Slinda Mechanism of Action

Pharmacotherapeutic group: Hormonal contraceptives for systemic use, progestogens. ATC code: G03AC10.
PHARMACOLOGY: Pharmacodynamics: Mechanism of action: Slinda is a progestogen-only-pill which contains the progestogen drospirenone, derived from spironolactone.
In a therapeutic dosage, drospirenone also possesses antiandrogenic and mild antimineralocorticoid properties. It has no estrogenic, glucocorticoid and antiglucocorticoid activity. This gives drospirenone a pharmacological profile closely resembling the natural hormone progesterone.
There are indications from clinical studies that for combined hormonal contraceptives containing 3 mg drospirenone and 0.02 mg ethinylestradiol, the mild antimineralocorticoid properties result in a mild antimineralocorticoid effect.
Pharmacodynamic effects: The contraceptive effect of Slinda is achieved primarily by inhibition of ovulation. Drospirenone exhibits a strong anti-gonadotropic activity inhibiting follicular stimulation and ovulation by suppression of the luteinising hormone (LH). In addition, drospirenone has an effect on the cervix increasing the viscosity of the cervical mucus. Drospirenone also exerts progestational effects on the endometrium, which becomes thinner.
Clinical efficacy and safety: The ovulation inhibition potential of Slinda (drospirenone 4 mg non-micronized administered daily for 24 days) as reflected by the ovarian activity [follicular growth, endogenous estradiol and progesterone serum concentrations (Hoogland score)] in comparison to 0.075 mg of desogestrel administered daily for 28 days over two treatment cycles was assessed in a randomized, open-label Phase II study conducted in 60 healthy young women. In cycle 1, no ovulation was observed in either treatment. Whereas one ovulation was observed for Slinda and 0.075 mg of desogestrel group in cycle 2.
In a Phase II study performed in 130 women, Slinda maintained the inhibition of ovulation in spite of four fixed scheduled delayed intakes of 24 hours each on day 3, 6, 11 and 22.
In two multicenter Phase III European clinical trials, one single-arm study and one controlled study vs. desogestrel 0.075 mg, 1596 women have been treated for 9 up to 13 consecutive cycles with Slinda and 341 with desogestrel for 9 months. In the pooled analysis of these two studies the following Pearl Indexes were calculated: Pearl Index (18-45 years of age), user + method failure: 0.73 (upper limit 95% confidence interval 1.43).
Pearl Index (18-35 years of age), user + method failure: 0.93 (upper limit 95% confidence interval 1.84).
In a single arm multicenter Phase III clinical trial performed in 39 US sites, the efficacy population consisted of 953 females ≤ 35 years of age with 5,547 evaluable cycles. During these cycles, 17 (1.8%) pregnancies were reported (irrespectively of confirmation by urine and serum pregnancy tests at the study site) leading to a Pearl Index (95% CI) of 4.0 (2.3, 6.4).
Bleeding pattern: The bleeding pattern during use of Slinda was assessed in a 9-month comparative, double blind trial vs desogestrel 0.075 mg, used continuously.
The occurrence of a withdrawal bleeding (defined as a bleeding starting during the 4 hormone-free days of Slinda lasting for up to 8 consecutive days), was highest - occurring in less than 40% - during the first cycles and decreased with time. After 9 months of use, a withdrawal bleeding was recorded in less than 20% of users.
The mean number of bleeding/spotting days in the Slinda group vs the desogestrel group during the cycles 2-4 was 13.1 ± 13.0 vs 16.9 ± 16.9, respectively (p=0.0149). The mean number of bleeding/spotting days during cycles 7-9, was 9.7 ± 10.4 vs 10.8 ± 13.3, respectively.
In the same study, the proportion of subjects without any bleeding/spotting during cycles 2-4 was 20.1% for Slinda and 13.5% for desogestrel. The proportion of subjects without any bleeding/spotting increased in cycles 7-9 to 26.7% for Slinda and to 32.1% in the desogestrel group.
The number of subjects with prolonged bleeding (>10 consecutive days) for Slinda vs desogestrel was 18.1% and 26.1%, respectively, during cycles 2-4 and 9.1% and 16.7%, respectively, during cycles 7-9.
The rate of subjects who withdrew from the study due to bleeding related adverse events was 3.3% in the Slinda group and 6.6% in the desogestrel group.
Paediatric population: A phase III study was conducted in Europe to evaluate tolerability, safety and acceptability of Slinda 103 adolescents were included in a 6-cycle core part and 7 additional cycles (extension phase) for a total of 13 cycles, Slinda was well tolerated and accepted by the subjects.
Bleeding pattern with Slinda was assessed and data were generally consistent with those from the Phase 3 studies in adults. Slinda was associated with a decrease in the percentage of subjects experiencing bleeding or spotting over time.
Pharmacokinetics: Absorption: Orally administered drospirenone is rapidly and almost completely absorbed. Maximum concentrations of Slinda active substance in plasma of about 28 ng/ml are reached at about 3-4 h after single ingestion. Concomitant ingestion of food has no influence on the extent of absorption of drospirenone.
The pharmacokinetics of Slinda after single and repeated dose has been studied in comparison with the marketed product containing 3 mg of micronized drospirenone in combination with ethinyl estradiol. After multiple dose administration, the relative bioavailability of Slinda was 76.51% for AUC_t,ss. The accumulation ratio expressed by Rac (AUC) was 1.9256 while it was 2.7684 for the combined product. These findings indicate that the total exposure to drospirenone is lower for Slinda than for the combined product on the market in a cycle of 28 days.
Distribution: Drospirenone is 95% to 97% bound to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CBG). The mean apparent volume of distribution of drospirenone is approximately 4 l/kg.
Biotransformation: Drospirenone is extensively metabolized after oral administration. Two major non-pharmacologically active 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 P450 system. Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4.
In vitro, drospirenone is capable to inhibit weakly to moderately the cytochrome P450 enzymes CYP1A1, CYP2C9, CYP2C19 and CYP3A4.
Elimination: After oral administration, plasma drospirenone levels decrease with a terminal half-life of 32 h.
The metabolic clearance rate of drospirenone in serum is 1.5 ± 0.2 ml/min/kg. Drospirenone is excreted only in trace amounts in unchanged form. The metabolites of drospirenone are excreted with the faeces and urine at an excretion ratio of about 1.2 to 1.4.
Linearity/non-linearity: The pharmacokinetics of oral drospirenone is dose proportional following single doses ranging from 1-10 mg.
Steady-state conditions: During a treatment cycle, maximum steady-state concentrations of drospirenone in serum of about 40 ng/ml are reached after about 7 days of treatment. Plasma drospirenone levels accumulate by a factor of about 2 as a consequence of the ratio of terminal half-life and dosing interval.
Special populations: Effect of renal impairment: No studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of Slinda. However, steady-state serum drospirenone levels in women under treatment with a COC containing drospirenone with mild renal impairment (creatinine clearance CLcr, 50-80 mL/min) were comparable to those of women with normal renal function. The serum drospirenone levels were on average 37% higher in women with moderate renal impairment (CLcr, 30 - 50 mL/min) compared to those in women with normal renal function. Drospirenone treatment was also well tolerated by women with mild and moderate renal impairment. Drospirenone treatment did not show any clinically significant effect on serum potassium concentration.
Effect of hepatic impairment: No studies have been conducted to evaluate the effect of hepatic disease on the pharmacokinetics of Slinda. However, steroid hormones may be poorly metabolized in women with impaired liver function.
In a single dose study in women taking a COC containing drospirenone, oral clearance (CL/F) was decreased approximately 50% 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 did not translate into any apparent difference in terms of serum potassium concentrations. Even in the presence of diabetes and concomitant treatment with spironolactone (two 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: No clinically relevant differences in the pharmacokinetics of drospirenone between Japanese and Caucasian women have been observed.
Toxicology: Preclinical safety data: In laboratory animals, the effects of drospirenone were confined to those associated with the recognised pharmacological action. In particular, reproduction toxicity studies revealed embryotoxic and fetotoxic effects in animals which are considered as species specific. At exposures exceeding those in users of drospirenone, effects on sexual differentiation were observed in rat fetuses but not in monkeys. Environmental risk assessment studies have shown that drospirenone may pose a risk for the aquatic environment as the reproductive effects in fish were evident at 0.087 ug/L (the LOEC). (See Special precautions for disposal under Cautions for Usage.)