Activella (Page 6 of 10)

12.2 Pharmacodynamics

Generally, a serum estrogen concentration does not predict an individual woman’s therapeutic response to Activella nor her risk for adverse outcomes. Likewise, exposure comparisions across different estrogen products to infer efficacy or safety for the individual woman may not be valid.

12.3 Pharmacokinetics



Estradiol is absorbed through the gastrointestinal tract. Following oral administration of Activella tablets, peak plasma estradiol concentrations are reached within 5 to 8 hours. The oral bioavailability of estradiol following administration of Activella 1 mg/0.5 mg when compared to a combination oral solution is 53%. Administration of Activella 1 mg/0.5 mg with food did not modify the bioavailability of estradiol.

Norethindrone Acetate

After oral administration, norethindrone acetate is absorbed and transformed to norethindrone. Norethindrone reaches a peak plasma concentration within 0.5 to 1.5 hours after the administration of Activella tablets. The oral bioavailability of norethindrone following administration of Activella 1 mg/0.5 mg when compared to a combination oral solution is 100%. Administration of Activella 1 mg/0.5 mg with food increases norethindrone AUC0-72 by 19% and decreases Cmax by 36%.

The pharmacokinetic parameters of estradiol (E2 ), estrone (E1 ), and norethindrone (NET) following oral administration of 1 Activella 1 mg/0.5 mg or 2 Activella 0.5 mg/0.1 mg tablet(s) to healthy postmenopausal women are summarized in Table 3.



1 x Activella

1 mg/0.5 mg


2 x Activella

0.5 mg/0.1 mg


Meana (%CV)b

Meana (%CV)b

Estradiolc (E2 )

AUC0-t (pg/mL*h)

766.5 (48)

697.3 (53)

Cmax (pg/mL)

26.8 (36)

26.5 (37)

tmax (h): median (range)

6.0 (0.5-16.0)

6.5 (0.5-16.0)

t1/2 (h)d

14.0e (29)

14.5f (27)

Estronec (E1 )

AUC0-t (pg/mL*h)

4469.1 (48)

4506.4 (44)

Cmax (pg/mL)

195.5 (37)

199.5 (30)

tmax (h): median (range)

6.0 (1.0-9.0)

6.0 (2.0-9.0)

t1/2 (h)d

10.7 (44)g

11.8 (25)g

Norethindrone (NET)

AUC0-t (pg/mL*h)

21043 (41)

8407.2 (43)

Cmax (pg/mL)

5249.5 (47)

2375.4 (41)

tmax (h) : median (range)

0.7 (0.7-1.25)

0.8 (0.7-1.3)

t1/2 (h)

9.8 (32)h

11.4 (36)i

AUC = area under the curve, 0 – last quantifiable sample

Cmax = maximum plasma concentration,

tmax = time at maximum plasma concentration,

t1/2 = half-life,

a geometric mean; b geometric % coefficient of variation; c baseline unadjusted data; d baseline unadjusted data; e n=18; f n=16;

g n=13; h n=22; I n=21

Following continuous dosing with once-daily administration of Activella 1 mg/0.5 mg,serum concentrations of estradiol, estrone, and norethindrone reached steady-state within two weeks with an accumulation of 33 to 47% above concentrations following single dose administration. Unadjusted circulating concentrations of E2 , E1 , and NET during Activella 1 mg/0.5 mg treatment at steady-state (dosing at time 0) are provided in Figures 1a and 1b.

Figure 1a: Mean Baseline-Uncorrected Estradiol and Estrone Serum Concentration-Time Profiles Following Multiple Doses of Activella 1 mg/0.5 mg (N=24)

Figure 1a
(click image for full-size original)

Figure 1b: Mean Baseline-Uncorrected Norethindrone Serum Concentration-Time Profile Following Multiple Doses of Activella 1 mg/0.5 mg (N=24

Figure 1b
(click image for full-size original)



The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estradiol circulates in the blood bound to SHBG (37%) and to albumin (61%), while only approximately 1 to 2% is unbound.

Norethindrone Acetate

Norethindrone also binds to a similar extent to SHBG (36%) and to albumin (61%).



Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Norethindrone Acetate

The most important metabolites of norethindrone are isomers of 5a-dihydro-norethindrone and tetrahydro-norethindrone, which are excreted mainly in the urine as sulfate or glucuronide conjugates.



Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The half-life of estradiol following single dose administration of Activella 1 mg/0.5 mg is 12 to 14 hours.

Norethindrone Acetate

The terminal half-life of norethindrone is about 8 to 11 hours.

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