CAMCEVI (Page 3 of 5)

8.2 Lactation

Risk Summary

The safety and efficacy of CAMCEVI have not been established in females. There is no information regarding the presence of leuprolide in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in a breastfed child, a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.

8.3 Females and Males of Reproductive Potential

Infertility

Males

Based on findings in animals and mechanism of action, CAMCEVI may impair fertility in males of reproductive potential [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and efficacy of CAMCEVI in pediatric patients have not been established.

8.5 Geriatric Use

Of the 137 patients who received CAMCEVI in the FP01C-13-001 study, 74% were 65 years of age or older, while 37% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

11 DESCRIPTION

CAMCEVI is a sterile formulation of leuprolide mesylate for subcutaneous injection. CAMCEVI is designed to deliver approximately 42 mg of leuprolide over 6 months.

Leuprolide mesylate is a synthetic nonapeptide analog of naturally occurring GnRH and is a GnRH agonist. The analog possesses greater potency than the natural hormone. 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 mesylate (salt) with the following structural formula. The pH of 50 mg/mL solution of leuprolide mesylate in water is approximately 5.7.

structure
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CAMCEVI is supplied as a kit with a pre-filled, single-dose, sterile syringe for subcutaneous injection. Each pre-filled syringe delivers 42 mg leuprolide (equivalent to approximately 48 mg leuprolide mesylate), poly(D, L-lactide) (184 mg) polymer and N -methyl-2-pyrrolidone (136 mg).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Leuprolide, a GnRH agonist, acts as an inhibitor of gonadotropin secretion. Animal and human studies indicate that following an initial stimulation of gonadotropins, chronic administration of leuprolide results in suppression of ovarian and testicular steroidogenesis. This effect is reversible upon discontinuation of drug therapy.

In humans, subcutaneous administration of single daily doses of leuprolide result in an initial increase in circulating levels of LH and FSH, leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males). However, continuous daily administration of leuprolide results in decreased levels of LH and FSH. In males, testosterone is reduced to below castration levels. These decreases generally occur within 2 to 4 weeks after initiation of treatment, and castration levels of testosterone in prostatic cancer patients have been demonstrated for periods of up to 5 years.

12.2 Pharmacodynamics

Mean serum testosterone concentrations transiently increased, then fell to below castrate threshold levels (≤ 50 ng/dL) within 3 weeks following administration of the dose of leuprolide, and generally remained below castrate thresholds levels throughout treatment.

12.3 Pharmacokinetics

Leuprolide concentration is variable, exhibiting an initial rapid increase followed by a rapid decline over the first 3 days before reaching steady concentrations for the duration of the dosing interval. The mean serum leuprolide Cmax was 94.5 and 99 ng/mL following the first and second doses of CAMCEVI, respectively. The mean serum concentration was maintained at 0.497–2.57 and 0.507–2.39 ng/ml after Day 3 post the first and second doses, respectively. The mean AUC0-6 mon was 224 and 268 day.ng/mL following the first and second doses of CAMCEVI, respectively.

Absorption

The median Tmax of leuprolide was 3.2 and 2.1 hours following the first and second doses of CAMCEVI, respectively.

Distribution

The mean steady‑state volume of distribution of leuprolide was 27 L following an intravenous bolus in healthy male volunteers. Protein binding of leuprolide ranged from 43% to 49% in vitro.

Elimination

The mean systemic clearance was 7.6 L/h and terminal elimination half‑life of approximately 3 hours following an intravenous bolus of leuprolide in healthy male volunteers.

Metabolism
Administration of radiolabeled leuprolide was metabolized to smaller inactive peptides which may then be further catabolized.

Excretion

Excretion of leuprolide has not been evaluated with CAMCEVI.

Specific Populations

No clinically significant differences in the systemic exposure of leuprolide were observed based on age (51 to 88 years), race/ethnicity (White, Black, Asian), or body weight (54 to 134 kg). The effect of renal or hepatic impairment on the pharmacokinetics of leuprolide has not been evaluated.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Two‑year carcinogenicity studies were conducted with leuprolide in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose‑related increase 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 a dose as high as 60 mg/kg for 2 years. Patients have been treated with leuprolide for up to 3 years with doses as high as 10 mg/day and for 2 years with doses as high as 20 mg/day without demonstrable pituitary abnormalities.

Mutagenicity studies have been performed with leuprolide using bacterial and mammalian systems. These studies provided no evidence of mutagenic potential.

Leuprolide may reduce male and female fertility. Administration of leuprolide to male and female rats at doses of 0.024, 0.24, and 2.4 mg/kg as monthly depot formulation for up to 3 months (approximately as low as 1/30 of the human dose based on body surface area using an estimated daily dose in animals and humans) caused atrophy of the reproductive organs, and suppression of reproductive function. These changes were reversible upon cessation of treatment.

14 CLINICAL STUDIES

The efficacy of CAMCEVI was evaluated in an open label, single arm, multinational study FP01C-13-001 (NCT02234115) in patients with advanced prostate carcinoma who have a baseline morning serum testosterone level >150 ng/dL and Eastern Cooperative Oncology Group performance status ≤ 2. CAMCEVI was administered subcutaneously at a dose of 42 mg initially on Day 0 and on Week 24.

The population (n = 137) had a median age of 71 years (range 51 to 88) and was 90% White, 6% Black, and 4% Asian. Disease stage was distributed as follows: 23% metastatic (M1), 27% locally advanced (T3/4 NX M0 or any T N1 M0), 26% localized (T1 or T2 N0 M0), and 24% not classifiable. The median testosterone concentration at baseline was 440 ng/dL.

The major efficacy outcome measure was medical castration rate, defined as achieving and maintaining serum testosterone suppression to ≤ 50 ng/dL by Week 4 through Week 48 of treatment. Following the first injection of CAMCEVI, serum testosterone levels were suppressed to ≤ 50 ng/dL by Week 4 (+/-7 days) in 98.5% of the patients; and from Week 4 through Week 48 in 97.0% of patients (95% CI: 92.2-98.9) estimated using the Kaplan-Meier method. The time course of percent change from baseline in testosterone suppression are shown in Figure 1. The percentage of patients with testosterone suppression to ≤ 20 ng/dL was 69.3% on Day 28.

Figure 1 CAMCEVI Mean (95% CI) Percentage Change from Baseline in Serum Testosterone Concentration Over Time (N =137)

figure
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In the clinical trial, PSA levels were monitored and were lowered on average by 51% after 4 weeks after administration of CAMCEVI, 83% after 3 months and remained suppressed throughout the 48 weeks of treatment. These PSA results should be interpreted with caution because of the heterogeneity of the patient population studied. No evidence has shown that the rapidity of PSA decline correlates with clinical benefit.

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