Natazia estradiol valerate and estradiol valerate/dienogest Kit — NDC 50419-409-00 (Billing 50419-0409-00)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action COCs lower the risk of becoming pregnant primarily by suppressing ovulation.

12.2Pharmacodynamics The estrogen in Natazia is estradiol valerate, a synthetic prodrug of 17ß-estradiol. The progestin in Natazia is dienogest (DNG). DNG displays properties of 19-nortestosterone derivatives as well as properties associated with progesterone derivatives.

Cardiac Electrophysiology The effect of Natazia on QT prolongation was evaluated in a randomized, double-blind, positive (moxifloxacin 400 mg) and negative (placebo) controlled crossover study in healthy subjects. A total of 53 subjects were administered Natazia (containing 3 mg dienogest and 2 mg estradiol valerate), dienogest 10 mg, and placebo as once daily doses for 4 days, and moxifloxacin 400 mg as a single oral dose. The upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc based on Fridericia’s correction method (QTcF) was below 10 msec, the threshold for regulatory concern.

12.3Pharmacokinetics Absorption After oral administration of estradiol valerate, cleavage to 17β-estradiol and valeric acid takes place during absorption by the intestinal mucosa or in the course of the first liver passage. This gives rise to estradiol and its metabolites, estrone and other metabolites. Maximum serum estradiol concentrations of 73.3 pg/mL are reached at a median of approximately 6 hours (range: 1.5–12 hours) and the area under the estradiol concentration curve [AUC(0–24h)] was 1301 pg·h/mL after single ingestion of a tablet containing 3 mg estradiol valerate under fasted condition on Day 1 of the 28-day sequential regimen.

Bioavailability of dienogest is about 91%. Maximum serum dienogest concentrations of 91.7 ng/mL are reached at a median of approximately 1 hour (range: 0.5–1.5 hour) and the area under the dienogest concentration curve [AUC(0–24h)] was 964 ng/mL after single oral administration of Natazia tablet containing 2 mg estradiol valerate/3 mg dienogest under fasted condition. The pharmacokinetics of dienogest are dose-proportional within the dose range of 1–8 mg.

Steady state is reached after 4 days of the same dosage of 2 mg dienogest. The mean accumulation ratio for AUC (0–24h) is approximately 1.24. The mean plasma pharmacokinetic parameters at steady state following repeated oral doses of a 2 mg estradiol valerate/3 mg dienogest combination tablet in fertile women under fasted condition are reported in Table 1.

Table 1 Arithmetic Mean (SD) Serum Pharmacokinetic Parameters at Steady-state (on Day 24) following Repeated Oral Doses of 2 mg EV/3 mg DNG on Days 8-24 of the 28 day Regimen in Fertile Women under Fasted Condition (N=15) Parameter Dienogest Estradiol Estrone C max C max = Maximum serum concentration 85.2 (19.7) ng/ml 70.5 (25.9) pg/ml 483 (198) pg/ml T max Tmax = Time to reach maximum concentration (h) Median (range) for T max 1.5 (1–2) 3 (1.5–12) 4 (3–12) AUC AUC(0-24h) = Area under the concentration-time curve from 0 h data point up to 48 h post-administration (0–24h) 828 (187) ng·h/ml 1323 (480) pg·h/ml 7562 (3403) pg·h/ml t ½ (h) 12.3 (1.4) NA NA: Data not available NA Food Effect Concomitant food intake in women resulted in a 28% decrease for dienogest C max and 23% increase of estradiol C max while the exposure (AUC) of both dienogest and estradiol did not change.

Distribution In serum, 38% of estradiol is bound to sex hormone-binding globulin (SHBG), 60% to albumin and 2–3% circulates in free form. An apparent volume of distribution of approximately

1.2L/kg was determined after intravenous (IV) administration. A relatively high fraction (10%) of circulating dienogest is present in the free form, with approximately 90% being bound non-specifically to albumin. Dienogest does not bind to SHBG and corticosteroid-binding globulin (CBG).

The volume of distribution at steady state (V d,ss ) of dienogest is 46 L after the IV administration of 85 mcg 3 H-dienogest. Metab… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action COCs lower the risk of becoming pregnant primarily by suppressing ovulation.

12.3Pharmacokinetics Absorption After oral administration of estradiol valerate, cleavage to 17β-estradiol and valeric acid takes place during absorption by the intestinal mucosa or in the course of the first liver passage. This gives rise to estradiol and its metabolites, estrone and other metabolites. Maximum serum estradiol concentrations of 73.3 pg/mL are reached at a median of approximately 6 hours (range: 1.5–12 hours) and the area under the estradiol concentration curve [AUC(0–24h)] was 1301 pg·h/mL after single ingestion of a tablet containing 3 mg estradiol valerate under fasted condition on Day 1 of the 28-day sequential regimen.

Bioavailability of dienogest is about 91%. Maximum serum dienogest concentrations of 91.7 ng/mL are reached at a median of approximately 1 hour (range: 0.5–1.5 hour) and the area under the dienogest concentration curve [AUC(0–24h)] was 964 ng/mL after single oral administration of Natazia tablet containing 2 mg estradiol valerate/3 mg dienogest under fasted condition. The pharmacokinetics of dienogest are dose-proportional within the dose range of 1–8 mg.

Steady state is reached after 4 days of the same dosage of 2 mg dienogest. The mean accumulation ratio for AUC (0–24h) is approximately 1.24. The mean plasma pharmacokinetic parameters at steady state following repeated oral doses of a 2 mg estradiol valerate/3 mg dienogest combination tablet in fertile women under fasted condition are reported in Table 1.

Table 1 Arithmetic Mean (SD) Serum Pharmacokinetic Parameters at Steady-state (on Day 24) following Repeated Oral Doses of 2 mg EV/3 mg DNG on Days 8-24 of the 28 day Regimen in Fertile Women under Fasted Condition (N=15) Parameter Dienogest Estradiol Estrone C max C max = Maximum serum concentration 85.2 (19.7) ng/ml 70.5 (25.9) pg/ml 483 (198) pg/ml T max Tmax = Time to reach maximum concentration (h) Median (range) for T max 1.5 (1–2) 3 (1.5–12) 4 (3–12) AUC AUC(0-24h) = Area under the concentration-time curve from 0 h data point up to 48 h post-administration (0–24h) 828 (187) ng·h/ml 1323 (480) pg·h/ml 7562 (3403) pg·h/ml t ½ (h) 12.3 (1.4) NA NA: Data not available NA Food Effect Concomitant food intake in women resulted in a 28% decrease for dienogest C max and 23% increase of estradiol C max while the exposure (AUC) of both dienogest and estradiol did not change.

Distribution In serum, 38% of estradiol is bound to sex hormone-binding globulin (SHBG), 60% to albumin and 2–3% circulates in free form. An apparent volume of distribution of approximately

1.2L/kg was determined after intravenous (IV) administration. A relatively high fraction (10%) of circulating dienogest is present in the free form, with approximately 90% being bound non-specifically to albumin. Dienogest does not bind to SHBG and corticosteroid-binding globulin (CBG).

The volume of distribution at steady state (V d,ss ) of dienogest is 46 L after the IV administration of 85 mcg 3 H-dienogest. Metabolism After oral administration of estradiol valerate, approximately 3% of the dose is directly bioavailable as estradiol. Estradiol undergoes an extensive first-pass effect and a considerable part of the dose administered is already metabolized in the gastrointestinal mucosa.

The CYP 3A family is known to play the most important role in human estradiol metabolism. Together with the pre-systemic metabolism in the liver, about 95% of the orally administered dose becomes metabolized before entering the systemic circulation. The main metabolites are estrone and its sulfate or glucuronide conjugates.

Dienogest is extensively metabolized by the known pathways of steroid metabolism (hydroxylation, conjugation), with the formation of endocrinologically mostly inactive metabolites. CYP3A4 was identified as a predominant enzyme catalyzing the metabolism of dienogest. Excretion Estradiol and its metabolites are mainly excreted in urine, with about 10% being excreted in the feces.

The terminal half-life of estradiol is approximately… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics The estrogen in Natazia is estradiol valerate, a synthetic prodrug of 17ß-estradiol. The progestin in Natazia is dienogest (DNG). DNG displays properties of 19-nortestosterone derivatives as well as properties associated with progesterone derivatives.

Cardiac Electrophysiology The effect of Natazia on QT prolongation was evaluated in a randomized, double-blind, positive (moxifloxacin 400 mg) and negative (placebo) controlled crossover study in healthy subjects. A total of 53 subjects were administered Natazia (containing 3 mg dienogest and 2 mg estradiol valerate), dienogest 10 mg, and placebo as once daily doses for 4 days, and moxifloxacin 400 mg as a single oral dose. The upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc based on Fridericia’s correction method (QTcF) was below 10 msec, the threshold for regulatory concern.

14 CLINICAL STUDIES

14.1Oral Contraceptive Clinical Trials The study conducted in North America (U.S. and Canada) was a multicenter, open-label, single-arm, unintended pregnancy study. There were 490 healthy subjects between 18 and 35 years of age (mean age: 25.1 years) who were treated for up to 28 cycles of 28 days each. The racial demographic of enrolled women was: Caucasian (76%), Hispanic (13%), African-American (7%), Asian (3%), and Other (1%).

The weight range for treated women was 40 to 100 kg (mean weight: 62.5 kg) and the BMI range was 14 to 30 kg/m 2 (mean BMI: 23.3 kg/m 2 ). Of treated women, 15% discontinued the study treatment due to an adverse event, 13% were lost to follow up, 10% withdrew their consent, 8% discontinued due to other reason, 1% discontinued due to protocol deviation, and 1% discontinued due to pregnancy. The study conducted in Europe (Germany, Austria and Spain) was a multicenter, open-label, single-arm contraceptive reliability study.

There were 1,377 healthy subjects between 18 and 50 years of age (mean age: 30.3 years) who were treated for 20 cycles of 28 days each. The racial demographic of enrolled women was predominantly Caucasian (99.2%). The weight range for treated women was 38 to 98 kg (mean weight: 63.8 kg) and the BMI range was 15 to 31.8 kg/m 2 (mean BMI: 22.8 kg/m 2 ).

Of treated women, 10% discontinued the study treatment due to an adverse event, 5% discontinued due to other reason, 2% were lost to follow up, 2% discontinued due to protocol deviation, 2% withdrew their consent, and 1% discontinued due to pregnancy. The Pearl Index (PI) was the primary efficacy endpoint used to assess contraceptive reliability and was assessed in each of the two studies, assuming all subjects were at risk of pregnancy in all medication cycles unless back-up contraception was documented. The PI is based on pregnancies that occurred after the onset of treatment and within 7 days after the last pill intake.

Cycles in which conception did not occur, but which included the use of back-up contraception, were not included in the calculation of the PI. The PI also includes patients who did not take the drug correctly. The estimated PI for the North American study is 1.64 and the estimated PI for the European study is 1.04.

The Kaplan-Meier method was also used to calculate the contraceptive failure rate. The summary of the Pearl Indexes and cumulative contraceptive failure rates are provided in Table 2: Table 2: Summary of the Pearl Indexes and the Cumulative Contraceptive Failure Rates Study Age Group Relative Treatment Exposure Cycles Total treatment exposure time without back-up contraception Number of Pregnancies within 13 Cycles and 7 Days after Last Treatment Pearl Index Upper Limit of 95% CI Contraceptive Failure Rate at the End of First Year North America 18–35 3,969 5 1.64 3.82 0.016 Europe 18–35 11,275 9 1.04 1.97 0.010

14.2Heavy Menstrual Bleeding Clinical Trials The efficacy and safety of Natazia were evaluated in two multi-regional, multicenter, double-blind, randomized, placebo-controlled clinical trials. Study 308960 was performed in the United States and Canada and Study 308961 was performed in Australia and 9 European countries. The studies were identical in design.

The studies enrolled women, 18 years of age or older, with a diagnosis of dysfunctional uterine bleeding characterized as heavy, prolonged and/or frequent bleeding without organic pathology. Heavy menstrual bleeding (HMB) was defined as menstrual blood loss of 80 mL or more in at least 2 bleeding episodes. The diagnosis of HMB was documented through the collection of used sanitary protection (pads and tampons) to quantify blood loss assessed by the alkaline hematin method.

Overall, about 85% of the subjects qualified for the study because they had heavy menstrual bleeding symptoms. A total of 421 women with a mean age of 38.2 and a mean BMI of 25.5 were randomized to the two clinical studies, for a total of 269 women in the N… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility In a 24-month carcinogenicity study in mice dosed orally with dienogest by gavage with doses of 5, 15 and 50 mg/kg/day (males) and 10, 30 and 100 mg/kg/day (females), the systemic exposures in the females were 1.1, 3.5, and 10.6 times the exposure (AUC of dienogest) of women taking a 3 mg dose. A statistically significantly higher incidence of stromal polyps of the uterus was observed in females given 100 mg/kg. In a similar study in rats given 1, 3, and 10 mg/kg for 104 weeks, 0.2, 1.4, and 6.1 times the exposure of women taking a 3 mg dose, there were no statistically significant drug-related neoplasms [see Warnings and Precautions ( 5.2 , 5.3 )] .

Dienogest was not mutagenic in in vitro reverse mutation tests in bacteria, in chromosome aberration tests in human peripheral lymphocytes, mouse lymphoma cells, and Chinese hamster lung cells, and tests of unscheduled DNA synthesis (UDS) in rat and human liver cells. Dienogest was also negative in an in vivo mouse micronucleus test, a rat liver initiation-promotion model, and an in vitro/in vivo UDS test in female rats.