Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties
Pharmacotherapeutic group: Other gynecologicals, Intravaginal contraceptives, vaginal ring with progestagen and estrogen, ATC code: G02BB01

Mechanism of action
NuvaRing contains etonogestrel and ethinylestradiol. Etonogestrel is a 19-nortestosterone- derived progestagen and binds with high affinity to progesterone receptors in the target organs.
Ethinylestradiol is an estrogen widely used in contraceptive products. The contraceptive effect of NuvaRing is based on various mechanisms, the most important of which is the inhibition of ovulation.

Clinical efficacy and safety
Clinical studies were performed worldwide (US, EU, and Brazil) in women between the ages of 18 and 40 years. The contraceptive efficacy appeared to be at least comparable with that known for combined oral contraceptives. The following table shows the Pearl Indices (number of pregnancies per 100 woman years of use) found in the clinical studies with NuvaRing.

Analysis Method              Pearl Index               95 % CI               No of Cycles ITT (user + method              0.96                 0.64 – 1.39                37,977 failure)
PP (method failure)              0.64                0.35 – 1.07                28,723 
With the use of higher-dosed COCs (0.05 mg ethinylestradiol) the risk of endometrial and ovarian cancer is reduced. Whether this also applies to a lower dosed contraceptive like NuvaRing remains to be determined.

BLEEDING PATTERN
A large comparative study with 150/30 µg levonorgestrel/ethinylestradiol OC (n= 512 vs n= 518) evaluating vaginal bleeding characteristics over 13 cycles showed low incidences of breakthrough spotting or bleeding for NuvaRing (2.0-6.4%). Furthermore, vaginal bleeding was exclusively restricted to the ring-free interval for most subjects (58.8-72.8 %).

EFFECTS ON BONE MINERAL DENSITY
The effects of NuvaRing (n=76) on bone mineral density (BMD) were studied in comparison to a non-hormonal intrauterine device (IUD) (n=31) in women over a period of two years. No adverse effects on bone mass have been observed.

Paediatric population
The safety and efficacy of NuvaRing in adolescents under the age of 18 have not been studied.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties
Etonogestrel

Absorption
Etonogestrel released by NuvaRing is rapidly absorbed by the vaginal mucosa. Maximum serum concentrations of etonogestrel of approximately 1,700 pg/mL are reached at about 1 week after insertion. Serum concentrations show small fluctuations and slowly decrease to approximately 1,600 pg/mL after 1 week, 1,500 pg/mL after 2 weeks and 1,400 pg/mL after 3 weeks of use. Absolute bioavailability is approximately 100%, which is higher than after oral administration. Cervical and intrauterine etonogestrel levels were measured in a small number of women using NuvaRing or an oral contraceptive containing 0.150 mg desogestrel and 0.020 mg ethinylestradiol. The observed levels were comparable.

Distribution
Etonogestrel is bound to serum albumin and to sex hormone binding globulin (SHBG). The apparent volume of distribution of etonogestrel is 2.3 L/kg.

Biotransformation
Etonogestrel is metabolised by the known pathways of steroid metabolism. The apparent clearance from serum is about 3.5 L/h. No direct interaction was found with the co-administered ethinylestradiol.

Elimination
Etonogestrel serum levels decrease in two phases. The terminal elimination phase is characterised by a half-life of approximately 29 hours. Etonogestrel and its metabolites are excreted at a urinary to biliary ratio of about 1.7:1. The half-life of metabolite excretion is about 6 days.

Ethinylestradiol

Absorption
Ethinylestradiol released by NuvaRing is rapidly absorbed by the vaginal mucosa. Maximum serum concentrations of about 35 pg/mL are reached 3 days after insertion and decrease to 19 pg/mL after 1 week, 18 pg/mL after 2 weeks and 18 pg/mL after 3 weeks of use. The monthly systemic ethinylestradiol exposure (AUC0-∞) with NuvaRing is 10.9 ng.h/mL. Absolute bioavailability is approximately 56%, which is comparable with oral administration of ethinylestradiol. Cervical and intrauterine ethinylestradiol levels were measured in a small number of women using NuvaRing or an oral contraceptive containing 0.150 mg desogestrel and 0.020 mg ethinylestradiol. The observed levels were comparable.

Distribution
Ethinylestradiol is highly but non-specifically bound to serum albumin. An apparent volume of distribution of about 15 L/kg was determined.

Biotransformation
Ethinylestradiol is primarily metabolised by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed. These are present as free metabolites and as sulphate and glucuronides conjugates. The apparent clearance is about 35 L/h.

Elimination
Ethinylestradiol serum levels decrease in two phases. The terminal elimination phase is characterised by a large individual variation in half-life, resulting in a median half-life of approximately 34 hours. Unchanged ethinylestradiol is not excreted; ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 1.3:1. The half-life of metabolite excretion is about 1.5 days.

Special populations

Paediatric population
The pharmacokinetics of NuvaRing in healthy postmenarcheal female adolescents under the age of 18 have not been studied.

Effect of renal impairment
No studies were performed to evaluate the effect of renal disease on the pharmacokinetics of NuvaRing.

Effect of hepatic impairment
No studies were conducted to evaluate the effect of hepatic disease on the pharmacokinetics of NuvaRing. However, steroid hormones may be poorly metabolised in women with impaired liver function.

Ethnic groups
No formal studies were performed to assess pharmacokinetics in ethnic groups.