Jane S. Ricciuti, RPh, MS


November 29, 2004

In This Article


(lutropin alfa) Subcutaneous Injection

Manufacturer: Serono

Drug Approval Classification: Original New Drug Application (Approval Date: 10/8/04)

Indication: Luveris (lutropin alfa) is indicated for concomitant use with Gonal-f (follitropin alfa) for stimulation of follicular development in infertile hypogonadotropic hypogonadal women with profound luteinizing hormone (LH) deficiency (LH < 1.2 IU/L). A definitive effect on pregnancy in this population has not been demonstrated. The safety and effectiveness of concomitant administration of lutropin alfa with any other preparation of recombinant human follicle-stimulating hormone (FSH) or urinary human FSH are unknown.

Dosing: It is recommended that 75 IU lutropin alfa be concomitantly administered subcutaneously with 75 IU to 150 IU follitropin alfa as 2 separate injections in the initial treatment cycle. Treatment duration should not normally exceed 14 days unless signs of imminent follicular development are present. To complete follicular development and effect ovulation in the absence of an endogenous LH surge, human chorionic gonadotropin (hCG) should be given 1 day after the last dose of lutropin alfa and follitropin alfa. Treatment with hCG should be withheld if the ovaries are abnormally enlarged or if excessive estradiol production has occurred.

Clinical Summary: Lutropin alfa is a lyophilized powder composed of recombinant human luteinizing hormone, r-hLH. Lutropin alfa exhibits biological activity comparable to that of human pituitary LH. In the ovaries, during the follicular phase, LH stimulates theca cells to secrete androgens, which will be used to produce estradiol, supporting FSH-induced follicular development. Lutropin alfa administered with follitropin alfa are used to stimulate development of a potentially competent follicle and to indirectly prepare the reproductive tract for implantation and pregnancy.

Clinical Studies: Three pivotal trials are described for the use of lutropin alfa to demonstrate efficacy in the stimulation of follicular development. The first study was a randomized, open-label, dose-finding study conducted in 38 women in Europe and Israel, to evaluate lutropin alfa at doses of 0, 25, 75, or 225 IU. The primary endpoint was a composite endpoint for follicular development. Patients who were administered 75 IU of lutropin alfa had a 64% rate of follicular development success compared with 45% that were classified as failures. Patients who were administered 225 IUs saw a success rate of 70% vs a 40% failure rate.

The second study (Study 21008) was a double-blind, placebo-controlled, randomized, multinational, single-cycle study conducted in the United States, Canada, Israel, and Australia to assess the safety and efficacy of 75 IU lutropin alfa administered subcutaneously. Thirty-nine patients were randomized and treated in a 2:1 ratio to concomitant treatment with 75 IU lutropin alfa and 150 IU follitropin alfa (26 patients) or placebo and 150 IU follitropin alfa (13 patients). The efficacy endpoint for this study was a composite endpoint for follicular development. Success was seen in 65% of patients on the lutropin/follitropin arm compared with 15% in the placebo/follitropin arm.

The third clinical trial was an open-label, multicenter extension of Study 21008 to allow patients to continue treatment with 75 IU lutropin alfa. Thirty-one of the 39 patients from Study 21008 were treated for up to 3 cycles in the extension trial. Of the 31 patients, 27 (87.1%) achieved follicular development, 20 (64.5%) achieved pregnancy (ie, positive pregnancy test, serum hCG ≥ 10 mIU/mL), and 16 (51.6%) achieved clinical pregnancy. Of the 11 placebo patients from Study 21008, 7 (63.6%) achieved follicular development and 4 (36.4%) achieved clinical pregnancy when treated with 75 IU lutropin alfa and follitropin alfa.

Adverse Effects: The most commonly reported adverse events in clinical trials were headache (10.2%), nausea (6.8%), and ovarian hyperstimulation (5.9%).

There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for ovulation induction; however, a causal relationship has not been established.

Pharmacokinetics: Following repeated subcutaneous administration, a modest accumulation takes place (accumulation ratio of 1.6 ± 0.8). Following administration of lutropin alfa 150 IU, r-hLH pharmacokinetics are:

  • Maximum concentration (Cmax [IU/L]) 1.1 ± 0.3

  • Time to maximum concentration (tmax [h]) 6 (3-9)

  • Area under the drug-concentration curve (AUC [h·IU/L]) 44 ± 44

  • Half-life (t½ [h]) 14 ± 8

Luveris (lutropin alfa) Injection Labeling

(somatropin) Injection

Manufacturer: Novo Nordisk

Drug Approval Classification: Supplemental New Drug Application (Approval Date: 10/13/04)

New Indication: This supplemental NDA provides for the use of Norditropin (somatropin) to treat adults with growth hormone deficiency.

Norditropin (somatropin) Injection Labeling

Norditropin (somatropin) Injection

(somatropin) Injection

Manufacturer: Serono

Drug Approval Classification: Supplemental New Drug Application (Approval Date: 10/15/04)

New Indication: This supplemental NDA provides for the use of Saizen (somatropin) for the replacement of endogenous growth hormone in adults with growth hormone deficiency (GHD).

Dosing: The starting dose recommended in adult patients with GHD is 0.005 mg/kg/day. The dosage may be increased to not more than 0.01 mg/kg/day after 4 weeks, depending upon patient tolerance to treatment.

Clinical Summary: A multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted in 115 adults with GHD comparing the effects of somatropin and placebo on body composition. Patients in the active treatment arm were treated with somatropin at an initial dose of 0.005 mg/kg/day for 1 month, which was increased to 0.01 mg/kg/day if tolerated for the remaining 5 months of the study. The primary endpoint was the change from baseline in lean body mass (LBM) measured by dual energy x-ray absorptiometry (DXA) after 6 months. The change in baseline LBM after 6 months of therapy with somatropin was +1.9 compared with -0.2 in patients who were on the placebo arm (P < .001).

Adverse Effects: The most frequently reported adverse events associated with somatropin include:

  • Arthralgia (23.3%)

  • Headache (18.3%)

  • Influenza-like symptoms (15%)

  • Peripheral edema (15%)

  • Back pain (10%)

Saizen (somatropin) Injection Labeling

Saizen (somatropin) Injection

(histrelin) Implant

Manufacturer: Valera Pharmaceuticals, Inc.

Drug Approval Classification: Original New Drug Application (Approval Date: 10/12/04)

Indication: This new drug application provides for the use of Vantas (histrelin implant) for the palliative treatment of advanced prostate cancer.

Dosing: The recommended dose of Vantas is 1 implant for 12 months. Each implant contains 50 mg histrelin acetate. 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 must be removed after 12 months of therapy. At the time an implant is removed, another implant may be inserted to continue therapy.

Clinical Summary: Vantas (histrelin implant) is a sterile, non-biodegradable, diffusion-controlled reservoir drug delivery system designed to deliver histrelin continuously for 12 months upon subcutaneous implantation. Histrelin acetate is a synthetic nonpeptide analogue of the naturally occurring gonadotropin releasing hormone (GnRH) or luteinizing hormone releasing hormone (LH-RH). Histrelin acetate, an LH-RH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses.

In an open-label, multicenter, phase 3 study, 138 patients with prostate cancer were treated with a single Vantas implant and were evaluated for at least 60 weeks. Serum testosterone levels were assessed as the primary efficacy endpoint to evaluate both achievement and maintenance of castrate testosterone suppression, with treatment success being defined as a serum testosterone level ≤ 50 ng/dL. At Week 52, the study included the option for removal and insertion of a new implant, with evaluation for an additional 52 weeks (the "extension phase").

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

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

Adverse Effects: Hot flashes were the most common adverse event reported (65.5 % of patients). Local reactions after implant insertion included bruising (7.2% of patients) and pain/soreness/tenderness (3.6% of patients). Other, less frequently reported reactions included erythema (2.8% of patients) and swelling (0.7% of patients).

Vantas (histrelin implant) Labeling


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