CLINICAL PHARMACOLOGY
Pharmacodynamics
Norelgestromin is the active progestin largely responsible for the progestational activity that occurs in women following application of ORTHO EVRA®. Norelgestromin is also the primary active metabolite produced following oral administration of norgestimate (NGM), the progestin component of the oral contraceptive products ORTHO-CYCLEN® and ORTHO TRI-CYCLEN®.
Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).
Receptor and human sex hormone-binding globulin (SHBG) binding studies, as well as studies in animals and humans, have shown that both NGM and NGMN exhibit high progestational activity with minimal intrinsic androgenicity90-93. Transdermally-administered norelgestromin, in combination with ethinyl estradiol, does not counteract the estrogen-induced increases in SHBG, resulting in lower levels of free testosterone in serum compared to baseline.
One clinical trial assessed the return of hypothalamic-pituitary-ovarian axis function post-therapy and found that FSH, LH, and Estradiol mean values, though suppressed during therapy, returned to near baseline values during the 6 weeks post therapy.
Pharmacokinetics
Absorption
Following a single application of ORTHO EVRA®, both NGMN and EE reach a plateau by approximately 48 hours. Pooled data from the 3 clinical studies have demonstrated that steady state is reached within 2 weeks of application. The mean steady state Css concentrations ranged from 0.305-1.53 ng/mL for NGMN and from 11.2-137 pg/mL for EE.
Absorption of NGMN and EE following application of ORTHO EVRA® to the buttock, upper outer arm, abdomen and upper torso (excluding breast) was examined. While absorption from the abdomen was slightly lower than from other sites, absorption from these anatomic sites was considered to be therapeutically equivalent.
The mean (%CV) pharmacokinetic parameters Css and AUC0-168 for NGMN and EE following a single buttock application of ORTHO EVRA® are summarized in Table 1 .
In multiple dose studies, AUC0-168 for NGMN and EE was found to increase over time ( Table 1 ). In a three-cycle study, these pharmacokinetic parameters reached steady-state conditions during Cycle 3 ( Figures 1 and 2 ). Upon removal of the patch, serum levels of EE and NGMN reach very low or non-measurable levels within 3 days.
Table 1: Mean (%CV%CV is % of Coefficient of variation = 100 (standard deviation/mean)) Pharmacokinetic Parameters of Norelgestromin (NGMN) and Ethinyl Estradiol (EE) Following 3 Consecutive Cycles of ORTHO EVRA® Wear on the Buttock | Analyte | Parameter | Cycle 1
Week 1 | Cycle 3
Week 1 | Cycle 3
Week 2 | Cycle 3
Week 3 |
|---|
| nc = not calculated, |
| NGMN | Css (ng/mL) | 0.70 (39.4) | 0.70 (41.8) | 0.80 (28.7) | 0.70 (45.3) |
| AUC0-168 (ng.h/mL) | 107 (44.2) | 105 (43.2) | 132 (43.4) | 120 (43.9) |
| t1/2 (h) | nc | nc | nc | 32.1 (40.3) |
| EE | Css (pg/mL) | 46.4 (38.5) | 47.6 (36.4) | 59.0 (42.5) | 49.6 (54.4) |
| AUC0-168 (pg.h/mL) | 6796 (39.3) | 7160 (40.4) | 10054 (41.8) | 8840 (58.6) |
| t1/2 (h) | nc | nc | nc | 21.0 (43.2) |
Figure 1: Mean Serum NGMN Concentrations (ng/mL) in Healthy Female Volunteers Following Application of ORTHO EVRA® on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal)
Figure 2: Mean Serum EE Concentrations (pg/mL) in Healthy Female Volunteers Following Application of ORTHO EVRA® on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal.)
The absorption of NGMN and EE following application of ORTHO EVRA® was studied under conditions encountered in a health club (sauna, whirlpool and treadmill) and in a cold water bath. The results indicated that for NGMN there were no significant treatment effects on Css or AUC when compared to normal wear. For EE, increased exposures were observed due to sauna, whirlpool and treadmill. There was no significant effect of cold water on these parameters.
Results from a study of consecutive ORTHO EVRA® wear for 7 days and 10 days indicated that serum concentrations of NGMN and EE dropped slightly during the first 6 hours after the patch replacement, and recovered within 12 hours. By Day 10 of patch administration, both NGMN and EE concentrations had decreased by approximately 25% when compared to Day 7 concentrations.
Metabolism
Since ORTHO EVRA® is applied transdermally, first-pass metabolism (via the gastrointestinal tract and/or liver) of NGMN and EE that would be expected with oral administration is avoided. Hepatic metabolism of NGMN occurs and metabolites include norgestrel, which is highly bound to SHBG, and various hydroxylated and conjugated metabolites. Ethinyl estradiol is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.
Distribution
NGMN and norgestrel (a serum metabolite of NGMN) are highly bound (>97%) to serum proteins. NGMN is bound to albumin and not to SHBG, while norgestrel is bound primarily to SHBG, which limits its biological activity. Ethinyl estradiol is extensively bound to serum albumin and induces an increase in the serum concentrations of SHBG (See CLINICAL PHARMACOLOGY, Transdermal versus Oral Contraceptives, Table 3 ).
Elimination
Following removal of patches, the elimination kinetics of NGMN and EE were consistent for all studies with half-life values of approximately 28 hours and 17 hours, respectively. The metabolites of NGMN and EE are eliminated by renal and fecal pathways.
Transdermal versus Oral Contraceptives
The ORTHO EVRA® transdermal patch was designed to deliver EE and NGMN over a seven-day period while oral contraceptives (containing NGM 250 µg / EE 35 µg) are administered on a daily basis. Figures 3 and 4 present mean pharmacokinetic (PK) profiles for EE and NGMN following administration of an oral contraceptive (containing NGM 250 µg / EE 35 µg) compared to the 7-day transdermal ORTHO EVRA® patch (containing NGMN 6.0 mg / EE 0.75 mg) during cycle 2 in 32 healthy female volunteers.
Figure 3: Mean Serum Concentration-Time Profiles of NGMN Following Once-Daily Administration of an Oral Contraceptive for 2 cycles or Application of ORTHO EVRA® for 2 cycles to the Buttock in Healthy Female Volunteers. [Oral contraceptive: Cycle 2, Days 15-21, ORTHO EVRA®: Cycle 2, week 3]
Figure 4: Mean Serum Concentration-Time Profiles of EE Following Once-Daily Administration of an Oral Contraceptive for 2 cycles or Application of ORTHO EVRA® for 2 cycles to the Buttock in Healthy Female Volunteers. [Oral contraceptive: Cycle 2, Days 15-21, ORTHO EVRA®: Cycle 2, week 3]
Table 2 provides the mean (%CV) for NGMN and EE pharmacokinetic (PK) parameters.
Table 2: Mean (%CV) NGMN and EE Steady State Pharmacokinetic Parameters Following Application of ORTHO EVRA® and Once-daily Administration of an Oral Contraceptive (containing NGM 250 µg / EE 35 µg) in Healthy Female Volunteers | Parameter | ORTHO EVRACycle 2, Week 3 | ORAL CONTRACEPTIVE Cycle 2, Day 21 |
|---|
| NGMN NGM is rapidly metabolized to NGMN following oral administration | | |
| Cmax (ng/mL) | 1.12 (33.6) | 2.16 (25.2) |
| AUC0-168 (ng.h/mL) | 145 (36.8) | 123 (30.2)
|
| Css (ng/mL) | 0.888 (36.6) | 0.732 (30.2)
|
| EE | | |
| Cmax (pg/mL) | 97.4 (31.6) | 133 (27.7) |
| AUC0-168 (pg.h/mL) | 12,971 (33.1) | 8,281(26.9) |
| Css (pg/mL) | 80.0 (33.5) | 49.3 (26.9) |
In general, overall exposure for NGMN and EE (AUC and Css) was higher in subjects treated with ORTHO EVRA® for both Cycle 1 and Cycle 2, compared to that for the oral contraceptive, while Cmax values were higher in subjects administered the oral contraceptive. Under steady-state conditions, AUC0-168 and Css for EE were approximately 55% and 60% higher, respectively, for the transdermal patch, and the Cmax was about 35% higher for the oral contraceptive, respectively. Inter-subject variability (%CV) for the PK parameters following delivery from ORTHO EVRA® was higher relative to the variability determined from the oral contraceptive. The mean pharmacokinetic profiles are different between the two products and caution should be exercised when making a direct comparison of these PK parameters.
In Table 3 , percent change in concentrations (%CV) of markers of systemic estrogenic activity (Sex Hormone Binding Globulin [SHBG] and Corticosteroid Binding Globulin [CBG]) from Cycle 1 Day 1 to Cycle 1 Day 22 is presented. Percent change in SHBG concentrations was higher for ORTHO EVRA® users compared to women taking the oral contraceptive; percent change in CBG concentrations were similar for ORTHO EVRA® and oral contraceptive users. Within each group, the absolute values for SHBG were similar for Cycle 1, Day 22 and Cycle 2, Day 22.
Table 3: Mean Percent Change (%CV) in SHBG and CBG Concentrations Following Once-daily Administration of an Oral Contraceptive (containing NGM 250 µg / EE 35 µg) for One Cycle and Application of ORTHO EVRA® for One Cycle in Healthy Female Volunteers | Parameter | ORTHO EVRA® | ORAL CONTRACEPTIVE |
|---|
| (% change from | (% change from |
|---|
| Day 1 to Day 22) | Day 1 to Day 22) |
|---|
| SHBG | 334 (39.3) | 200 (43.2) |
| CBG | 153 (40.2) | 157 (33.4) |
Special Populations
Effects of Age, Body Weight, Body Surface Area and Race:
The effects of age, body weight, body surface area and race on the pharmacokinetics of NGMN and EE were evaluated in 230 healthy women from nine pharmacokinetic studies of single 7-day applications of ORTHO EVRA®. For both NGMN and EE, increasing age, body weight and body surface area each were associated with slight decreases in Css and AUC values. However, only a small fraction (10-25%) of the overall variability in the pharmacokinetics of NGMN and EE following application of ORTHO EVRA® may be associated with any or all of the above demographic parameters. There was no significant effect of race with respect to Caucasians, Hispanics and Blacks.
Renal and Hepatic Impairment
No formal studies were conducted with ORTHO EVRA® to evaluate the pharmacokinetics, safety, and efficacy in women with renal or hepatic impairment. Steroid hormones may be poorly metabolized in patients with impaired liver function (see PRECAUTIONS ).
Drug Interactions
The metabolism of hormonal contraceptives may be influenced by various drugs. Of potential clinical importance are drugs that cause the induction of enzymes that are responsible for the degradation of estrogens and progestins, and drugs that interrupt entero-hepatic recirculation of estrogen (e.g. certain antibiotics)72.
The proposed mechanism of interaction of antibiotics is different from that of liver enzyme-inducing drugs. Literature suggests possible interactions with the concomitant use of hormonal contraceptives and ampicillin or tetracycline. In a pharmacokinetic drug interaction study, oral administration of tetracyclineHCl, 500 mg q.i.d. for 3 days prior to and 7 days during wear of ORTHO EVRA® did not significantly affect the pharmacokinetics of NGMN or EE.
The major target for enzyme inducers is the hepatic microsomal estrogen-2-hydroxylase (cytochrome P450 3A4)99. See also PRECAUTIONS, Drug Interactions .
Patch Adhesion
In the clinical trials with ORTHO EVRA®, approximately 2% of the cumulative number of patches completely detached. The proportion of subjects with at least 1 patch that completely detached ranged from 2% to 6%, with a reduction from Cycle 1 (6%) to Cycle 13 (2%). For instructions on how to manage detachment of patches, refer to the DOSAGE AND ADMINISTRATION section.
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