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Lunelle (Medroxyprogesterone Acetate / Estradiol Cypionate) - Description and Clinical Pharmacology

 
 



DESCRIPTION

LUNELLE™ Monthly Contraceptive Injection contains medroxyprogesterone acetate and estradiol cypionate as its active ingredients. The chemical name for medroxyprogesterone acetate is pregn-4-ene-3,20-dione,17-(acetyloxy)-6-methyl-(6(alpha))-. The empirical formula is C24H34O4 and its molecular weight is 386.53. Medroxyprogesterone acetate is a white to off-white, odorless crystalline powder that is stable in air and melts between 200°C and 210°C. It is freely soluble in chloroform, soluble in acetone and dioxane, sparingly soluble in alcohol and methanol, slightly soluble in ether, and practically insoluble in water. The chemical name for estradiol cypionate is estra-1,3,5,(10)-triene-3,17-diol,(17(beta))-,17-cyclopentanepropanoate. Estradiol cypionate is a white to off-white crystalline powder that melts between 149°C and 153°C. It is soluble in alcohol, acetone, chloroform, and dioxane; sparingly soluble in vegetable oils; and practically insoluble in water. The empirical formula is C26H36O3 and its molecular weight is 396.57. The structural formulas for these ingredients are represented below:

LUNELLE™ Monthly Contraceptive Injection is available as a 0.5 mL aqueous suspension and contains 25 mg medroxyprogesterone acetate and 5 mg estradiol cypionate. Inactive ingredients are 0.9 mg methylparaben, 14.28 mg polyethylene glycol, 0.95 mg polysorbate 80, 0.1 mg propylparaben, 4.28 mg sodium chloride, and sterile water for injection.

CLINICAL PHARMACOLOGY

LUNELLE™ Monthly Contraceptive Injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension) when administered at the recommended dose to women every month inhibits the secretion of gonadotropins, which, in turn, prevents follicular maturation and ovulation. Although the primary mechanism of this action is inhibition of ovulation, other possible mechanisms of action include thickening and a reduction in volume of cervical mucus (which decrease sperm penetration) and thinning of the endometrium (which may reduce the likelihood of implantation).

PHARMACOKINETICS

Steady-state pharmacokinetic parameters of medroxyprogesterone acetate (MPA) and 17(beta)-estradiol (E2), the parent active moiety of estradiol cypionate (E2 C), following the third monthly injection of LUNELLE™ Monthly Contraceptive Injection are shown in Table 1.

Table 1. Pharmacokinetic Parameters of Medroxyprogesterone Acetate (MPA) and Estradiol (17(beta)-E2) after the 3rd Monthly Injection of LUNELLE™ Monthly Contraceptive Injection
in 14 Surgically Sterile Women
Cmax
(ng/mL)
Tmax
(day)
AUC0-28
(ng·day/mL)
AUC0-(infinity)
(ng·day/mL)
t1/2
(day)
MPA Mean 1.25 3.5 21.51 33.65 14.7
Min 0.94 1.0 14.44 22.02 6.2
Max 2.17 10.0 27.00 49.09 36.0
17(beta)-E2 Mean 0.25 2.1 2.74 2.99 8.4
Min 0.14 1.0 1.65 1.65 2.6
Max 0.48 7.0 3.56 3.89 20.4
Cmax= peak serum concentration; Tmax= time when Cmax is observed; AUC0-28= area under the concentration-time curve over 28 days; t1/2= terminal half-life; 1 nanogram = 103 picogram.

Absorption: Absorption of MPA and E2 from the injection site is prolonged after an intramuscular injection of LUNELLE™ Monthly Contraceptive Injection. The time to maximum plasma concentration (Tmax) typically occurs within 1 to 10 days postinjection for MPA and 1 to 7 days postinjection for E2. The peak concentrations (Cmax) generally range from 0.94 to 2.17 ng/mL for MPA and from 140 to 480 pg/mL for E2. The PK profile of E2 following administration of LUNELLE™ Monthly Contraceptive Injection is shown in Figure 1a.

Berne RM, Levy MN, 1988.

Effect of Injection Site: AUC0-28 for MPA values were statistically significantly higher following injection of LUNELLE™ Monthly Contraceptive Injection into the arm as compared to the anterior thigh (average increase was approximately 25%). The mean MPA Cmax was higher but not statistically significant (average increase 6 to 12%) when LUNELLE™ Monthly Contraceptive Injection was injected into the arm compared with the Cmax observed after injection into the hip or the anterior thigh. However, the average MPA trough (Cmin) concentrations and the half-lives were comparable for the three injection sites. E2 concentrations were not measured.

Distribution: Plasma protein binding of MPA averages 86%. MPA binding occurs primarily to serum albumin; no binding of MPA occurs with sex-hormone-binding globulin (SHBG). Estrogens circulate in blood bound to albumin, SHBG, (alpha)1-glycoproteins, and transcortin. Estradiol is primarily bound to SHBG and albumin and approximately 3% remains unbound. Unbound estrogens are known to modulate pharmacologic response.

Metabolism: MPA is extensively metabolized. Its metabolism primarily involves ring A and/or side-chain reduction, loss of the acetyl group, hydroxylation in the 2-, 6-, and 21-positions or a combination of these positions, resulting in numerous derivatives. E2 C undergoes ester hydrolysis after intramuscular injection of LUNELLE™ Monthly Contraceptive Injection, releasing the parent, active compound E2. Exogenously delivered or endogenously derived E2 is primarily metabolized to estrone and estriol, both of which are metabolized to their sulfate and glucuronide forms.

Elimination: Residual MPA concentrations at the end of a monthly injection of LUNELLE™ Monthly Contraceptive Injection are generally below 0.5 ng/mL, consistent with its apparent elimination half-life of 15 days. Most MPA metabolites are excreted in the urine as glucuronide conjugates with only small amounts excreted as sulfates. Following the peak concentration, serum E2 levels typically decline to 100 pg/mL by day 14 and are consistent with the apparent elimination half-life of 7 to 8 days. Estrogen metabolites are primarily excreted in the urine as glucuronides and sulfates.

Return of Ovulation: Return of ovulation correlated to some extent with MPA AUC0-84 days. Additionally, body weight and site of injection affected the AUC of MPA. AUC0-28 values are significantly higher when LUNELLE™ Monthly Contraceptive Injection is injected into the arm compared to the anterior thigh muscle and into women with BMI 2 compared to those with BMI >28 kg/m2. Consequently, return of ovulation may be delayed in women with BMI 2 who receive an injection in the arm.

PHARMACOKINETICS IN SUBPOPULATIONS

Race: The pharmacokinetics of MPA and E2 has been evaluated in different populations in separate studies. With the exception of one study in Thai women that demonstrated relatively higher Cmax and shorter Tmax values indicating more rapid absorption of both MPA and E2, the pharmacokinetics of MPA and E2 after the administration of LUNELLE™ Monthly Contraceptive Injection were similar in women from various ethnic backgrounds. Although pharmacokinetic differences were observed, the contraceptive efficacy was similar among all women of all ethnic backgrounds studied. Following discontinuation, ovulation returned earlier in Thai women.

Pediatric: Safety and efficacy of LUNELLE™ Monthly Contraceptive Injection have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under 16 years of age and users 16 years of age and older. Use of this product before menarche is not indicated.

Geriatric: LUNELLE™ Monthly Contraceptive Injection is intended for use in healthy women desiring contraception; studies in geriatric women have not been conducted.

Effect of Body Weight: No dosage adjustment is necessary based on body weight. The effect of body weight on the pharmacokinetics of MPA was assessed in a subset of women (n = 77, body mass index ranged from 18 to 45.5 kg/m2) enrolled in a Phase 3 trial. AUC0-28 values for MPA were significantly higher in thinner women with body mass index 2(average increase was approximately 20%) when compared to that in heavier women with body mass index > 28 kg/m2. The mean MPA Cmax was higher (average increase 42%) in thin/normal women with body mass index 2 compared with heavier women with body mass index > 28 kg/m2. The range of MPA trough (Cmin) concentrations and the half-lives were comparable for both groups.

Hepatic Insufficiency: No formal studies have evaluated the effect of hepatic disease on the disposition of LUNELLE™ Monthly Contraceptive Injection. However, steroid hormones may be poorly metabolized in patients with impaired liver function. (See CONTRAINDICATIONS.)

Renal Insufficiency: No formal studies have evaluated the effect of renal disease on the pharmacokinetics of LUNELLE™ Monthly Contraceptive Injection. However, since both steroidal components of LUNELLE™ Monthly Contraceptive Injection are almost exclusively eliminated by hepatic metabolism, no dosage adjustment is necessary in women with renal dysfunction.

DRUG-DRUG INTERACTIONS

No formal drug-drug interaction studies were conduct-ed with LUNELLE™ Monthly Contraceptive Injection. Aminoglutethimide administered concomitantly with LUNELLE™ Monthly Contraceptive Injection may significantly depress the serum concentrations of MPA. Users of LUNELLE™ Monthly Contraceptive Injection should be warned of the possibility of decreased efficacy with the use of this or any related drugs. (See PRECAUTIONS, DRUG INTERACTIONS.)

CLINICAL STUDIES

LUNELLE™ Monthly Contraceptive Injection has been studied for safety and efficacy in various comparative and introductory clinical trials around the world. One US study was performed with the goal of describing bleeding patterns in women using LUNELLE™ Monthly Contraceptive Injection compared to women using a standard oral contraceptive product. The group of LUNELLE™ Monthly Contraceptive Injection users in this study was 67.9% White, 15.5% Hispanic, 13.6% Black, 2.4% Asian, and 0.6% other.

In the clinical trials, reported 12-month pregnancy rates have been low ( The bleeding pattern over one year of use for LUNELLE™ Monthly Contraceptive Injection was examined in the US trial. Bleeding patterns during the last three months (months 9-12) of LUNELLE™ Monthly Contraceptive Injection use were compared with a concurrent group of standard oral contraceptive users. During this last three-month reference period, 58.6% of women using LUNELLE™ Monthly Contraceptive Injection experienced altered bleeding patterns (compared to 23.7% in the comparison group). See also WARNINGS, BLEEDING IRREGULARITIES. The one-year Life Table bleeding-related discontinuation rate for LUNELLE™ Monthly Contraceptive Injection was 6.1% for 782 participants in a US trial of up to 15 months duration. Bleeding patterns did not predict discontinuation from this large clinical trial.

Bleeding data from the US trial was re-analyzed based on injection intervals of 23 to 33 days. During the first injection interval, withdrawal bleeding lasted for more than 7 days in 42% of women, including 16% whose bleeding exceeded 10 days. The remaining 58% experienced bleeding for 7 days or less. Withdrawal bleeding began between days 20 and 25 (median 21) after initial injection in 48% of women using LUNELLE™ Monthly Contraceptive Injection.

At the end of one year of treatment, withdrawal bleeding lasted for more than 7 days in 29% of women, including 7% whose bleeding exceeded 10 days. The remaining 71% experienced bleeding 7 days or less in duration. Fifty percent of patients experienced withdrawal bleeding that began within 21-25 days (median 22) after their previous injection.

In any given injection interval, approximately 75% of women experienced a single withdrawal bleeding episode, without additional breakthrough bleeding or spotting, during that interval. In any given injection interval, approximately 15% of women experienced no bleeding and 10% experienced bleeding or spotting at various times in that injection interval.

In the US trial, weight gain was the most common adverse event leading to discontinuation of LUNELLE™ Monthly Contraceptive Injection (5.7% LUNELLE™ Monthly Contraceptive Injection group vs. 0.9% in the oral contraceptive comparator group). Weight change over 12 months in the LUNELLE™ Monthly Contraceptive Injection group ranged from 48 pounds lost to 49 pounds gained. Mean body weight change in the LUNELLE™ Monthly Contraceptive Injection group was a gain of 4 pounds after 13 injections and a gain of 5 pounds after 15 injections. Wide variability in individual weight gain or loss was observed; however, an increasing percentage of LUNELLE™ Monthly Contraceptive Injection users exhibited weight change in excess of 10 and 20 pounds with continued treatment. See also PRECAUTIONS, Weight Change.

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