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Drospirenone is a spironolactone analogue with antimineralocorticoid activity. Preclinical studies in animals and in vitro have shown that drospirenone has no androgenic, estrogenic, glucocorticoid and antiglucocorticoid activity. Preclinical studies in animals have also shown that drospirenone has antiandrogenic activity.
Estrogen-containing combinations such as YASMIN increase the blood level of sex-hormone-binding-globulin (SHBG), which is capable of binding and thus inactivating androgens such as testosterone. Moreover, the anti-androgenic activity of drospirenone partially counteracts the effects of endogenous androgens, blocking the binding of dihydrotestosterone (DHT) at the receptor level, which makes it a suitable option in the treatment of acne. Drospirenone may also help to reduce edema of the wall of the sebaceous follicle during the second half of the menstrual cycle, which is partly responsible for the flare-up of inflammatory lesions at this cycle phase.
Pharmacodynamics: Drospirenone inhibits ovulation and follicular development at an oral threshold dose of 2 mg. Drospirenone 3 mg, in combination with ethinylestradiol 0.030 mg, was found to be optimal for inhibition of ovulation and cycle control.
Drospirenone exhibited aldosterone antagonist activity at doses as low as 2 mg/day in healthy volunteers. Plasma renin activity and plasma aldosterone concentrations were increased, as was the excretion of aldosterone metabolites. The excretion of Na+ was transiently increased by drospirenone (2 or 3 mg) alone or in combination with ethinyl estradiol (0.030 mg). Serum Na+ and K+ concentrations remained unchanged. The potency of drospirenone was 6.6 times higher on average than that of spironolactone, using the Na+/K+ urinary ratio as the primary indicator of potency of the aldosterone antagonistic effect.
Drospirenone (2, 3, or 4 mg) in combination with ethinylestradiol (0.030 mg) displayed a favourable effect on the lipid profile with an increase in HDL and a slight decrease in LDL. Total cholesterol remained unchanged. In addition, oral glucose tolerance remained unchanged or was slightly decreased.
Drospirenone had no effect on the biosynthesis of sex hormone binding globulin (SHBG) and when administered in conjunction with ethinylestradiol (0.030 mg), resulted in SHBG and corticosteroid binding globulin increases consistent with the dosage of ethinylestradiol.
In vitro, drospirenone bound with low affinity to SHBG and did not bind at all to corticosteroid-binding globulin (CBG).
Clinical Trials: Contraception: The contraceptive efficacy of YASMIN (drospirenone and ethinylestradiol) was demonstrated in three pivotal, open-label, multicentre, clinical trials conducted in women 16 to 40 years of age (see Table 1).
Click on icon to see table/diagram/imageOf the 14 on-treatment pregnancies reported for YASMIN, there were 11 cases in which co-factors (missed tablets, diarrhea, etc) were identified that could have reduced the contraceptive efficacy. These cases may be accepted as user failures.
Detailed Pharmacology: Animal Pharmacology: Drospirenone: Drospirenone exhibits potent progestational activity in a variety of animal models. In ovariectomized pregnant rats treated with drospirenone 3 mg/day SC in combination with ethinylestradiol 0.1 μg/day SC, maintenance of pregnancy was comparable to intact control animals.
Drospirenone effectively inhibited ovulation in mice and rats with half-maximal effects observed at subcutaneous doses of approximately 0.1 and 1 mg/day, respectively, and an oral dose of 1 mg/day (rats). Following subcutaneous administration of drospirenone, a marked transformation of the endometrium was detected in castrated, infantile female rabbits, with a threshold dose of 100 to 300 μg/day. In vitro, drospirenone bound with high affinity to the progesterone receptor, and the binding affinity was not affected by the presence of ethinylestradiol.
In addition to its progestational activity, drospirenone also has antiandrogenic activity. Oral or subcutaneous administration of drospirenone (0.3-10 mg/day for 7 days) dose-dependently inhibited testosterone-induced growth of the seminal vesicle and prostate in castrated, testosterone-substituted rats. This activity does not appear to be centrally mediated in rats because decreases in the relative weights of male accessory sex organs occur in the absence of significant changes in testes weights or serum luteinizing hormone levels. Oral or subcutaneous administration of drospirenone (10 mg/day) to pregnant rats during the final trimester of pregnancy resulted in the feminization of male fetuses, characterized by a significant shortening of the anogenital distance and the length of the urethra.
Significant antimineralocorticoid activity, characterized by increased sodium excretion and an increase of the urinary Na+/K+ ratio, was observed following single oral or subcutaneous administration of drospirenone to adrenalectomized, aldosterone-substituted rats. Drospirenone was five to ten times more potent than spironolactone, and its aldosterone antagonist activity was not affected by concomitant administration of ethinylestradiol. When administered for 21 days to ovariectomized female rats, drospirenone (10 mg/day) stimulated the Na+/K+ excretion ratio over the entire treatment period, while spironolactone (10 mg/day) became ineffective after the initial treatment phase due to counter-regulation. Drospirenone also exhibited significant antimineralocorticoid activity in vitro, inhibiting aldosterone-stimulated electrogenic sodium transport 10 times more effectively than either spironolactone or progesterone. In vitro, drospirenone binds with high affinity to the mineralocorticoid receptor.
Drospirenone has no androgenic activity. This was demonstrated in vitro by the lack of stimulation of androgen receptor-driven gene transcription. In vivo in castrated male rats, drospirenone (10 mg/day) did not stimulate the growth of accessory sex organs above castration level. The same dose had no virilizing effect on the process of sexual differentiation of female rat fetuses.
Drospirenone is devoid of estrogenic, gluco- and antiglucocorticoid activity, as concluded from the absence of an influence on vaginal epithelial cornification in rats, adrenal weight changes in rats, and thymus regression in adrenalectomized, glucocorticoid-substituted rats, respectively.
Drospirenone did not affect smooth muscle organs (ileum, trachea, uterus) in vivo (rabbit) or in vitro (guinea pigs). In female mice, drospirenone did not affect central nervous system function at single oral doses up to 100 mg/kg.
Ethinylestradiol: Ethinylestradiol is a potent estrogen with qualities similar to estradiol. In contrast to estradiol, it is highly effective after oral administration. The relative oral potency of ethinylestradiol's antigonadotropic and antifertility effects (eg, inhibition of ovulation, inhibition of implantation) is 3 to 30 times higher than that of orally administered estradiol.
Ethinylestradiol also exhibits effects on carbohydrate, protein, and lipid metabolism similar to those of other estrogens: in rats, hepatic glycogen content and serum triglycerides are significantly increased, whereas serum cholesterol is decreased. In addition, a small but significant increase in the liver weight can be seen. Phospholipids were also raised after treatment for 1 month. The effects on lipid and carbohydrate metabolism may be attributed to an indirect glucocorticoid activity of estrogens. It is well established that estrogens in the rat cause a stimulation of the adrenals and a depletion of corticoids. The increased glucocorticoid level may be responsible for an induction of gluconeogenesis concomitant with high fasting blood glucose levels.
Pharmacokinetics: See Table 2.
Click on icon to see table/diagram/imageAbsorption: The absolute bioavailability of drospirenone (DRSP) from a single entity tablet is about 76%. The absolute bioavailability of ethinylestradiol (EE) is approximately 40% as a result of presystemic conjugation and first-pass metabolism. The absolute bioavailability of YASMIN which is a combination tablet of drospirenone and ethinylestradiol has not been evaluated.
Serum concentrations of DRSP and EE reached peak levels within 1-3 hours after administration of YASMIN. After single-dose administration of YASMIN, the relative bioavailability, compared to a suspension, was 107% and 117% for DRSP and EE, respectively.
The pharmacokinetics of DRSP are dose proportional following single doses ranging from 1-10 mg. Following daily dosing of YASMIN, steady state DRSP concentrations were observed after 10 days. There was about 2- to 3-fold accumulation in serum Cmax and AUC(0-24h) values of DRSP following multiple-dose administration of YASMIN (see Table 2).
For EE, steady-state conditions are reported during the second half of a treatment cycle. Following daily administration of YASMIN, serum Cmax and AUC(0-24h) values of EE accumulate by a factor of about 1.5 to 2.0.
Effect of Food: The rate of absorption of DRSP and EE following single administration of two YASMIN tablets was slower under fed conditions, with the serum Cmax being reduced about 40% for both components. The extent of absorption of DRSP, however, remained unchanged. In contrast, the extent of absorption of EE was reduced by about 20% under fed conditions.
Distribution: DRSP and EE serum levels decline in two phases. The apparent volume of distribution of DRSP is approximately 4 L/kg and that of EE is reported to be approximately 4-5 L/kg.
DRSP does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG) but binds about 97% to other serum proteins. Multiple dosing over 3 cycles resulted in no change in the free fraction (as measured at trough levels). EE is reported to be highly, but nonspecifically, bound to serum albumin (approximately 98.5%) and induces an increase in the serum concentrations of both SHBG and CBG. EE-induced effects on SHBG and CBG were not affected by variation of the DRSP dosage in the range of 2 to 3 mg.
Metabolism: The two main metabolites of DRSP found in human plasma were identified to be the acid form of DRSP, generated by opening of the lactone ring, and the 4,5-dihydrodrospirenone-3-sulfate, formed by reduction and subsequent sulfation. These metabolites were shown not to be pharmacologically active. DRSP is also subject to oxidative metabolism catalyzed by CYP3A4.
EE is subject to significant gut and hepatic first-pass metabolism. EE and its oxidative metabolites are primarily conjugated with glucuronides or sulfate. CYP3A4 in the liver are responsible for the 2-hydroxylation which is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion.
Excretion: DRSP serum levels are characterized by a terminal disposition phase half-life of approximately 30 hours after both single- and multiple-dose regimens. Excretion of DRSP was nearly complete after ten days and amounts excreted were slightly higher in feces compared to urine. DRSP was extensively metabolized and only trace amounts of unchanged DRSP were excreted in urine and feces. At least 20 different metabolites were observed in urine and feces. About 38% to 47% of the metabolites in urine were glucuronide and sulfate conjugates. In feces, about 17% to 20% of the metabolites were excreted as glucuronides and sulfates.
For EE, the terminal disposition phase half-life has been reported to be approximately 24 hours. EE is not excreted unchanged. EE is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic circulation.
Special Populations and Conditions: Pediatrics: The safety and efficacy of YASMIN has not been established in women under the age of 16 years. Use of this product before menarche is not indicated.
Geriatrics: YASMIN is not indicated for use in postmenopausal women.
Race: The effect of race on the disposition of YASMIN has not been evaluated.
Hepatic Insufficiency: YASMIN is contraindicated in patients with hepatic dysfunction (see Precautions). The mean terminal half-life of DRSP for women with moderate hepatic impairment was 1.8 times greater than for women with normal hepatic function.
Renal Insufficiency: YASMIN is contraindicated in patients with renal insufficiency (see Precautions).
The effect of renal insufficiency on the pharmacokinetics of DRSP (3 mg daily for 14 days) and the effect of DRSP on serum potassium levels were investigated in female subjects (n=28, age 30-65) with normal renal function and mild and moderate renal impairment. All subjects were on a low potassium diet. During the study, 7 subjects continued the use of potassium-sparing drugs for the treatment of the underlying illness. On the 14th day (steady-state) of DRSP treatment, the serum DRSP levels in the group with mild renal impairment (creatinine clearance CLcr, 50-80 mL/min) were comparable to those in the group with normal renal function (CLcr, >80 mL/min). The serum DRSP levels were on average 37% higher in the group with moderate renal impairment (CLcr, 30-50 mL/min) compared to those in the group with normal renal function. DRSP treatment was well tolerated by all groups. DRSP treatment did not show any clinically significant effect on serum potassium concentration. Although hyperkalemia was not observed in the study, in five of the seven subjects who continued use of potassium-sparing drugs during the study, mean serum potassium levels increased by up to 0.33 mEq/L. Therefore, potential exists for hyperkalemia to occur in subjects with renal impairment whose serum potassium is in the upper reference range and who are concomitantly using potassium sparing drugs.
Toxicology: Acute Toxicity: Table 3 as follows summarizes the median lethal doses (LD50) determined in acute toxicity studies with drospirenone. (See Table 3.)
Click on icon to see table/diagram/imageThe principle clinical signs observed in mice and rats were similar in all studies and included apathy; gait and posture disturbances; and at higher doses, twitching, spasms, and/or unconsciousness. Deaths generally occurred within 3 to 4 days of dosing.
Single high doses of drospirenone to female Beagle dogs were generally well tolerated, with compound-related effects limited to vomiting, transient changes in food/water consumption, and slight changes in serum biochemistry and coagulation parameters. No deaths occurred.
Long-term Toxicity: The long-term toxicity of drospirenone, alone and in combination with ethinylestradiol, was investigated after daily intragastric administration of the following doses. (See Table 4.)
Click on icon to see table/diagram/imageCompound-related findings were generally limited to pharmacologic and exaggerated pharmacologic effects expected following administration of an exogenous progestogen or estrogen/progestogen combination. No organ toxicity was observed.
Changes observed following administration of drospirenone alone included: alterations in lipid, carbohydrate and protein metabolism (rats: ≥1 mg/kg/day); increased body weight gain and food consumption (rats: ≥3 mg/kg/day); decreased liver weights accompanied by decreased hepatic glycogen content (monkeys: ≥2 mg/kg/day); increased liver weights accompanied by increased hepatic DNA and protein content (rats: ≥50 mg/kg/day); changes in electrolyte excretion (rats: ≥10 mg/kg/day; monkeys: 10 mg/kg/day); decreased ovarian weights (mice: 30 mg/kg/day); decreased (mice: 30 mg/kg/day) or slightly increased (monkeys: 10 mg/kg/day) adrenal gland weights; microscopic changes in endocrine target organs (mice: ≥3 mg/kg/day; rats: ≥3 mg/kg/day; monkeys: ≥0.2 mg/kg/day).
A spectrum of compound-related estrogenic, progestogenic and antimineralocorticoid effects was observed following administration of the combination to female mice, rats, and monkeys. In addition, the antagonism of some estrogenic effects (decreased body weight and food consumption [rats]; hematologic changes [rats, monkeys], and increased uterine weights [mice]), and antagonism of some progestogenic effects (increased body weight and food consumption [rats]) were observed.
Synergism of other effects was observed in mice and rats and included atrophy of ovarian interstitial glands, decreased luteal mass and sexual cycles in mice, and decreased ovarian weights and increased hepatic N-demethylase activity in rats. In comparison with administration of either substance alone, administration of the combination to rats and cynomolgus monkeys eliminated some single substance effects (alterations in hepatic cytochrome P450 content). Overt toxicity was limited to one possible compound-related death in cynomolgus monkeys administered the combination at a dose of 3 mg/kg drospirenone + 0.03 mg/kg ethinyl estradiol for 11 weeks.
Toxicokinetic monitoring showed that on the basis of AUC(0-24h) values, the highest doses used in mice (30 mg/kg/day), rats (15 mg/kg/day), and monkeys (10 mg/kg/day) which did not produce overt signs of toxicity led to roughly 10.6 times (mice), >12 times (rats), and ca 22 times (monkeys) higher systemic exposure as compared to human exposure at the therapeutic dose.
Carcinogenicity: The carcinogenic potential of drospirenone, alone and in combination with ethinylestradiol, was investigated in female mice and rats after daily intragastric administration of the following doses. (See Table 5.)
Click on icon to see table/diagram/imageNo carcinogenicity was observed after two years of treatment with drospirenone as a single compound in mice or rats. Mortality was increased in rats at the highest dose of drospirenone.
The increased food intake of the rats with a resultant increase in body weight was considered as the reason for the reduction in their life span. In the mouse study there were no effects on the survival of the animals observed after treatment with drospirenone.
Tumorigenic effects of the drug combination in mice were manifested by an increased incidence of pituitary adenomas at all doses, overall mammary tumors at the mid and low doses, and uterine adenocarcinomas at the mid and high doses in comparison with controls. The same qualitative tumor pattern (however, quantitatively more pronounced, especially in the pituitary) was seen in groups treated with ethinylestradiol alone. As drospirenone alone elicited no tumorigenic response, the tumorigenic potential of the combination was attributed to ethinylestradiol.
Treatment of rats with the drug combination resulted in an increased incidence of hepatic adenomas at the high dose and of total liver tumors from the mid dose onwards. A similar effect on liver tumor induction was seen in groups receiving ethinylestradiol alone. Therefore, this effect on the liver could be attributed to the activity of ethinylestradiol.
Compared to the control group, a tendency towards an increased rate of endometrial adenoma with a concomitant decrease in the rate of adenocarcinoma was seen in the uteri from the animals of the low-dose combination group. In the mid- and high-dose combination groups, no endometrial adenomas or adenocarcinomas were noted, ie, there was a reduction in the rate of uterine tumours below the control level. A clear-cut increase in these uterine tumour incidences was induced by ethinylestradiol when given alone from the mid dose onwards. Thus, the presence of drospirenone in the drug combination apparently led to a suppression of the deleterious estrogenic effect on the uterus. Treatment with ethinylestradiol at the high dose led to an increased incidence of adenocarcinoma in the mammary glands. This effect was also completely counteracted by drospirenone in the drug combination group.
Evaluation of concomitant drug plasma concentrations revealed that exposure to drospirenone on the basis of AUC(0-24h) values amounted to roughly 0.1-, 0.5-, and 3-fold multiples of human exposure after the low, mid, and high doses, respectively. The corresponding exposure multiples for drospirenone in the rat were approximately 0.5, 3.5, and 10 to 12 times human steady-state exposure.
Mutagenicity: No mutagenic effect of drospirenone was demonstrated in vitro in bacterial (Salmonella typhimurium, Escherichia coli) or mammalian (human lymphocyte, Chinese hamster) cells in the presence or absence of extrinsic metabolic activation. Drospirenone did not increase the occurrence of micronucleated red blood cells in vivo following single intragastric administration of 1000 mg/kg to mice.
Drospirenone increased unscheduled DNA synthesis in primary hepatocytes of female rats in vitro in a dose-dependent manner at a concentration of 10 to 60 μg/mL. Intragastric administration of drospirenone 10 mg/kg/day to rats for 14 consecutive days generated two forms of DNA adducts in male and female rat livers. Low levels of three compound-related DNA adducts were also observed in the livers of female mice given drospirenone 10 mg/kg/day, alone or in combination with 0.1 mg/kg/day ethinylestradiol, in the carcinogenicity study. In contrast to these findings observed in rodent livers, results from an in vitro study conducted with drospirenone 5 μg/mL in human liver slices did not indicate a DNA adduct forming potential of drospirenone in human tissue. Given the lack of any drospirenone-related liver tumour formation in mice and rats, the biological relevance of this interaction with DNA in the rodent liver with regard to risk assessment in humans is questionable.
Reproduction and Teratology: The reproductive toxicity of drospirenone, alone and in combination with ethinylestradiol, was investigated in rats, rabbits, and monkeys following intragastric administration at the following doses: See Table 6.
Click on icon to see table/diagram/imageAs expected from the pharmacological activity of an estrogen/progestogen combination, estrous cycle disturbances and a transient impairment of fertility were observed in rats when treated for 6 weeks prior to mating with doses of 5 mg/kg/day drospirenone + 0.05 mg/kg/day ethinylestradiol and higher. Pre- and postimplantation losses were significantly increased when 10 mg/kg/day drospirenone + 0.1 mg/kg/day ethinyl estradiol were administered during the preimplantation phase of gestation in rats.
No teratogenicity was observed following intragastric administration of drospirenone, alone or in combination with ethinylestradiol, to female rats, rabbits, and/or monkeys, prior to mating or during gestation. Compound-related maternal toxicity, characterized by decreased body weight gain (rats) and occasional vomiting (monkeys), was observed. The incidence of abortions was increased following administration of high doses of drospirenone (100 mg/kg/day) to pregnant rabbits, and a dose-dependent increase in abortions occurred following the administration of all doses to monkeys. Embryotoxicity and slight retardations of fetal development (eg, delayed ossification of feet bones, sternebrae, vertebrae; incomplete ossification of skull; slight increase in visceral abnormalities) were observed in the rat and rabbit at drospirenone doses of 15 mg/kg/day and 100 mg/kg/day, respectively.
Virilization of female fetuses (attributed to ethinylestradiol) and feminization of male fetuses (attributed to drospirenone) were observed following administration of the drug combination to pregnant rats on Days 14 through 21 of pregnancy, beginning at doses of 5+0.05 mg/kg and 15+0.15 mg/kg, respectively. If exposure estimates from nonpregnant rats are extrapolated to pregnant animals, the administration of 15 mg/kg/day drospirenone would result in plasma exposure levels which are at least 10 times higher than the steady-state human exposure after intake of YASMIN.
Prolonged or incomplete parturition or inability to deliver was observed when the drug combination was administered to rats from Day 15 of gestation through Day 3 postpartum. In the rat peri-/postnatal study, treatment from Days 15-18 of gestation and Days 1-22 postpartum caused a dose-dependent delay in postnatal development (body weight, physical and functional parameters) and a dose-dependent increased mortality of the F1 offspring. These observations were attributed to the negative effects of drospirenone and/or ethinylestradiol on lactogenesis and milk secretion.
A reduced reproductive performance of the F1 animals was observed at the dose of 45 mg/kg/day drospirenone + 0.45 mg/kg/day ethinylestradiol. This was attributed to an impairment of sex organ development in the male offspring due to the antiandrogenic activity of drospirenone.
