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Pharmacology: Pharmacodynamics: The contraceptive effect of combined oral contraceptives (COCs) is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the cervical secretion.
A large, prospective 3-armed cohort study has shown that the frequency of venous thromboembolism (VTE) diagnosis ranges between 8 to 10/10,000 woman years in low estrogen dose (<50 mcg ethinylestradiol) COC users. The most recent data suggest that the frequency of VTE diagnosis is approximately 4.4/10,000 woman years in nonpregnant non-COC users, and ranges between 20-30/10,000 pregnant women or postpartum. The incidence of VTE in women with or without other risk factors for VTE who used ethinylestradiol/drospirenone 0.03 mg/3 mg is in the same range as that for users of levonorgestrel-containing COCs and other COCs (various other COC brands). This has also been confirmed in a prospective controlled database study comparing users of ethinylestradiol 0.03 mg/drospirenone 3 mg to other COC users showing similar incidence of VTE among the cohorts.
As well as protection against pregnancy, COCs have several positive properties which, next to the negative properties (see Warnings and Side Effects), can be useful in deciding on the method of birth control. The cycle is more regular and the menstruation is often less painful and bleeding is lighter. The latter may result in a decrease in the occurrence of iron deficiency.
Drospirenone has beneficial properties in addition to contraception. It has antimineralocorticoid activity that can prevent weight gain and other symptoms caused by fluid retention. It counteracts the estrogen-related sodium retention, providing for a very good tolerance and has positive effects on premenstrual syndrome. In combination with ethinylestradiol, drospirenone displays a favorable lipid profile with an increase in HDL. Drospirenone exerts antiandrogenic activity leading to a positive effect on the skin and to a reduction in acne lesions and sebum production. In addition, drospirenone does not counteract the ethinylestradiol-related SHBG increase, which is useful for binding and inactivating the endogenous androgens.
Drospirenone is devoid of any androgenic, estrogenic, glucocorticoid and antiglucocorticoid activity. This, in combination with the antimineralocorticoid and antiandrogenic properties, gives drospirenone a biochemical and pharmacological profile closely resembling the natural hormone, progesterone. Apart from this, there is evidence of a reduced risk of endometrial and ovarian cancer. Furthermore, the higher dosed COCs (0.05 mg ethinylestradiol) have been shown to reduce the incidence of ovarian cysts, pelvic inflammatory disease, benign breast disease and ectopic pregnancy. Whether this also applies to lower dosed COCs remains to be confirmed.
Pharmacokinetics: Drospirenone: Absorption: Orally administered drospirenone is rapidly and almost completely absorbed. Peak serum concentrations of approximately 37 ng/mL are reached at about 1-2 hrs after single ingestion. Bioavailability is about 76-85%. Concomitant ingestion of food has no influence on bioavailability.
Distribution: Drospirenone is bound to serum albumin and does not bind to sex hormone-binding globulin (SHBG) or corticoid-binding globulin (CBG). Only 3-5% of the total serum drug concentrations are present as free steroid, 95-97% are nonspecifically bound to albumin. The ethinylestradiol-induced increase in SHBG influences the serum protein-binding of drospirenone. The apparent volume of distribution of drospirenone is about 3.7-4.2 L/kg.
Metabolism: Drospirenone is completely metabolized. The major metabolites in the plasma are the acid form of drospirenone, generated by opening of the lactone ring, and the 4,5-dihydro-drospirenone-3-sulfate, both of which are formed without involvement of the P-450 system. It is metabolized to a minor extent by cytochrome P-450 3A4 based on in vitro data. The clearance rate from serum is about 1.2-1.5 mL/min/kg. When drospirenone was acutely co-administered with ethinylestradiol, no direct interaction was found.
Elimination: Drospirenone serum levels decrease in 2 phases. The terminal disposition phase is characterized by a t½ of 31 hrs. Drospirenone is not excreted in unchanged form. Its metabolites are excreted at a biliary-to-urinary ratio of about 1.2:1.4. The t½ of metabolite excretion with the urine and feces is about 1.7 days.
Steady-State Conditions: Drospirenone pharmacokinetics is not influenced by SHBG levels. Following daily ingestion, drug serum levels increase about 2- to 3-fold reaching steady-state conditions during the 2nd half of a treatment cycle.
Effect of Renal Impairment: Steady-state serum drospirenone levels in women with mild renal impairment (creatinine clearance [CrCl], 50-80 mL/min) were comparable to those of women with normal renal function (CrCl >80 mL/min). The serum drospirenone levels were on average 37% higher in women with moderate renal impairment (CrCl, 30-50 mL/min) compared to those in women with normal renal function. Drospirenone treatment was well tolerated by all groups. Drospirenone treatment did not show any clinically significant effect on serum potassium concentration.
Effect of Hepatic Impairment: In women with moderate hepatic function, (Child-Pugh B) mean serum drospirenone concentration-time profiles were comparable to those of women with normal hepatic function during the absorption/distribution phases with similar Cmax values. The mean terminal t½ of drospirenone for volunteers with moderate hepatic impairment was >1.8 times than for volunteers with normal hepatic function. About 50% decrease in apparent oral clearance (CL/f) was seen in volunteers with moderate hepatic impairment as compared to those with normal liver function. The observed decline in drospirenone clearance in volunteers with moderate hepatic impairment compared to normal volunteers did not translate into any apparent difference in terms of serum potassium concentrations between the 2 groups of volunteers. Even in the presence of diabetes and concomitant treatment with spironolactone (2 factors that can predispose a patient to hyperkalemia) an increase in serum potassium concentrations above the upper limit of the normal range was not observed. It can be concluded that drospirenone is well tolerated in patients with mild or moderate hepatic impairment (Child-Pugh B).
Ethnic Groups: The impact of ethnic factors on the pharmacokinetics of drospirenone and ethinylestradiol was studied after single and repeated daily oral administration to young, healthy Caucasian and Japanese women. The results showed that ethnic differences between Japanese and Caucasian women had no clinically relevant influence on the pharmacokinetics of drospirenone and ethinylestradiol.
Ethinylestradiol: Absorption: Orally administered ethinylestradiol is rapidly and completely absorbed. Peak serum concentrations of about 54-100 pg/mL are reached within 1-2 hrs. During absorption and first-liver passage, ethinylestradiol is metabolized extensively, resulting in a mean oral bioavailability of about 45% with a large interindividual variation of about 20-65%. Concomitant intake of food reduced the bioavailability of ethinylestradiol in about 25% of the investigated subjects while no change was observed in the others.
Distribution: Ethinylestradiol is highly but nonspecifically bound to serum albumin (approximately 98%) and induces an increase in the serum concentrations of SHBG. An apparent volume of distribution of about 2.8-8.6 L/kg was determined.
Metabolism: Ethinylestradiol is subject to presystemic conjugation in both small bowel mucosa and the liver. It is primarily metabolized by aromatic hydroxylation, but a wide variety of hydroxylated and methylated metabolites are formed, and these are present as free metabolites and as conjugates with glucuronides and sulfate. The clearance rate was reported to be 2.3-7 mL/min/kg.
Elimination: Ethinylestradiol serum levels decrease in 2 disposition phases characterized by half-lives of about 1 hr and 10-20 hrs, respectively. Unchanged drug is not excreted; ethinylestradiol metabolites are excreted at a urinary-to-biliary ratio of 4:6. The t½ of metabolite excretion is about 1 day.
Steady-State Conditions: Steady-state conditions are reached during the 2nd half of a treatment cycle when serum drug levels are higher by 40-110% as compared to a single dose.
Toxicology: Preclinical Safety Data: Preclinical data reveal no special risks for humans based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. However, it should be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.
