Dose Proportionality

In a study comparing one Viadur^® implant to two Viadur^® implants, mean serum leuprolide concentrations were proportional to dose.

Special Populations

Geriatrics

The majority (88%) of the 131 patients studied in clinical trials were age 65 and over.

Pediatrics

The safety and effectiveness of Viadur^® in pediatric patients have not been established (see CONTRAINDICATIONS).

Race

In the patients studied (80 Caucasian, 23 Black, 3 Hispanic), mean serum leuprolide concentrations were similar.

Renal and Hepatic Insufficiency

The pharmacokinetics of the drug in hepatically and renally impaired patients have not been determined.

Drug-Drug Interactions

No pharmacokinetic drug-drug interaction studies were conducted with Viadur^®.

CLINICAL STUDIES

In two open-label, non-comparative, multicenter studies, 131 patients with prostatic cancer were treated with Viadur^® and evaluated for up to two years. Two-thirds of the patients had stage C or less advanced disease. The dose-ranging study assessed serum testosterone as the primary efficacy endpoint in 51 patients treated with either one [n=27] or two [n=24] implants for 12 months. The confirmatory study evaluated achievement and maintenance of serum testosterone suppression in 80 patients each treated with one implant for 12 months. Both studies included a removal procedure and insertion of a new implant with evaluation for 12 additional months.

Following the initial insertion in patients receiving one implant, mean serum testosterone concentrations increased from 422 ng/dL at baseline to 690 ng/dL on Day 3, then decreased to below baseline by week two (Figure B). Serum testosterone decreased below the 50 ng/dL castrate threshold by week four in all but one patient [106 of 107 patients, 99%]. Once serum testosterone suppression was achieved [one patient was not continuously suppressed until week 28], testosterone remained suppressed below the castrate threshold for the duration of the treatment phase.

Most patients [n=118] had a new implant inserted for a second year of therapy following removal of the first implant(s). No patient experienced a clinically significant increase in serum testosterone [acute-on-chronic phenomenon] upon removal of the original implant(s) and insertion of a new implant. Suppression of serum testosterone was maintained in all patients through the two-month follow-up period following removal of the first implant(s) and insertion of a new implant.

Serum Prostate Specific Antigen (PSA) was monitored as a secondary endpoint in the clinical studies with Viadur^®. Serum PSA decreased in all patients after they began treatment with Viadur^®. At six months, PSA concentrations decreased from baseline by at least 90% in 74.2% of the 97 evaluable patients.

Periodic monitoring of serum testosterone and PSA concentrations is recommended, especially if the anticipated clinical or biochemical response to treatment has not been achieved.

VIADUR INDICATIONS AND USAGE

Viadur^® is indicated in the palliative treatment of advanced prostate cancer.

VIADUR CONTRAINDICATIONS

• Viadur^® is contraindicated in patients with hypersensitivity to GnRH, GnRH agonist analogs, or any of the components in Viadur^®. Anaphylactic reactions to synthetic GnRH or GnRH agonist analogs have been reported in the literature.²
• Viadur^® is contraindicated in women and in pediatric patients and was not studied in women or children. Moreover, leuprolide acetate can cause fetal harm when administered to a pregnant woman. Major fetal abnormalities were observed in rabbits but not in rats after administration of leuprolide acetate throughout gestation. There were increased fetal mortality and decreased fetal weights in rats and rabbits. The effects on fetal mortality are expected consequences of the alterations in hormonal levels brought about by this drug. The possibility exists that spontaneous abortion may occur.

WARNINGS

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 (see PRECAUTIONS).

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.

PRECAUTIONS

General

Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy (see WARNINGS).

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.

Information for Patients

An information leaflet for patients is included with the product.

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.

Drug Interactions

See PHARMACOKINETICS.

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.

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/m², 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/m² (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.

Pregnancy, Teratogenic Effects

Pregnancy Category X (see CONTRAINDICATIONS).

Pediatric Use

Viadur^® is contraindicated in pediatric patients and was not studied in children

(see CONTRAINDICATIONS).

VIADUR ADVERSE REACTIONS

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 (see WARNINGS and PRECAUTIONS).

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 (see INSERTION AND REMOVAL PROCEDURES for correct implant placement).

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

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.

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.

OVERDOSAGE

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.

VIADUR DOSAGE AND ADMINISTRATION

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. (See INSERTION AND REMOVAL PROCEDURES.)

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.

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.

Identifying the Insertion Site

• Have the patient lie on his back on the examination table, with his left arm (if the patient is left-handed, the right arm) flexed at the elbow and externally rotated so that his hand is out to his side.

  Using a pen and ruler, mark a site on the inner, upper arm approximately 8-10 cm above the elbow crease in the groove between the biceps and triceps muscles. Make sure that the site is unaffected by movement of the muscles.

Preparing the Sterile Field

• To establish a sterile field, carefully open the sterile Viadur^® Kit. The sterile kit contains:

  
  

  1 scalpel

  1 forceps

  1 syringe

  1 package 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

  1 mosquito clamp

• The implant tray contains:

  
  

  1 sealed vial, which contains the Viadur^® implant

  1 sterile implanter

  1 sealed container of lidocaine HCl USP 2%, 10 mL

To open the vial, remove the metal band from the bottle and pull up the stopper. Carefully drop the implant from the bottle onto the sterile field. Then, carefully drop the implanter and the container of lidocaine onto the sterile field.