Introduction
Use of oral progestin mono-preparations (progestin-only pills)
Of all the factors influencing a womanʼs choice of contraceptive method – its effectiveness,
personal preferences of the patient, potential additional benefits [1] – most important is the associated risk profile. For several years, the WHO has
published a comprehensive set of guidelines on the use of hormonal contraceptive methods,
providing advice for and against the use of certain (hormonal) contraceptive methods
in a variety of medical scenarios (pre-existing conditions, concomitant medications,
etc.) [2]. Its recommendations are grouped into four categories. Methods that on the grounds
of a specific medical history fall into category 1 can be recommended without restriction.
In contrast, category 4 methods are associated with a high risk to health and should
be avoided. Category 2 and 3 methods should only be administered after a rigorous
risk-benefit assessment, and while the benefits of category 2
contraceptives generally outweigh the risks, category 3 methods should only be
used if no alternative is available [2]. The advantages of the WHO guidelines are evident. They provide very concrete treatment
recommendations, ensure a measure of safety from a legal standpoint, and it is relatively
easy to employ and document them in consultations. However, even in a set of guidelines
as extensive as those published by the WHO it is impossible to cover all specific
risk scenarios.
Many potential risks of hormonal contraception can be attributed to the oestrogen
component [3], [4], which is why in various scenarios the WHO guidelines classify combined hormonal
contraceptives (CHCs) under category 4 and are therefore contraindicated ([Table 1]). The most important factor in this respect is the increase in the risk of thrombosis
due to exogenously administered oestrogens (especially ethinyloestradiol, a constituent
of most combined contraceptives), which has been observed for all forms of administration
(tablet, patch or vaginal ring) [4], [5], [6]. Progestins in CHCs modulate the thromboembolic risk, resulting in estimated incidences
of a venous thromboembolic event (VTE) of 5 – 7 per 10 000 women per year of use for
levonorgestrel-containing and
norgestimate/norethisterone-containing CHCs and 9 – 12, for gestodene/desogestrel/drospirenone-containing
CHCs [6]. On the other hand, the current state of knowledge suggests that progestin mono-preparations
do not increase VTE risk, with the exception of depot injections containing high doses
of medroxprogesterone acetate [5].
Table 1 Extract from the WHO guidelines on the use of combined hormonal contraceptives (CHCs)
and POPs in specific medical scenarios. Complete overview: see [2].
|
Risk factor
|
|
CHC
|
Patch/ring
|
POP
|
|
VTE: venous thromboembolic event, ATE: arterial thromboembolic event, I: initiation,
C: continuation
|
|
VTE/pulmonary embolism
|
Medical history
|
4
|
4
|
2
|
|
Acute
|
4
|
4
|
2
|
|
Anticoagulation discontinued
|
4
|
4
|
2
|
|
Fam. history (grade 1)
|
2
|
2
|
1
|
|
VTE and operations
|
Major surgery, prolonged immobilisation
|
4
|
4
|
2
|
|
Without prolonged immobilisation
|
2
|
2
|
1
|
|
Minor surgery, without immobilisation
|
1
|
1
|
1
|
|
Thrombogenic mutation
|
Factor V Leiden and prothrombin mutations, for instance
|
4
|
4
|
2
|
|
Ischaemic heart disease
|
Acute or in history
|
4
|
4
|
2 (I)/3(C)
|
|
Stroke
|
|
4
|
4
|
2 (I)/3(C)
|
|
Multiple risk factors for ATE
|
Including age, smoking, diabetes, hypertension, dyslipidaemia
|
3/4
|
3/4
|
2
|
|
Age
|
Menarche up to < 18 years old
|
NDA
|
NDA
|
1
|
|
< 40 years old
|
1
|
1
|
1
|
|
> 40 years old
|
2
|
2
|
1
|
|
Smoking
|
< 35 years old
|
2
|
2
|
1
|
|
> 35 years old
-
< 15 cigarettes
-
> 15 cigarettes
|
3
4
|
3
4
|
1
1
|
|
Hypertension (without other risk factors)
|
After hypertension (in the absence of measured values)
|
3
|
3
|
2
|
|
Well-controlled hypertension
|
3
|
3
|
1
|
|
140 – 159/90 – 99 mmHg
|
3
|
3
|
1
|
|
≥ 160/≥100 mmHg
|
4
|
4
|
2
|
|
Vascular disorder
|
4
|
4
|
2
|
|
Non-vascular disorder
|
2
|
2
|
2
|
|
Neuropathy/retinopathy/nephropathy
|
3/4
|
3/4
|
2
|
|
Other vascular disorders or diabetes for > 20 years
|
3/4
|
3/4
|
2
|
Over time, CHCs have been developed with very low doses of ethinyloestradiol (EE)
(10 – 30 µg) or oestradiol (E2), or ovulation inhibitors with no oestrogen component at all [7].
A recent review by Khialani et al. [3] clearly found that the EE component in CHCs is responsible for the increase in cardiovascular
risk and in a dose-dependent manner.
Oral progestin mono-preparations were originally intended for use during breastfeeding,
as the highest risk of VTE occurs during the postpartum period and oestrogens can
reduce milk production, depending on dosage. Termed the “mini-pill”, they contain
very low doses and only inhibit ovulation in about 50% of cycles. The contraceptive
action is mainly caused by an increase in cervical mucus viscosity, disruption of
tubal motility and premature secretory transformation of the endometrium. The Pearl
Index (PI) for these preparations is significantly worse than that for CHCs. The introduction
of the higher-dose, and thus much more reliable, ovulation-inhibiting progestin mono-preparation
containing desogestrel has made the concept of oestrogen-free contraception attractive
to a much larger population of women.
Progestin structure and receptor interaction
Depending on their structure, progestins interact differently with the bodyʼs various
steroid receptors. Steroid receptors are located both within the cell body and on
the membrane of target cells and influence protein biosynthesis at the level of DNA
transcription.
The following receptors bind progestins:
-
Progesterone receptors (PRs). PR has two isoforms: PR-A and PR-B. PR-A mainly acts
by repressing the transcriptional activity of PR-B as well as that of oestrogen, androgen,
glucocorticoid and mineralocorticoid receptors. PR-B, in contrast, has an activating
effect on transcription.
-
Androgen receptors. Activation of androgen receptors mediates androgenic effects,
for example those that result in hair growth and sebaceous gland activity. Some progestins
bind to these receptors and can either block or activate them.
-
Oestrogen receptors. These receptors exert an effect in many different tissues; in
the context of use of contraceptives, their most important effect is to induce endometrial
proliferation.
-
Glucocorticoid receptors. Glucocorticoid receptors have been linked with activation
of the coagulation system.
-
Mineralocorticoid receptors. These receptors modulate sodium retention.
Progestins are grouped on the basis of the differing strength with which they activate
these receptors: androgenic, anti-androgenic, slightly anti-androgenic, neutral or
anti-mineralocorticoidic partial effects. Of the progestins used in treatment, only
DRSP and (synthetic) progesterone have anti-mineralocorticoid effects, whereas levonorgestrel,
norgestimate and desogestrel have androgenic effects, and DRSP, dienogest, cyproterone
acetate (CPA) and chlormadinone acetate (CMA) have anti-androgenic effects [8].
The anti-androgenic effect, which has been demonstrated in cell cultures and animal
models [9], is not in CHC solely due to the progestin component, but also to the fact that
the EE-induced increase in sex hormone binding globulin (SHBG) reduces the level of
free testosterone in the body.
Classification of progestins based on their market introduction
It has become common practice to employ the following “historical” classification
scheme. This distinguishes between first, second, third and fourth CHC generations.
-
First generation: norethynodrel, norethisterone acetate
-
Second generation: levonorgestrel
-
Third generation: gestodene, desogestrel, norgestimate
-
Fourth generation: DRSP
Cyproterone acetate (CPA) and chlormadinone acetate (CMA) were never incorporated
into this categorisation, because oral contraceptives containing CPA were originally
classified as drugs to treat hyperandrogenaemia in women requiring contraception.
CMA has only been introduced in a small number of European countries and is not available
internationally. The same applies to dienogest, which was developed in Germany [9].
Advantages of progestin mono-preparations
Progestin mono-preparations can be recommended in many scenarios where combined contraceptives
fall under WHO category 3 or 4.
The German S3 guideline explicitly states that progestin mono-preparations do not
significantly increase VTE risk. Only depot medroxyprogesterone acetate (DPMA), which
is injected every three months, has been found in one study to increase VTE risk (3.6-fold).
Absolute contraindications (category 4) for the use of CHCs include, acute VTE, a
history of VTEs, surgery with prolonged immobilisation or the presence of thrombogenic
mutations, such as factor V Leiden. In contrast, POPs fall into category 2 and can
generally be recommended after weighing up their risk-benefit ratio ([Table 1]) [2]. Obesity (BMI > 30 kg/m2) is also classified as a potential risk factor for CHC use, and only falls under
category 2 if no further risk factors exist. However, if obesity is additionally associated
with hypertension, hyperlipidaemia or diabetes mellitus, oestrogen-free contraceptive
methods should be preferred [10]. Even moderate hypertension (140 – 159/90 – 99 mmHg) or well-controlled hypertension
can be affected by CHCs, making it necessary to carefully consider and monitor their
use (category 3) or contraindicate their use in the
presence of further risk factors [2]. Severe hypertension (≥ 160/≥100 mmHg), as well as vascular disorders in general,
are contraindications for oestrogen-containing contraceptives according to the WHO,
while POPs can generally be recommended in all these scenarios (category 1 or 2).
Diabetes mellitus does not, in itself, restrict CHC use (category 2). However, as
soon as it is additionally accompanied by vascular damage, neuropathies or retinopathies,
CHCs should only be employed in exceptional cases or are contraindicated, while POPs
are considered to be unproblematic (category 2). Smoking is another important VTE
risk factor that becomes more pronounced with increasing age and the number of cigarettes
smoked. Accordingly, CHC use in women younger than 35 years falls under category 2,
while in patients older than 35, CHCs should only be used in exceptional cases and
after careful consideration of other risks (category 3) and are
contraindicated if more than 15 cigarettes are consumed per day. However, according
to the WHO [2], POPs can be used by all women smokers regardless of age or amount of nicotine consumed.
The German S3 guidelines on contraception adopt the same approach as the WHO, likewise
the recommendations and risk assessments of the European Medicines Agency (EMA). In
the latest version of these (implemented by the BfArM in December 2018), the EMA presents
the most recent risk assessment of the occurrence of venous thromboembolism. A new
finding is that combination preparations with dienogest also significantly increase
the risk of such VTEs ([Table 2]).
Table 2 VTE risk of combined hormonal contraceptives as per the EMA/BfArM [6], [7].
|
Progestins in CHC combined with ethinyloestradiol
|
Relative risk vs. levonorgestrel
|
Estimated incidence (per 10 000 women and year of usage)
|
|
Non-pregnant non-user
|
–
|
2
|
|
Levonorgestrel
|
Reference
|
5 – 7
|
|
Norgestimate/
norethisterone
|
1.0
|
5 – 7
|
|
Dienogest
|
1.6
|
8 – 11
|
|
Gestodene/desogestrel/drospirenone
|
1.5 – 2.0
|
9 – 12
|
|
Etonogestrel/
norelgestromin
|
1.0 – 2.0
|
6 – 12
|
|
Chlormadinone/nomegestrol acetate (E2)
|
Still to be verified
|
Still to be verified
|
Based on these examples alone, it is clear that CHCs are not an option, or only a
very limited option, for a subset of female patients. Consequently, oestrogen-free
hormonal contraception is highly important. In addition to oral progestin mono-preparations
(the progestin-only pill [POP]), long-term methods based on a levonorgestrel intrauterine
system (LNG-IUS), sub-dermal implants (etonogestrel) or injected depot medroxyprogesterone
acetate (DMPA) are available. Although the long-term options mentioned are highly
effective methods of contraception [11], [12], they are not equally suitable for all patient groups. DMPA, for instance, not only
seems to have an adverse effect on thrombosis risk [13], long-term use (> 4 years) also leads to an increased risk of bone fracture, which
is attributable to a reduction in bone mineral density [14].
Hence, this method is contraindicated in women under 18 years of age and is not
recommended as a first-choice method [14]. Currently available sub-dermal implants with etonogestrel, on the other hand, have
no proven adverse effect on bone density and thrombosis risk, but appear to have an
unfavourable effect on bleeding patterns [15]. LNG-IUS contraception is highly effective, does not prevent ovulation, has a favourable
side-effect profile and is usually well accepted [16]. Problematic, however, is the fact that intrauterine implantation is rejected by
some women and is expensive.
In addition, there is increasing evidence of a potential link between LNG IUS and
adverse psychiatric side effects such as panic attacks [17].
Oral progestin mono-preparations are suitable for both short-term and longer-term
hormonal contraception. Preparations that do not inhibit ovulation and whose contraceptive
effectiveness is based primarily on thickening of the cervical mucus and desynchronisation
of endometrial development have the disadvantage that they rely on a very narrow time
window (3 h), and their contraceptive effectiveness, consequently, is highly dependent
on user compliance. Accordingly, the Pearl Index value for the 30 µg levonorgestrel-only
preparation is 4.14 [18].
In contrast, continuous oral POP with 75 µg desogestrel reliably suppresses ovulation,
and, hence, requires less strict dosing regimens (12 h time window for a missed pill)
and a Pearl Index comparable to that of standard CHCs [12], [19].
Compared to CHC, progestin mono-preparations do not increase the risk of stroke, myocardial
infarction and thrombosis [4], [14], [20] (with the exception of DMPA) and are also recommended for breastfeeding women. In
addition, oestrogen-related side effects such as nausea, mastodynia and oedema do
not occur. In addition, their continuous use makes them well suited for treating cycle-related
complaints such as dysmenorrhoea, premenstrual syndrome, hypermenorrhoea and menstrual
migraine, which have been shown to improve in many cases [11], [19].
Disadvantages of progestin mono-preparations
Oestrogen-free hormonal contraception, nevertheless, has traditionally also been associated
with specific drawbacks. These include bleeding disorders such as bleeding between
periods, spotting or prolonged bleeding. The fragility of the superficial vessels
in the endometrium plays a role in these, as do local changes in steroid response,
structural changes, tissue permeability and local factors contributing to neovascularisation
[21], [22]. Bleeding disorders occur in up to 50% of users of the 75 µg desogestrel POP [19] and are a common reason for patients to discontinue treatment [23], which is problematic as poor compliance can reduce contraceptive effectiveness.
Other frequently cited side effects of oestrogen-free contraceptive methods include
androgenisation symptoms such as acne. The oestrogen component of combined contraceptives
induces SHBG formation in the liver, resulting in increased binding of testosterone
and dihydrotestosterone, which can then no longer bind to and activate androgen receptors.
Progestins with partial anti-androgenic effects reinforce the anti-androgenic effect
of combination preparations. None of the progestin mono-preparations approved to date
for contraception use progestins with an anti-androgenic partial effect, and so none
of the mentioned anti-androgenic effects are likely to come into play.
The use of hormonal contraceptives can result in mood swings, and even oestrogen-free
hormonal contraceptives seem to increase the risk of antidepressant use [24]. However, the extent to which various progestins result in psychobehavioral side
effects in various ways or to varying degrees still needs to be investigated [25].
The issue of whether contraceptive use in adolescents is safe is frequently discussed.
In particular, in the case of oestrogen-free ovulation inhibitors the concern is that
suppressing endogenous oestradiol synthesis without an exogenous supply of oestrogen
could impair attainment of adequate bone density. Long-term use of DMPA does indeed
lead to an increased lifetime risk of fracture. In contrast, LNG-IUS, the etonogestrel
implant and the 75 µg desogestrel POP are not expected to negatively impact bone density,
as oestradiol levels during use of these preparations are within ranges considered
safe for bone formation [25]. However, no explicit studies on safety and efficacy in adolescents have been conducted
for any of the preparations mentioned.
In the search for new contraceptives, the oestrogen-free 75 µg desogestrel pill has
proven to be a safe and effective alternative [18]. However, its 12-hour window to remedy a missed pill still gives it a narrower window
than preparations containing 20 µg EE/3 mg DRSP [26] and 1.5 mg E2/2.5 mg nomegestrol acetate [27], which have a 24-hour window to remedy a missed pill. Also, due to the bleeding
irregularities associated with 75 µg desogestrel, the rate of premature discontinuation
of treatment is higher [20]. [Table 3] lists the oral progestin mono-preparations currently available on the market and
their partial effects.
Table 3 Partial effects of selected progestins that are components of progestin mono-preparations
(see also [8]).
|
Progestin mono-preparations
|
Progestogenic
|
Anti-gonadotropic
|
Anti-oestrogenic
|
Oestrogenic
|
Androgenic
|
Anti-androgenic
|
Glucocorticoidic
|
Anti-mineralocorticoidic
|
Pro-coagulatory
|
|
Norethisterone
|
+
|
+
|
+
|
+
|
+
|
–
|
–
|
–
|
+
|
|
Levonorgestrel
|
+
|
+
|
+
|
–
|
+
|
–
|
–
|
–
|
–
|
|
Desogestrel
|
+
|
+
|
+
|
–
|
+
|
–
|
–
|
–
|
–
|
|
Drospirenone
|
+
|
+
|
+
|
–
|
–
|
+
|
–
|
+
|
–
|
Recent development of the 4 mg drospirenone (DRSP)-only pill
The DRSP-only pill contains 4 mg of non-micronised DRSP (and is hence a progestin
mono-preparation) and is administered in a 24/4 regimen. This was selected to improve
the bleeding profile and maintain oestradiol levels at a level similar to those during
the early follicular phase of the natural menstrual cycle. Furthermore, since DRSP
has a half-life of 30 – 34 hours, effectiveness should be maintained even if a pill
is missed. Clinical development was based on the medical necessity to develop an oestrogen-free
pill with the following characteristics:
-
A contraceptive effectiveness comparable to that of CHC (= doubled ovulation-inhibiting
dosage!).
-
An improvement in bleeding pattern compared to other oestrogen-free preparations due
to a cyclic regimen of 24 consecutive DRSP tablets followed by 4 placebo tablets.
This induces planned withdrawal bleeding to reduce bleeding between periods and/or
spotting.
-
A wide window of effectiveness. The new 4 mg DRSP preparation has a 24-hour window
of effectiveness in which a missed pill can be remedied.
-
A reduced risk of osteoporosis. Maintaining early follicular oestradiol levels should
result in normal bone metabolism without increasing the risk of osteoporosis or fracture.
-
An anti-androgenic and anti-mineralocorticoidic partial effect
-
Treatment adherence and acceptance of this treatment regimen
Effectiveness
Preclinical data
Pharmacological properties
DRSP is a progestin (a synthetic progestogen) chemical analogue of spironolactone.
In addition to its anti-oestrogenic and anti-gonadotropic effects, it also has anti-androgenic
and anti-mineralocorticoidic partial effects ([Table 3]) [28].
Pharmacokinetics
Results from initial preclinical pharmacokinetic studies revealed that 4 mg of non-micronised
DRSP would provide an area under the curve equivalent to that of 3 mg of commercially
available micronised DRSP/20 µg EE. Therefore, a dose of 4 mg per tablet was chosen
for this progestin mono-preparation. This prediction was based on the knowledge that
DRSPʼs pharmacokinetics are linear in nature [30], [31].
Systemic exposure to DRSP was lower (77% relative bioavailability) after taking the
4 mg tablet of non-micronised DRSP than after taking a combination pill containing
3 mg micronised DRSP and 20 µg EE [32]. The higher DRSP exposure after taking the combined pill is presumably due to the
superior absorption of micronised versus non-micronised DRSP. In addition, an inhibitory
effect of EE on sulphotransferase 1A1 has been discussed. This enzyme is involved
in the metabolism of DRSP and catalyses the formation of the metabolite 4,5-dihydrodrospirenone-3-sulphate
[32], [33].
Phase II trials
DRSPʼs anti-gonadotropic effect results in inhibition of ovulation
The anti-gonadotropic effect of 4 mg DRSP has been demonstrated in phase II trials.
Inhibition of ovulation (defined as occurring when serum progestogen levels fall below
16 nmol/l) was demonstrated in healthy young women (n = 20) over two administration
cycles. This finding was confirmed in another study that investigated the ovulation
inhibition of 4 mg DRSP taken in a 24/4 regimen compared with continuous administration
of 75 µg desogestrel over two administration cycles in healthy women aged 18 – 35 years.
In this study, ovulation was suppressed just as effectively by the 4 mg DRSP regimen
as by the 75 µg desogestrel regimen [34].
Inhibition of ovulation in spite of delayed administration
The ability of 4 mg DRSP to maintain ovulation inhibition even when a pill is delayed
was investigated in an open randomised trial in which young healthy women (n = 127)
delayed taking the pill for 24 h on pre-determined cycle days [35]. This trial showed that the ovulation rate with 4 mg DRSP was much lower than with
traditional POPs (30 – 40%). It was comparable to, or even slightly lower than, the
ovulation rate with CHCs (1.1 – 2.0%) and lower than the ovulation rate with 75 µg
desogestrel after three planned 12-hour delays (1%) [36].
Phase III trials
Effectiveness
The contraceptive effectiveness of 4 mg DRSP has been confirmed by phase III clinical
trials, two from Europe [37], [38] and one from the US [39]. A pooled analysis of the two European trials resulted in a Pearl Index of 0.73
(95% confidence interval [CI] 0.3133, 1.4301) (14 329 cycles with 4 mg DRSP) and a
corrected Pearl Index (taking into account sexual activity and use of other contraceptive
methods) of 0.79 (95% CI 0.3410, 1.5562) [38].
The pooled analysis of a subgroup of 1251 women ≤ 35 years of age yielded similar
results: an overall Pearl Index (based on 11 145 cycles) of 0.93 (95% CI 0.4029, 1.8387)
and a corrected Pearl Index (based on 10 173 cycles) of 1.02 (95% CI 0.4414, 2.0144)
[38]. The findings of both studies show that the contraceptive effectiveness of 4 mg
DRSP is comparable to that of currently available CHCs ([Table 4]). In the US study of 915 non-breastfeeding women ≤ 35 years of age, the Pearl Index
was 2.9 (95% CI 1.5, 5.1) [38]. The rate of discontinuation in the three clinical trials (27.8% and 19.8% in the
European trials [37], [38] and 65% in the US trial [39]) could potentially bias the results for the primary endpoint and the safety profile,
including adverse events.
Table 4 Contraceptive effectiveness of the 4 mg DRSP mono-preparation: Pearl Index data from
the European pivotal trials.
|
Pearl Index
|
Archer et al. [37]
|
Palacios et al. [38]
|
Pooled analysis
|
|
Drospirenone 4 mg (n = 713)
|
Drospirenone 4 mg (n = 858)
|
Desogestrel 75 µg (n = 332)
|
Drospirenone 4 mg (n = 1571)
|
|
Total
|
|
Total number of treatment cycles
|
7638
|
6691
|
2487
|
14 329
|
|
Pregnancies, n (%)
|
3 (0.4)
|
5 (0.6)
|
1 (0.3)
|
8 (0.5)
|
|
Pearl Index overall, %
|
0.5106
|
0.9715
|
0.5227
|
0.7258
|
|
95% CI (lower limit, upper limit)
|
0.1053, 1.4922
|
0.3154, 2.2671
|
0.0132, 2.9124
|
0.3133, 1.4301
|
|
Post correction (additional contraceptive methods and sexual activity status)
|
|
Total number of cycles with sexual activity and without additional contraception
|
7191
|
5977
|
2224
|
13 168
|
|
Pregnancies, n (%)
|
3 (0.4)
|
5 (0.6)
|
1 (0.3)
|
8 (0.5)
|
|
Corrected Pearl Index, %
|
0.5423
|
1.0875
|
0.5845
|
0.7898
|
|
95% CI (lower limit, upper limit)
|
0.1118, 1.5850
|
0.3531, 2.5379
|
0.0148, 3.2568
|
0.3410, 1.5562
|
|
Method failures
|
|
Total number of perfect medication cycles
|
6101
|
4641
|
1816
|
10 742
|
|
Pregnancies, n (%)
|
3 (0.4)
|
5 (0.6)
|
1 (0.3)
|
8 (0.5)
|
|
Pearl Index method failures, %
|
0.6392
|
1.4006
|
0.7159
|
0.9682
|
|
95% CI (lower limit, upper limit)
|
0.1318, 1.8681
|
0.4548, 3.2684
|
0.0181, 3.9885
|
0.4180, 1.9077
|
|
Overall pregnancy rate
|
|
%
|
0.50
|
0.70
|
0.34
|
0.73
|
|
95% CI (lower limit, upper limit)
|
0.00, 1.07
|
0.09, 1.31
|
0.00, 1.01
|
0.17, 1.27
|
The higher rate of trial withdrawals in the USA compared to the European pivotal trials
is not unusual and the fact that 86% of participants reported being satisfied with
the DRSP treatment puts this finding into context. Furthermore, a minimum of 5000
cycles was required to obtain one PI value. This was clearly exceeded [38].
Safety
Haemostaseological parameters
A long-term study investigated the influence of 4 mg DRSP on coagulation factors and
potential thromboembolic risks from a haemostaseological perspective [40]. The study included 39 women who took 4 mg DRSP for 9 cycles (24/4 regimen) and
29 subjects who took 75 µg desogestrel daily over the same period. The following haemostaseological
parameters were investigated: resistance to activated protein C, antithrombin III,
D-dimer, C-reactive protein and coagulation factors VII and VIII [40]. The study revealed that 4 mg DRSP had no effect on haemostaseological parameters
and did not affect the balance between pro-coagulatory and anti-coagulatory factors.
Thromboembolic events
Over the period of the entire clinical development programme (> 20 000 cycles), no
reports of VTEs in women taking 4 mg DRSP were reported [41]. The documented risk factors included a family history of thromboembolic events,
evidence of a predisposition to vascular or metabolic disease, smoking if over 35
years of age, not smoking and over 40 years of age, and a body mass index (BMI) of
≥ 30 kg/m2. In the US study, at least 367 participants (36.5%) had a VTE risk factor [39], while in the European studies 139 (16.2%) and 104 (14.6%) of participants, respectively,
had a VTE risk factor [37], [38].
These observations are consistent with the fact that 4 mg DRSP was neutral with regard
to the haemostaseological parameters examined in the above-mentioned long-term study.
Future epidemiological studies will be needed to corroborate the clinical data on
cardiovascular safety [41].
Effect on mild hypertension
Previous studies have shown that 6-month use of a drospirenone/oestrogen combination
was associated with a modest decrease in systolic blood pressure (SBP) and diastolic
blood pressure (DBP) compared with a levonorgestrel/oestrogen combination [42], [43]. This minor effect on blood pressure was also demonstrated in a study that compared
the influence of a contraceptive containing 3 mg DRSP and EE with a preparation containing
150 µg desogestrel and EE [43]. The observed effect is most likely attributable to the anti-mineralocorticoidic
effect of DRSP.
The two European pivotal trials also investigated the effect of 4 mg DRSP on blood
pressure. The first study demonstrated a median decrease of 8 mmHg (SBP) and 5 mmHg
(DBP) in participants with a baseline SBP of ≥ 130 mHg and a baseline DBP of ≥ 85 mmHg
(n = 137) [36], [37]. In participants with a baseline SBP of < 130 mmHg and a baseline DBP of < 85 mmHg
(n = 548), the absolute median change was 0 mmHg for both SBP and DBP [41].
Oestradiol levels and bones
A study of 64 volunteers [26] revealed that the E2 level on day 24 of the second administration cycle was just below 51 pg/ml (187 pmol/l),
higher than the levels on day 3 of the first cycle, which can be considered to be
baseline levels. Thus, 24 days of treatment with 4 mg DRSP did not reduce E2 levels below the baseline levels of day 3. The difference in E2 levels compared to the control group (75 µg desogestrel) was not statistically significant.
Under the recommended regimen (24/4), endogenous E2 production can occur in the ovaries, as the 4-day break should be sufficient to increase
FSH levels. This was confirmed with the values from day 3 of the second administration
cycle, which were higher than the values on day 27 of the first administration cycle.
The new dosing regimen (24/4 regimen of 4 mg DRSP compared to a 28-day regimen of
75 µg desogestrel) resulted in higher E2 levels
at the end of administration cycle 2 than those on day 3 of the first administration
cycle [26].
During the 4 mg DRSP 24/4 regimen, mean E2 levels do not fall below 30 pg/ml (110.1 pmol/l) [25]. This value is considered a potential limit for the onset of osteoclast activity
in bone, as demonstrated in the study by Doran et al. [44].
Changes in body weight
No significant changes in mean body weight occurred among users of 4 mg DRSP during
the various short and long-term studies [36], [37], [38], [40]. This confirms data from the literature indicating that use of DRSP is not associated
with weight gain or significant changes in body fat percentage [44].
Tolerance
Bleeding pattern: control of bleeding profile with 4 mg DRSP in comparison to 75 µg
desogestrel.
A phase III clinical trial over 9 administration cycles compared bleeding profiles
of women treated with 4 mg DRSP and women treated with 75 µg desogestrel [46], [47]. The percentage of women with bleeding and spotting decreased in the 4 mg DRSP group
from 69.2% in administration cycle 2 to 56.3% in administration cycle 9, and in the
75 µg desogestrel group from 74.05% to 45.3%. The median number of bleeding and spotting
days decreased from 10 days in the 4 mg DRSP group in the first reference period (administration
cycles 2 – 4) to 6 days in the last reference period (administration cycles 7 – 9),
and from 12 to 7 days in the 75 µg desogestrel group. Most of these days were days
with spotting rather than bleeding. The differences were statistically significant.
In addition, during administration cycles 5 – 9, the proportion of women with prolonged
bleeding (> 10 days) was significantly lower in the 4 mg DRSP group than in the 75 µg
desogestrel group (p < 0.001). Premature study withdrawal due to abnormal uterine
bleeding (AUB) occurred in 3.3% of DRSP and 6.6% of 75 µg desogestrel users (p < 0.001)
[46], [47]. In summary, the results of the clinical trials revealed that 4 mg DRSP controlled
bleeding patterns better than did 75 µg desogestrel. [Table 5] presents data on bleeding patterns from the trials.
Table 5 Median number of planned and unplanned bleeding or spotting days and premature study
withdrawals associated with AUB (abnormal uterine bleeding) in specified reference
periods.
|
Variable
|
Archer et al. [37]
|
Palacios et al. [{38.39}]
|
|
Drospirenone 4 mg (n = 713)
|
Drospirenone 4 mg (n = 858)
|
Desogestrel 75 µg (n = 332)
|
|
Data are shown as n (%)
a 8 – 10 for study 301, 7 – 9 for study 302
* p < 0.05 drospirenone vs. desogestrel
** p < 0.001 drospirenone vs. desogestrel
|
|
Total bleeding and spotting days
|
|
Cycles 2 – 4
Cycles 5 – 7
Cycles 8 – 10/7 – 9a
Cycles 11 – 13
|
11
8
6
5
|
10*
6
6
|
12
7
7
|
|
Unplanned bleeding and spotting days
|
|
Cycles 2 – 4
Cycles 5 – 7
Cycles 8 – 10/7 – 9a
Cycles 11 – 13
|
6
5
3
3
|
5**
4*
4*
|
12
7
7
|
|
Premature withdrawal from the trial due to bleeding disorders
|
30 (4.2)
|
28 (3.3)
|
22 (6.6)
|
Endometrial safety
Endometrial thickness was assessed in a dedicated endometrial safety study [48]. The mean maximum double endometrial thickness was 5.5 mm, and after 13 administration
cycles it was reduced by an average of 2.6 mm. Biopsies were taken to assess changes
in the endometrium. After one year of treatment with 4 mg DRSP, not a single case
of hyperplasia occurred [48].
Use in Special Groups
Adolescents
A study was designed to prospectively assess the safety and tolerability of 4 mg DRSP
(24/4) in 111 adolescent females aged 12 – 17 years [48]. The study consisted of six 28-day administration cycles and a further optional
extension phase of 7 administration cycles. The number of participants reporting dysmenorrhoea
decreased from 47 (46.1%) before screening to 14 (29.8%) after administration cycle
6, and to 8 (17%) after administration cycle 13. At the same time, the percentage
of women who used painkillers to treat dysmenorrhoea decreased. Only five participants
(4.9%) withdrew prematurely from the study due to irregular bleeding and one (1%)
due to amenorrhoea. No treatment-related serious adverse events and no pregnancies
occurred. At the conclusion of the study, 82.4% of the participants rated the tolerability
of 4 mg DRSP as excellent or good [49].
Overweight and obese women
Obesity leads to physiological changes, such as increased cardiac output or changes
in liver enzyme function, compared to individuals of normal weight. Some liver changes
have the potential to alter the absorption, distribution, metabolism and elimination
of drugs, reducing their efficacy [50].
The contraceptive effectiveness of DRSP in overweight and obese women has been confirmed
in a pooled analysis of European studies from the clinical development programme of
the 4 mg DRSP preparation [37], [38]. Four reported pregnancies (PI = 1.89) occurred in women with a BMI of 25 – 30 kg/m2 (n = 301), while no pregnancies occurred in participants with a BMI ≥ 30 kg/m2 (n = 71) (PI = 0.0).
The clinical programme demonstrated the favourable thromboembolic safety profile of
4 mg DRSP, also for women with VTE risk factors. Cigarette smoking in women > 35 years
of age was the most common risk factor in the European studies (10.1% and 12%, respectively)
[37], [38], [41]. In the US study [39], [41], this incidence was 5.1%. The most common risk factor in the US study was a BMI
of > 30 kg/m2, accounting for 35% of the participants. In the European studies, only 5.8% and 3.5%,
respectively, of the participants had a BMI above 30 kg/m2.
The incidence of women with a family history of thromboembolic events or of women
with predisposing factors for cardiovascular or metabolic disease was lower in all
studies.
In conclusion, even in women with risk factors for venous thromboembolic events (VTEs),
such as being over 35 years of age, tobacco use and obesity, no venous or arterial
thromboembolic events occurred [40].
Breastfeeding women
A prospective study investigated the amount of DRSP transferred to breast milk after
reaching a steady state [51]. DRSP 4 mg per day was administered for 7 days to reach this steady-state concentration.
The mean AUC (0 – 24 h) of DRSP in plasma 24 h after administration of the last dose
was 635.33 ng h/ml. The mean Cmax was 48.64 ng/ml. The mean AUC (0 – 24 h) of DRSP in the motherʼs milk 24 h after
administration of the last dose was 134.35 ng h/ml. The mean Cmax was 10.34 ng/ml. On average, 18.13% of plasma DRSP entered breast milk and the highest
concentration measured in breast milk was 17.55% of plasma DRSP. The mean total quantity
of DRSP that passed into breast milk was 4478 ng during a 24-hour period, equivalent
to 0.11% of the maternal daily dose. Hence, no effects on breastfed newborns/infants
are expected with the DRSP 4 mg preparation at the recommended dosages, as these amounts
are considered to be
negligible [52].
