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Gracial Product Monograph
Product Monograph
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For further information, please contact: N.V. Organon, PO Box 20, 5340 BH Oss, The Netherlands, www.organon.com

40 µg ethinylestradiol/25 µg desogestrel (7x)
30 µg ethinylestradiol/125 µg desogestrel (15x)
Product Monograph

© 2000 N.V. Organon
All rights reserved, including that of translation into other languages. No part of this publication may be
reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying,
recording or any information storage and retrieval system, without permission in writing from N.V. Organon.
ISBN 90 687 80 239

Contents
Page
1. INTRODUCTION 1
1.1 Rationale for Gracial 4
2. PHARMACOKINETICS 6
2.1 Desogestrel 6
Absorption 6
Metabolism 6
Distribution 7
Elimination 7
2.2 Ethinylestradiol 8
3. PHARMACODYNAMICS 10
3.1 Receptor affinity 10
3.2 Selectivity index 11
3.3 Effects on the pituitary ovarian axis 12
3.4 Effects on cervical mucus 15
4. CONTRACEPTIVE EFFICACY 16
5. ACCEPTABILITY 17
5.1 Cycle control 17
Irregular bleeding 18
Withdrawal bleeding 18
5.2 Side effects 20
5.3 Body weight 21
5.4 Continuation rate 21
6. GRACIAL AND MILD TO
MODERATE ACNE 22
6.1 Effect on SHBG and testosterone 22
6.2 Clinical effects 23
7. SAFETY ASPECTS 27
7.1 Venous thromboembolism 28
Hemostasis 28
Epidemiological data 29
7.2 Arterial disease 33
Lipid metabolism 33
Carbohydrate metabolism 35
Blood pressure 35
Epidemiological data 35
7.3 Gynecological cancer 38
Breast cancer 39
Cervical, ovarian and endometrial cancer 40

Contents
Page
8. SUMMARY 42
9. REFERENCES 43
10. SUMMARY OF PRODUCT
CHARACTERISTICS 48

1. Introduction
•Gracial is the first combiphasic oral contraceptive, with
an estrogen-dominant phase of seven days, followed by
a progestogen-dominant phase of 15 days
• The control of irregular bleeding that this regimen
offers makes Gracial ideal for women with
unacceptable irregular bleeding patterns
•Gracial has also been shown to have beneficial effects
on mild to moderate acne
Benefits of
the Pill
The introduction of combined oral contraceptives (OCs) in the
early sixties made effective and reversible contraception for
women available for the first time.
The obvious benefits of the Pill – prevention of unwanted
pregnancy and consequent reduction in the need for abortion,
the possibility of family planning and the realization of sexual
liberation – were quickly recognized. Pill users also
appreciated the regulation of the menstrual cycle, the
decrease in premenstrual complaints and the possibility of
timing their menstrual periods.
After some initial hesitation, use of the Pill increased rapidly.
By 1999, some 90 million women were using an oral
contraceptive, and their number is still growing.
Although new forms of contraception may be developed in the
near future, the Pill is likely to maintain its important position
as a contraceptive, and more and more women are likely to
become long-term users. Meanwhile, the development of
newer OC formulations, with less systemic effects, has made
the Pill acceptable for a wider spectrum of women.
1

Introduction
Since all the current low-dose OCs containing new-generation
progestogens are safe and reliable, more attention can be
given to the development of preparations that are ‘fine-tuned’
to fit the individual needs of women.
Switchers
Reasons for
switching OCs
Most OC users who start with a low-dose preparation are
satisfied with this. However, for certain subgroups (e.g. women
with unacceptable irregular bleeding or subjective side
effects), the estrogen/progestogen doses of their firstprescribed
OC may not be in balance. These women may
benefit from switching to an OC preparation which has been
especially developed to meet their specific needs.
A study from the Netherlands showed that in 1993, 13.6% of
all OC users switched from one brand to another, mainly for
reasons of acceptability (Figure 1) (Oddens et al 1994).
stop use 12.2%
starters 9.4%
switchers 13.6%
Major Reasons:
• cycle control
• subjective side effects
• skin problems
• change to lighter pill
same brands 64.8%
Fig. 1: OC use and major reasons for brand switching
in the Netherlands in 1993
2

Introduction
Gracial
A recent study in 2,278 women showed specific reasons for
switching from their previous OC to Gracial, as shown in the
figure below (Vree 2000).
Incidence (%)
50
40
30
20
10
0
41.3%
Irregular
bleeding
27.0%
Other
menstrual
disorders
9.8%
Migraine/ Decreased
headache libido
3.2% 2.8% 2.7%
Increased
body
weight
Main reason for switching to Gracial
Fig. 2: Reasons for switching from other OCs to
Gracial
Acne
Vree 2000
Gracial is a Pill which is particularly suitable for women who
want to switch to a different OC because of unacceptable
irregular bleeding or subjective side effects. A number of
studies have also shown Gracial to have beneficial effects on
mild to moderate acne.
This product monograph discusses the clinical properties
of Gracial, an OC preparation with a unique combiphasic
regimen. The preparation contains DSG and EE in a relatively
estrogenic phase during the first seven days of the Pill cycle,
followed by a progestogenic phase of 15 days for the
remainder of the Pill cycle.
3

Introduction
1.1 Rationale for Gracial -
a combiphasic pill with 22 tablets
per cycle
Although most women are satisfied with the first low-dose OC
they are prescribed, each year more than 10% of all OC users
switch their Pill mainly because of unacceptable cycle control
and/or subjective side effects (Oddens et al 1994). In order to
continue with OC use, they need a preparation fitting their
individual needs.
Combiphasic
regimen
Step-up/
step-down
From clinical studies with OCs it seems that irregular bleeding
which occurs early in the cycle is due to a relative estrogen
deficiency, whereas mid- and late-cycle irregular bleeding can
be attributed to a lack of progestogen. Consequently an
innovative combiphasic dosage regimen has been developed
by Organon. It consists of two different estrogen and
progestogen phases, and differs considerably from the
standard biphasic Pill. The combiphasic regimen (Figure 3) has
a unique step-up/step-down sequence. This means that the
progestogen dose increases whilst the estrogen dose
decreases in the second phase of the Pill cycle.
EE 40 µg 30 µg
DSG
25 µg
125 µg
Pill-free
interval
7 22 28
days
Fig. 3: Step-up, step-down combiphasic regimen of
Gracial
4

Introduction
Estrogen
dominance
7 days
Progestogen
dominance
15 days
Excellent cycle
control
Gracial, the first combiphasic oral contraceptive, has an
estrogen-dominant phase of seven days (25 µg DSG + 40 µg
EE), which is followed by a progestogen-dominant phase of 15
days (125 µg DSG + 30 µg EE). The relative estrogenic
dominance during the first seven days controls irregular
bleeding in the first part of the cycle. From day 8 onwards, the
shift to progestogen dominance controls irregular bleeding
during the middle and latter part of the cycle. Theoretically,
this makes Gracial an ideal OC for women with unacceptable
irregular bleeding. It has been clearly demonstrated that
Gracial has exceptionally good cycle control characteristics
(Dieben, Op ten Berg et al 1994).
Table 1: Estrogen/progestogen balance of
DSG-containing OCs
EE dose Desogestrel dose E/P
(µg/cycle) (µg/cycle) balance
Mercilon 420 3150 1:7.5
Marvelon 630 3150 1:5.0
Laurina 665 2100 1:3.2
Gracial 730 2050 1:2.8
The new regimen allows a reduction of one third of the total
progestogen dose compared to Mercilon and Marvelon and a
completely different estrogen/progestogen balance compared
to other OCs containing EE and DSG (Newton 1994).
Conclusion
Gracial is a unique combiphasic oral contraceptive that is
particularly suitable for women who wish to switch to a
different OC because of unacceptable irregular bleeding or
subjective side effects. Gracial has also been shown to have
beneficial effects on androgenic skin disorders such as acne.
5

2. Pharmacokinetics
• After oral administration, desogestrel is rapidly
transformed into its active metabolite, etonogestrel
• Approximately 96–99% of circulating etonogestrel is
bound to plasma proteins, predominantly albumin and
SHBG
• EE undergoes rapid absorption after oral
administration, with peak plasma levels being reached
after approximately 1.5 hours
Etonogestrel
2.1 Desogestrel
Absorption
Desogestrel (DSG) itself is relatively inactive and most of its
pharmacological activity is attributed to its active metabolite
etonogestrel. In humans, oral doses of DSG are rapidly and
almost completely absorbed, mostly from the duodenum.
Following oral administration, DSG is rapidly and adequately
biotransformed into the active progestogen etonogestrel
(Hasenack et al 1986). In vitro studies indicate that
biotransformation occurs in both the liver and the intestinal
mucosa (Madden et al 1989;1990), the bioavailability being
62–81% after multiple dosing (Timmer et al 1990).
Metabolism
The biotransformation of DSG into etonogestrel takes place in
gastrointestinal and hepatic tissues within 30 minutes
following ingestion.
Potential drug
interactions
The main route of DSG metabolism is a cytochrome P450-
catalyzed hydroxylation followed by a dehydrogenation. The
hepatic cytochrome P450 enzyme system involved in the
metabolism of contraceptive steroids may be induced by
rifampicin, griseofulvin and a number of anticonvulsant drugs
(hydantoins, barbiturates, primidone, carbamazepine) (Geurts
et al 1993). Interactions with oxcarbazepine, rifabutin,
troglitazone and felbamate are also suspected. Animal studies
with phenobarbitone have shown that it induces the
metabolism of desogestrel and etonogestrel. Therefore, there
is a theoretical risk that the effectiveness of Gracial may be
reduced in women taking the specified enzyme-inducing drugs.
6

Pharmacokinetics
ENG
predominantly
bound to albumin
and SHBG
Half-life ENG
30 hours
Distribution
After absorption and bioactivation, etonogestrel is distributed
throughout the body. Studies have shown that etonogestrel is
about 96–98% bound to proteins, predominantly to albumin
and sex hormone-binding globulin (SHBG). The EE-induced
increase of plasma SHBG after multiple dosing induces a shift
towards more binding of etonogestrel to SHBG relative to
albumin (Hammond et al 1984).
Elimination
Etonogestrel is eliminated from the body, mainly as
conjugated and polyhydroxylated metabolites (Viinikka et al
1980). The elimination half-life of desogestrel is about 30
hours (Archer et al 1994). Desogestrel and its metabolites are
excreted with urine and feces, the ratio being 1.5:1 (Viinikka
et al 1980).
Etonogestrel
(ng/ml)
1.5
1.0
0.5
Day 22
Day 7
2 4 6 8 12 24 h
Fig. 4: Etonogestrel serum concentration on days 7
and 22 of Gracial administration
Jung-Hoffmann et al 1992
7

Pharmacokinetics
ENG mainly
bound to
albumin and
SHBG
2.2 Ethinylestradiol (EE)
Following oral administration of Gracial, ethinylestradiol (EE) is
absorbed within 1.5 hours (Jung-Hoffman et al 1992) and
then distributed throughout the body. The absolute
bioavailability of EE after multiple dosing of a DSG/EE
combination has been calculated as approximately 59% (Back
et al 1987). Plasma EE is 98.5% protein bound, almost
entirely to albumin (Kuhl 1990).
The metabolism of EE involves cytochrome P450-mediated
hydroxylation, with 2-hydroxy-EE and 2-methoxy-EE as the
major metabolites (Purba et al 1987).
Half-life EE
29 hours
EE is eliminated from the body principally as conjugated
metabolites and the elimination half-life has been calculated
at about 29 hours (Bergink et al 1990). Excretion occurs via
urine and feces at a ratio of 1:1.6 (Speck et al 1976).
EE pg/ml)
100
50
Day 7
2 4 6 8 12 24 h
EE (pg/ml)
100
50
Day 22
2 4 6 8 12 24 h
Fig. 5: Ethinylestradiol serum concentration on days
7 and 22 of Gracial administration
Jung-Hoffmann et al 1992
8

Pharmacokinetics
Conclusion
Gracial contains the progestogen desogestrel, which is rapidly
absorbed and transformed following oral administration to its
active metabolite, etonogestrel. Etonogestrel is 96–99%
bound to plasma proteins, mainly albumin and SHBG and is
eliminated from the body in urine and feces. Ethinylestradiol is
98.5% bound to plasma proteins, mainly albumin.
9

3. Pharmacodynamics
•Etonogestrel has a high selectivity index
• The 22-day regimen of Gracial permits a very low
progestogen dose in the first seven days of the cycle,
without compromising contraceptive reliability
•Gracial inhibits follicle development and ovulation
3.1 Receptor affinity
Different progestogens have different hormonal profiles: in
addition to the progestogenic activity required for the
inhibition of ovulation, progestogens may also possess some
degree of androgenic activity. This is neither required nor
desirable in OCs because of adverse effects such as
androgenic skin disorders.
Desogestrel is derived, like levonorgestrel, gestodene and
norgestimate, from 19-nortestosterone. Desogestrel is,
however, differentiated from levonorgestrel and other
progestogens by a methylene group at position 11, which
interferes with the binding of desogestrel to androgen
receptors.
CH 3
H 2
C
11
12
CH 2
13
17
OH
C
CH
2
1
9
10 8
14
15
16
3 5
4
6
7
Fig. 6: Structure of desogestrel
10

Pharmacodynamics
In vitro receptor-binding studies are useful in predicting the
hormonal characteristics of progestogens. Such studies have
shown that desogestrel has very little affinity for progesterone,
estrogen or androgen receptors (Bergink et al 1981; Breiner et
al 1986; Juchem and Pollow 1990). However, its active
metabolite etonogestrel exhibits:
• significantly stronger affinity for the progesterone receptor
than levonorgestrel or norethisterone
•very low affinity for the androgen receptor (considerably
lower than levonorgestrel or gestodene)
• negligible binding to the estrogen receptor (Bergink et al
1981, 1983; Hoppen and Hammann 1987; Juchem and
Pollow 1990; Kloosterboer et al 1988)
3.2 Selectivity index
The hormonal characteristics of a progestogen can be
assessed by its binding affinity for progesterone and androgen
receptors in in vitro receptor-binding studies as well as by in
vivo bioassay techniques in animal models. In addition,
progestogenic activity can also be assessed in women by
employing clinical endpoints such as the dose needed for
complete ovulation inhibition and effects on the endometrium
and cervical mucus.
Low risk of
adverse
androgenic
events
The receptor-binding affinity studies have indicated that
etonogestrel has a high affinity for the progesterone receptor,
only a low affinity for the androgen receptor and no significant
binding affinity for the estrogen and glucocorticoid receptors.
Figure 7 shows the selectivity index (relative binding affinity to
progesterone versus androgen receptors) of etonogestrel, the
active metabolite of DSG, and the progestogens
norethisterone, levonorgestrel and gestodene. (Kloosterboer et
al 1987).
11

Pharmacodynamics
40
30
20
10
0
norethisterone
levonorgestrel etonogestrel gestodene
Fig. 7: Selectivity index of various progestogens
Kloosterboer et al 1987
Suppression of
LH and FSH
secretion
The selectivity index was higher for etonogestrel than for the
other progestogens, norethisterone, levonorgestrel or
gestodene. Receptor-binding studies do have certain
limitations because the pharmacokinetics and
pharmacodynamics of each compound are not considered.
Nevertheless, they give an indication of the intrinsic properties
of a progestogen and may contribute to the evaluation of
animal and human data. This can be useful when comparing
OCs with similar hormone doses and dose regimens.
3.3 Effects on the pituitary ovarian axis
The contraceptive efficacy of combined oral contraceptives is
primarily due to the ovulation-inhibiting effect of the
progestogen component at the level of the hypothalamus and
pituitary gland. Gonadotrophin (LH and FSH) secretion is
suppressed and as a result follicular maturation and ovulation
are inhibited.
Etonogestrel has been shown to have strong ovulationinhibiting
properties when given in a daily oral dose of 60 µg
(Skouby 1976; Cullberg et al 1982).
Gracial contains a daily dose of desogestrel of 25 µg for seven
days and 125 µg for the consecutive 15 days. The 22-day
regimen permits an extremely low progestogen dose in the
first seven days of the cycle, without compromising
contraceptive reliability.
12

Pharmacodynamics
In an ultrasound study, Van der Vange et al (1988)
investigated the effects of Gracial on ovarian activity, utilizing
a "standard" 21- (7+14) day regimen. They found that the low
progestogen dosage in the combiphasic regimen permitted
more ovarian activity than did a conventional 30 µg EE
monophasic pill containing DSG. However there was, in every
case, complete inhibition of ovulation.
Jung-Hoffman et al (1992) demonstrated that Gracial caused
significant suppression of LH and FSH levels. This was
confirmed by Kuhl et al (1993) (Figure 8) who demonstrated a
significant reduction in gonadotrophin and a profound
suppression of estradiol and progesterone levels, indicating
impairment of follicular development and reliable inhibition of
ovulation.
Conclusion
Pharmacodynamic studies have demonstrated that Gracial
suppresses gonadotrophin secretion and reliability inhibits
ovulation.
13

Pharmacodynamics
mIU/ml
7
6
5
4
3
2
1
0
pg/ml
160
140
120
100
80
60
40
20
0
ng/ml
10
9
8
7
6
5
4
3
2
1
0
Pretreatment
cycle
Pretreatment
cycle
Pretreatment
cycle
= LH
= FSH
Cycle 1 Cycle 3 Cycle 6
LH and FSH
Cycle 1 Cycle 3 Cycle 6
Estradiol
Cycle 1 Cycle 3 Cycle 6
Progesterone
Posttreatment
cycle
Posttreatment
cycle
Posttreatment
cycle
Fig. 8: Changes in FSH, LH, estradiol and
progesterone serum concentrations on day
21–24 of the pretreatment cycle, day 18–22
of the first, third and sixth treatment cycle
and day 21–24 of the post-treatment cycle
Kuhl et al 1993
14

Pharmacodynamics
Prevention of
sperm
penetration
3.4 Effect on cervical mucus
Apart from ovulation inhibition, combined OCs have a second
contraceptive effect: they block the cervical ostium to
spermatozoa by keeping the cervical mucus thick and viscous
(Diczfalusy 1968).
During a normal menstrual cycle, the cervical ostium opens
and the mucus becomes more liquid around the time of
ovulation, facilitating sperm penetration. Gracial has been
shown to inhibit these changes, thus preventing penetration of
spermatozoa into the uterus. A low ‘Spinnbarkeit’ together
with absence of ‘ferning’ have been consistently observed
(Organon Scientific Development Group 1980).
Conclusion
Pharmacodynamic studies have demonstrated that Gracial
suppresses gonadotrophin secretion and reliably inhibits
ovulation. Gracial also keeps the cervical mucus thick and
viscous, thus preventing penetration of spermatozoa into
the uterus.
15

4. Contraceptive
efficacy
• The Pearl Index of Gracial is 0.0 for method failure and
0.1 for user failure, confirming that Gracial is a very
reliable Pill
Pearl Index
Contraceptive reliability can be expressed by means of the
Pearl Index, which is an indication of the number of
pregnancies likely to occur per 100 women per year during
use of the method. Combined OCs belong to the group of
contraceptives with the lowest Pearl Index of any reversible
method of contraception: the Pearl Index of modern low-dose
OCs is usually in the range of 0.1–1.
The Pearl Index can be differentiated into the Pearl Index for
‘user failure’ (including those pregnancies occurring when the
Pill is incorrectly taken, e.g. in the case of forgotten tablets,
vomiting, diarrhea, simultaneous use of interacting drugs) and
for ‘method failure’ (pregnancies occurring when the Pill has
been taken correctly).
In a large-scale, multicenter study of Gracial in which 12,850
cycles were evaluated (Table 2) (Dieben et al 1991) only one
pregnancy occurred and this was attributed to a missed Pill.
This gives a Pearl Index of 0.0 for method failure and 0.1 for
user failure.
Table 2: Pearl Index of Gracial
Pregnancies
Total investigated
cycles Method failure User failure
12,850 0 1
Pearl Index 0.0 0.1
Dieben et al 1991
The Pearl Index for Gracial is fully comparable with that of
conventional low-dose monophasic OCs.
Conclusion
The Pearl Index obtained confirms that Gracial is a very
reliable Pill.
16

5. Acceptability
•Gracial is associated with excellent cycle control and
the incidence of irregular bleeding is low
• The subjective side effects commonly reported by OC
users are less apparent during use of Gracial than
before OC use
• The effects of Gracial on body weight are negligible
•Gracial is a highly acceptable Pill that should prove
especially suitable for women who experience
unacceptable cycle control with any other low-dose OC
Bleeding during
OC use
Spotting and
breakthrough
bleeding
Withdrawal
bleeding
The acceptability of an OC is determined by subjective
parameters, such as the incidence of side effects like nausea,
headache and breast tenderness, and by more objective
parameters such as cycle control and body weight. These
factors will be discussed in this chapter.
5.1 Cycle control
One of the most important reasons for brand switching of OCs
is poor cycle control. Cycle control is evidenced by the pattern
of irregular bleeding and the heaviness and duration of
withdrawal bleeding.
Irregular bleeding is bleeding occurring during the tablettaking
period, subdivided in studies into spotting - scanty
bleeding requiring no hygienic measures or at most one
sanitary pad per day, and breakthrough bleeding - bleeding
requiring two or more sanitary pads per day.
Withdrawal bleeding is bleeding that starts during the tablet
free intervals. It is generally accepted and welcomed by Pill
users as long as it is not heavier or of longer duration than the
woman’s menstrual blood loss before commencing oral
contraception.
17

Acceptability
Effect of Gracial
on irregular
bleeding
Irregular bleeding
One of the objectives during the development of Gracial was
to minimise irregular bleeding. In a large-scale, European
multicenter study during which 882 women were followed
during a total of more than 12,000 cycles (Dieben et al
1991), excellent cycle control was noted. During Gracial use,
the overall incidence of breakthrough bleeding and/or spotting
decreased from 15.4% in the first cycle to 4% at the end of
the study period.
Subsequent detailed analysis of the study data (Dieben, Op
ten Berg et al 1994) demonstrated that during Gracial use the
incidence of breakthrough bleeding and/or spotting in
switchers decreased from 14.2% in cycle 1 to 8.1% in cycle 6
and to 5.7% by the end of the study period. Table 3 shows
the incidence of spotting and breakthrough bleeding in
switchers during Gracial use.
Table 3: Incidence of irregular bleeding (%) in women
using Gracial (switchers)
Switchers
Cycle S B S/B
1 6.8 6.0 1.4
3 4.4 4.9 0.3
6 4.2 3.6 0.3
12 3.5 2.2 0.0
(S=Spotting B=Breakthrough bleeding) Dieben, Op ten Berg et al 1994
The low incidence of irregular bleeding was associated with a
correspondingly low overall dropout rate of 2.2% after 18
cycles, as a result of irregular bleeding.
Withdrawal bleeding
Overall, withdrawal bleeding failed to occur in only 3.2% of
the 12,850 cycles evaluated in the European multicenter
study (Dieben et al 1991).
Withdrawal bleeding occurred in 92.4% in cycle 1, 95% in
cycle 3, 96.8% in cycle 6 and 98.2% in cycle 18 (Figure 9). In
90% of the women, withdrawal bleeding started within the
first four days of the tablet-free period.
18

Acceptability
Decrease in
amount and
duration of
withdrawal
bleeding
The duration of withdrawal bleeding decreased slightly during
the course of the study. Similarly, the amount of bleeding
decreased in 25% of the women while a slight increase in
amount of bleeding was reported by 5% (Dieben, Op ten Berg
et al 1994).
%
100
90
92.4%
95%
96.8%
98.2%
80
70
60
50
40
30
20
10
0
Cycle 1
Cycle 2
Cycle 6
Cycle 18
Fig. 9: Occurrence of withdrawal bleeding during
Gracial use
Dieben et al 1991
In a more recent study, cycle control was found to be
significantly improved after switching to Gracial (Vree 2000).
In this study, the incidence of spotting and breakthrough
bleeding decreased from 33.2% and 23.2% of women
respectively in the cycle before starting Gracial, to 6.8% and
3.4% of women at the end of the study period (Figure 10).
19

Acceptability
% of women
35
30
25
20
15
10
5
0
Spotting
Previous OC
Breakthrough bleeding
Gracial
Fig. 10: Incidence of spotting and breakthrough
bleeding before and after switching to Gracial
Vree 2000
Low incidence of
side effects
5.2 Side effects
As with all OCs, side effects with Gracial tended to be reported
more frequently in the first few cycles of use, thereafter
decreasing. Women who switched to Gracial from another OC
showed a marked improvement after 12 cycles (Table 4).
Table 4: Incidence of subjective side effects in switchers
Breast
Nausea Headache Nervousness Depression tenderness
Pretreatment 3.7% 9.4% 6.6% 4.5% 6.6%
Cycle 1 3.4% 3.7% 3.9% 0.8% 5.2%
Cycle 3 1.1% 5.2% 2.7% 1.1% 3.0%
Cycle 12 0% 2.5% 2.1% 0.4% 0.7%
Dieben, Op ten Berg et al 1994
In starters it has been shown that minor complaints commonly
reported by OC users are less apparent during the use of
Gracial than before OC use (Figure 11).
20

Acceptability
%
0
Nausea
Headache
Nervousness Depression
Breast
tenderness
-0.5
-1
-1.5
-2
-2.5
-3
-3.5
-4
-4.5
-1.5
-4
-3.3
-1.1
-3.1
Fig. 11: Changes in incidence of subjective side
effects after six cycles of Gracial (compared
to levels before Pill use) in starters
Dieben, Op ten Berg et al 1994
Negligible effect
on body weight
5.3 Body weight
Body weight was measured every three months in the
multicenter study. There was a mean increase in weight of
between 0.1 and 0.6 kg above pretreatment weight over 18
cycles. Since almost 20% of the study population were aged
under 20 and the actual weight changes were very small, it is
probable that they were merely a reflection of normal growth.
Therefore, as with other low-dose OCs, the effect of Gracial on
body weight is negligible and merely reflects the natural
growth in younger women.
5.4 Continuation rate
Overall dropout rate due to bleeding irregularities was 2.2%,
and 4.3% due to minor side effects. These very low figures
illustrate the high acceptability of Gracial.
Conclusion
The excellent cycle control during Gracial use, together with a
low incidence of subjective side effects and negligible effect on
body weight, makes Gracial a highly acceptable Pill. It should
prove especially suitable for women who experience
unacceptable cycle control with any other low-dose OC.
21

6. Gracial and mild to
moderate acne
•Gracial significantly increases levels of SHBG and
reduces free testosterone
• These serum changes in SHBG and free testosterone
result in a marked reduction in the incidence and
severity of acne
• The improvement in acne seen with Gracial is
comparable to that seen with cyproterone acetate
Androgenic skin
disorders
Occurrence or worsening of androgenic skin disorders is also a
reason for brand switching of oral contraceptives, especially in
younger women (Oddens et al 1994). This can be a
consequence of the androgenicity of the progestogen
component.
More androgenic OCs may worsen these skin disorders (and
even induce them in those previously free of such conditions).
One of the underlying factors is an increased total serum
testosterone and/or decreased sex hormone binding globulin
(SHBG) levels, leading to an increase in free serum
testosterone.
In general, exogenous estrogens increase SHBG levels. As a
consequence, more testosterone can be bound to SHBG,
resulting in a decrease of free testosterone in the blood. This
decrease of free testosterone in the blood can lead to an
improvement in mild to moderate acne.
6.1 Effect on SHBG and testosterone
Due to its unique dosage regimen, Gracial is slightly estrogen
dominant. In addition, the active progestogen component of
Gracial is the most selective of the progestogens used in
combined oral contraceptives. This profile suggests that
Gracial has beneficial effects on acne.
22

Gracial and mild to moderate acne
Increase in
SHBG levels
Jung-Hoffmann et al (1992) showed that Gracial induced a
significant increase in SHBG (+250%) which was sustained for
some weeks after discontinuation of therapy. This finding was
confirmed by Falsetti (1991) and by Kuhl et al (1993) who
subsequently also demonstrated a reduction of 55% of free
serum testosterone levels in Gracial users (Figure 12).
nmol/ml
250
200
150
100
50
0
pg/ml
3.0
2.5
2.0
1.5
1.0
0.5
0
Pre-treatment
cycle
Pre-treatment
cycle
Cycle 1 Cycle 2 Cycle 6
SHBG
Cycle 1 Cycle 3 Cycle 6
free testosterone
Posttreatment
cycle
Posttreatment
cycle
Fig. 12: Effects of Gracial treatment on serum SHBG
and free testosterone
Kuhl et al 1993
6.2 Clinical effects
In the study by Falsetti (1991), these serum changes in SHBG
and free testosterone levels were associated with a marked
reduction in the incidence and severity of acne. Of 30 women
suffering from a mainly mild to moderate grade of acne, 18
were cured after nine cycles of Gracial and in the remaining
12 only mild acne remained.
23

Gracial and mild to moderate acne
Gracial has
beneficial effects
on mild to
moderate acne
These findings have been confirmed in a study by Volpe et al
(1994) in which almost 80% of a group of 33 young women
with acne were cured or greatly improved during 12 cycles of
Gracial use.
Dieben and Vromans (1994) carried out a comparative study
of Gracial with a preparation containing 35 µg EE/2 mg
cyproterone acetate (EE/CPA) per day and found that in both
groups there was an equal reduction in degree of severity and
number of acne lesions. Overall there was no statistically
significant difference between the two preparations in their
effects on acne (Figure 13).
Mean acne grade
1.0
0.5
0.69
0.52
0.54
0.41
0
Pretreatment
cycle
EE/CPA
Cycle 4
Pretreatment
cycle
Gracial
Cycle 4
Fig. 13: Effects of Gracial and EE/CPA on acne
Dieben, Vromans 1994
24

Gracial and mild to moderate acne
Number and
severity of acne
lesions reduced
Recently, the effects of Gracial on acne were again compared
with those of an OC preparation containing ethinylestradiol and
cyproterone acetate (2.0 mg cyproterone acetate/35 µg EE)
(Melief 2000). The study (in which 172 women were randomized
to either treatment) found that Gracial progressively reduced
the number and severity of acne lesions during the six cycles of
treatment. In both groups, the majority of women with severe
acne shifted to a less severe acne category (Figure 14). The
efficacy of Gracial was comparable to the preparation containing
the antiandrogen cyproterone acetate and no statistically
significant differences were observed between the two groups.
%
100
90
80
70
60
50
40
30
20
10
0
%
100
90
80
70
60
50
40
30
20
10
0
A
0 3 6 0 3 6
Combiphasic EE/DSG
EE35/CPA
B
0 3 6 0 3 6
Combiphasic EE/DSG
EE35/CPA
Severe Moderate Mild No acne
Fig. 14: Objective (A) and subjective (B) classification
of severity of acne at pretreatment, Cycle 3
and Cycle 6
25
Melief 2000

Gracial and mild to moderate acne
Reduction in
severity of acne
Another recent noncomparative clinical evaluation of women
who switched from a different OC to Gracial showed a
reduction in the severity of acne during treatment with Gracial
(Figure 15) (Vree 2000).
100
80
52%
% of women
60
40
35%
77%
20
18%
0
Previous OC
(n=592)
No. of papules/pustules:
Gracial
(n=396)
1–5 6–10 >10
Fig. 15: Changes in acne severity after switching to
Gracial
Vree 2000
Conclusion
Gracial significantly increases SHBG levels and reduces free
testosterone, which results in an improvement in the incidence
and severity of mild to moderate acne comparable to that of
cyproterone acetate.
26

7. Safety aspects
• The effects of Gracial on hemostatic parameters are
comparable to those of classic triphasic regimens
•Gracial has mainly beneficial effects on lipid
metabolism and no clinically adverse effects on
carbohydrate metabolism
•Gracial has not been found to have any consistent
adverse effects on blood pressure
• The association between OCs and venous
thromboembolism is likely to be influenced by the
amount of estrogen in the Pill and not by the type of
progestogen
• The risk of AMI is significantly lower in users of third
generation OCs than that seen with older-generation Pills
• The risk of stroke in users of third-generation OCs is not
increased
• OC use substantially reduces the incidence of ovarian
and endometrial cancer
As oral contraceptives are used for long periods of time by
healthy young women for the main purpose of preventing
pregnancy, manufacturers have constantly striven to identify
and minimize potential health risks. From the time of its first
introduction, the Pill has provided virtually 100%
contraceptive efficacy. As a result, most of the developments
in oral contraception over the last 35 years have been driven
by the search for ever better safety and tolerability.
Consequently, any health risk attributable to modern OCs is
small in comparison to the risk to health posed by an
unwanted pregnancy.
Epidemiological
data
New epidemiological data have recently become available
which cast new light upon the association between
cardiovascular disease and OC use. In addition, new data
concerning gynecological cancer risk have also been
published.
27

Safety aspects
Gracial not
included in
epidemiology
Since Gracial has been on the market for a relatively short
period of time in relatively few countries, it has not been
included in the epidemiological studies on OCs and
cardiovascular disorders. Therefore, an overview of the effects
of Gracial on intermediate endpoints associated with lipid
metabolism, carbohydrate metabolism and hemostasis is also
presented in this chapter.
7.1 Venous thromboembolism
The association between OC use and the occurrence of
venous thromboembolism (VTE) is one of the most important
safety aspects that shaped the development of the Pill. It
became apparent within a few years after the introduction of
the Pill that this association was related to its estrogen
component. Studies clearly demonstrated that as the estrogen
dose was progressively reduced, from 100 µg to 50 µg EE by
the 1970s and then down to 30–35 µg, the incidence of
thrombotic events in oral contraceptive users decreased
accordingly (Vessey 1988; Gerstmann et al 1991; RCGP
1978; Farmer 1995).
Hemostasis
In the early years following the introduction of low-dose
(30 µg) Pills such as Marvelon, which utilizes the third-generation
progestogen desogestrel, epidemiological data for their effects
on VTE was not available. Therefore, measurable indicators on
the function of the vascular system, such as hemostatic
parameters, were investigated to determine the impact of OCs.
Effect on
hemostatic
parameters
Changes in hemostatic parameters with Gracial (both 22- and
21-day regimens) were comparable to a classic triphasic
regimen. The effects of Gracial on hemostatic parametes have
been compared with those of Triodeen (triphasic EE +
gestodene) over a period of six treatment cycles (van Enk et
al, manuscript in preparation). In general, there were
significant changes in all hemostatic parameters with both
Gracial and triphasic gestodene.
The following specific differences were noted. Gracial
produced a significantly larger increase in factor VII (in cycles
3 and 6), a significantly smaller increase in fibrinogen (in cycle
3) and plasminogen (in cycle 6), and significantly larger
decreases in antithrombin III (in cycle 6), protein S (total) (in
cycle 3), protein S (free) (in cycles 3 and 6) and plasminogen
activator inhibitor I (PAI-I-Act) (in cycles 3 and 6). After six
cycles of Gracial use, there was no significant change from
baseline in fibrinopeptide A.
28

Safety aspects
Gracial has a standard dose of EE (average of 33 µg/day) and
has demonstrated effects on hemostatic parameters
comparable to that of a classic triphasic regimen.
Initial confusion
Epidemiological data
In 1995 and 1996, new epidemiological data on the
association between Pill use and the risk of VTE became
available, which initially caused great confusion because they
were quite at variance with understanding of the issues at the
time (WHO 1995; Jick et al 1995; Spitzer et al 1996).
It was reported that OCs containing the same dose of 30 µg
EE were associated with different odds ratios for VTE
depending upon their progestogen component [levonorgestrel
(LNG), desogestrel (DSG) or gestodene (GSD)]. The odds ratio
of VTE in users of OCs containing DSG or GSD ranged between
1.5 and 2.2 compared to women using OCs containing LNG.
This finding was in contrast to the medical consensus from the
preceding 35 years of Pill research, in which the risk of VTE
had been shown to decline in parallel with reductions in the
EE dose, irrespective of the progestogen (RCGP 1974; Sartwell
et al 1969; Vessey et al 1977; Gerstmann et al 1991).
In the context of existing and new epidemiological data, it
appeared that the incidence of this venous complication in
women using a third-generation OC (a low dose of EE in
combination with either DSG or GSD) was approximately the
same as that in women using a second-generation OC (a low
dose of EE in combination with LNG) 10 years earlier.
Surprisingly, however, the incidence of VTE in the latter group
had reduced over time. It became clear that the observed
difference in risk of VTE between OC generations was due to a
reduction in the incidence of venous complications with the
second-generation Pills over time, rather than to an
unexpected increase with third-generation Pills.
Healthy user
effect
This decline in incidence of VTE over time has been attributed
to the so-called ‘healthy user’ effect (i.e. the selective removal
of high-risk persons from a cohort of users over time), which
has been operational with the introduction of each new oral
contraceptive (RCGP 1974, 1978; Jick et al 1995; WHO
1995; Gerstmann et al 1991; Vessey 1988; Lewis et al 1996).
In the group of women starting with the Pill, a certain
proportion is expected to have a not yet identified
predisposition to VTE. If these women develop VTE, they will
discontinue use of their OC as they become contraindicated.
29

Safety aspects
The incidence of VTE in the remaining ‘healthy user’ group
then becomes less and less over time. This is the major factor
responsible for the ‘healthy user’ effect.
OC1
OC2
Number of adverse events
time
Fig. 16: User cohort effect (the ‘healthy user’ effect)
or attrition of the susceptibles
(Lewis et al 1997)
Selective
prescribing
A second biasing factor was also operating in the
epidemiological studies called prescribing bias or selective
prescribing. The third-generation Pills were selectively
prescribed to women with risk factors for cardiovascular
disease, such as age, personal or family history of VTE, clinical
venous signs, chronic inflammatory disease, anesthesia or
plaster cast, obesity, diabetes, standing working position,
alcohol abuse, smoking or a combination of risk factors
(Lunsen van 1996; Lis et al 1993; Poulter et al 1996;
Heinemann et al 1996; Farmer 1996; Herings et al 1996;
Jamin and De Mouzon 1996; Lewis et al 1996; Farmer et al
1997; Lidegaard 1997; Dunn et al 1998). As a result of
selective prescribing, cardiovascular adverse effects could be
more frequently observed in users of the third-generation OCs.
30

Safety aspects
Adjusting for
bias
In more recent epidemiological studies (Farmer et al 1997,
1998; Lewis et al 1999; Lidegaard et al 1998; Suissa et al
1997), it was possible to adjust more appropriately for these
newly recognized biases than in previous studies. This was due
to a better understanding of the ways in which these biases
influence results. In this context, the user age and duration of
OC use appear to be closely related to prescribing bias and
the ‘healthy user’ effect. When adjusting for these factors, the
newer analyses consistently observed no difference in the risk
of VTE between second- and third-generation OC users, thus
confirming the likelihood that the initial differences in the
1995 studies were caused by bias and confounding.
The view that the initial studies were biased was substantiated
by a recent analysis by Farmer et al (1999), which reduced
the confounding effects of age and, indirectly, duration of use
to a minimum. This study observed no differences between
odds ratios for VTE in second- and third-generation OC users.
This finding was confirmed in the final analysis of the
Transnational study (Lewis et al 1999), which integrated the
full OC exposure history in their original case-control analysis.
The results of the final analysis are shown in the table below
and suggest that the odds ratio of VTE compared to non-users
is related to the dose of estrogen in the OC and is
independent of the type of progestogen used. The lowest
odds ratios (1.6–2.5) were associated with the low-dose, thirdgeneration
OCs and the highest (8.5) with the first-generation
OCs containing 50 µg estrogen or more. The odds ratios for
VTE with OCs containing 30 µg of EE but different
progestogens (DSG, GSD or LNG) were similar.
31

Safety aspects
Table 5: Relative risk estimates for VTE for different exposures compared
with non-use or second-generation OC use
Current exposure Reference group Odds ratio 95% CI
All OCs No current use 2.9 2.1-4.1
1st generation OCs No current use 8.5 3.0-23.9
2nd generation OCs No current use 2.9 1.9-4.2
Levonorgestrel OCs No current use 2.6 1.8-4.0
Norgestimate OCs No current use 3.7 2.2-6.1
3rd generation OCs No current use 2.3 1.5-3.5
Desogestrel/30 EE OCs No current use 2.5 1.6-4.1
Gestodene OCs No current use 2.3 1.4-3.6
Desogestrel/20 EE OCs No current use 1.6 0.9-2.9
3rd generation OCs 2nd generation OCs 0.8 0.5-1.3
(Lewis et al 1999)
Conclusion
It can be concluded that after appropriate adjustments for
relevant confounders and distorting factors, the risk of VTE is
similar for OCs containing the same estrogen doses,
irrespective of the progestogen component.
32

Safety aspects
7.2 Arterial disease
Epidemiological studies have suggested an association
between OCs and arterial disease. As the more androgenic
progestogens have been shown to have a greater adverse
effect on lipid metabolism (with a potential increase in the risk
of arterial diseases such as myocardial infarction and stroke;
Meade et al 1980; Kay 1982), new types of progestogens
were developed with a high level of progestogenic activity, but
substantially reduced androgenic properties.
Risk factors
Etiology
In the population at large, major recognized risk factors for
myocardial infarction (MI) have been identified: age, smoking,
diabetes, hypertension, hypercholesterolemia and a family
history of MI. Some studies, attempting to determine if
women with established risk factors for MI are especially at
risk of this disease while using OCs, have found an interaction
between current OC use and heavy smoking (Rosenberg et al
1990; Croft and Hannaford 1989), and between OC use and
older age (Mann and Inman 1975; Kreuger et al 1980).
The etiology of OC-associated venous thrombosis and
myocardial infarction may differ from each other in an
important aspect. Endothelial damage does not seem to be a
prerequisite for the formation of a venous thrombus (Godsland
and Crook 1996). In contrast, hemodynamic considerations
alone make it unlikely that an arterial thrombus will
accumulate on an entirely intact endothelium. An imbalance in
the normal cycle of arterial endothelial damage and repair, or
the endothelial and intimal lesions seen in OC users, could
result in platelet adhesion and activation and thrombus
accumulation in an apparently normal artery. This process will
be opposed by circulating factors which promote endothelial
integrity, and will be helped along by those factors which
disrupt endothelial function. There are three major candidates
for involvement in these processes: serum triglycerides, HDLcholesterol
and insulin (Godsland and Crook 1996).
Lipoprotein metabolism
Oral contraceptives have effects on a number of the serum
lipoproteins, but the most significant of these effects are
thought to be those on triglycerides and HDL-cholesterol.
33

Safety aspects
Oral contraceptives induce a rise in serum triglycerides which,
in contrast to that associated with atherosclerosis, is due to an
increase in synthesis rather than a decrease in clearance. In
epidemiological studies, triglycerides do not seem to be an
independent risk factor for cardiovascular disease in women.
In addition, other drugs which increase serum triglyceride
levels (e.g. postmenopausal estrogens, alcohol and
cholestyramine) reduce the risk of MI (Castelli 1988).
HDL-cholesterol appears to exert anti-atherosclerotic effects in
several ways (Godlands and Crook 1996). HDL-cholesterol
preserves endothelial integrity by: eliminating lipid
peroxidation products; stabilizing the vasodilator and antiplatelet
agent, prostacyclin; inhibiting endothelial-based
inflammatory responses via a diminution of expression of
endothelial wall adhesion molecules; protecting erythrocytes
against procoagulatory activity; ameliorating abnormal
vasoconstriction; suppressing smooth muscle cell proliferation.
Not surprisingly, elevated HDL levels are consistently
associated with low coronary artery disease rates, especially
in women (Castelli 1988).
Low-estrogen-dose OCs containing the older progestogen,
levonorgestrel, do not affect or reduce HDL, whereas those
containing third-generation progestogens tend to increase HDL
levels. This variation could be expected to result in differences
in MI rates in users of different brands of OCs and there is
evidence that this may be the case (WHO 1997; Jick et al
1996; Lewis et al 1997a, b; Lidegaard and Edström 1996).
Effect of Gracial
on lipid
metabolism
Gracial has demonstrated a clear and significant increase in
HDL-cholesterol (10–30%), a slight increase in LDLcholesterol,
an increase in triglycerides, a 25% decrease in
apolipoprotein E and a transitory decrease in Lp(a) (Kuhl et al
1993). These findings are consistent with an estrogendominant
Pill.
The effects of Gracial on lipid parameters were compared with
those of triphasic gestodene over a period of six cycles (Van
Enk et al, manuscript in preparation, NV Organon, Oss). In
general, there were significant changes in lipid parameters
with both OCs. At cycle 6, Gracial produced significantly larger
increases in HDL-cholesterol, HDL-3 cholesterol,
apolipoprotein A1 and triglycerides. LDL-cholesterol increased
more with triphasic gestodene.
34

Safety aspects
Since falling levels of LDL-cholesterol and rising levels of HDLcholesterol
are both considered positive changes, Gracial's
influence on lipid metabolism can be regarded as favorable.
Carbohydrate metabolism
Insulin resistance and accompanying hyperinsulinemia may
induce adverse changes in MI risk via metabolic mechanisms
and effects on blood pressure. Insulin can also have
deleterious effects on the vascular wall by inducing smooth
muscle proliferation and lipid deposition. All oral
contraceptives cause some degree of insulin resistance, but
the effects of currently used low-estrogen-dose OCs vary
considerably. The greatest degree of insulin resistance is seen
with Pills containing levonorgestrel and the least with those
containing desogestrel (Godsland and Crook 1996).
Effect of Gracial
on carbohydrate
metabolism
Gracial has been shown (Kuhl 1993) to have only minor
effects on plasma insulin and glucose levels following glucose
loading, and no clinically significant effect on fasting insulin
levels or plasma glucose levels.
These results are similar to those reported for other low-dose
oral contraceptives and show that Gracial has no clinically
significant effects on carbohydrate metabolism.
No adverse
effect on blood
pressure
Blood pressure
Older studies have shown small increases in blood pressure
with prolonged use of high-estrogen dose OCs. However,
Gracial has not been found to have any consistent adverse
effects on blood pressure.
In the multicenter study of Dieben et al (1991), blood
pressure was measured both before use and after every three
cycles of Gracial. Particular attention was paid to the 499
women who had not used oral contraception before
('starters'), as any change in blood pressure as a result of
Gracial use ought to be most evident in this group. In fact,
blood pressure changes were inconsistent and their magnitude
was close to the limits of error in measurement.
Epidemiological data
In the last few years, several studies have provided new
epidemiological data on arterial disease, acute myocardial
infarction (AMI) and stroke (Jick et al 1996; Heinemann et al
1997; Lewis et al 1997; Lidegaard 1998; Dunn 1999;
WHO 1996).
35

Safety aspects
Stroke
With regard to ischemic stroke, new data have been generated
in the WHO study (WHO 1996), the Transnational study
(Heinemann et al 1997) and a Danish case-control study
(Lidegaard and Kreiner 1998).
The studies are not entirely consistent in their findings. The
stroke publication of the WHO Collaborative Group provides
separate information for the participating centers in Europe
and for those in developing countries. Although the European
data show no difference in the risk of stroke between Pill
generations, the risk of stroke in second-generation OC users
is statistically significantly increased in the centers from the
developing countries, while no increase was found for users of
the third-generation OCs.
The odds ratios in the Transnational study (Heinemann et al
1997) are higher than those observed in the WHO study and
also depend on the type of control group. No differences
between OCs of the second- and third-generation were
observed.
The study by Lidegaard and Kreiner (1998) concluded that
OCs with 50 µg EE and OCs with second-generation
progestogens significantly increased the risk of cerebral
thromboembolic attacks (CTA), which include thrombotic
strokes. However, OCs with third-generation progestogens did
not have any significant influence on the risk of CTA.
Acute MI
The risk of myocardial infarction was assessed in five studies.
In the Transnational AMI study (Lewis et al 1997), the risk of
AMI was observed to be significantly increased in secondgeneration
OC users versus no use, and was not increased in
third-generation OC users compared to no use. When
comparing second- and third-generation OC users, a
statistically significant, three times lower risk was observed for
users of the third-generation OCs (OR 0.3, 95% CI 0.1–0.9).
The authors of the publication concluded that third-generation
OCs are the first class of OCs not to be associated with MI.
36

Safety aspects
*
3
2.5
***
**
OR of AMI
2
1.5
1
0.5
0
2nd-generation
3rd-generation
* 2nd gen vs. non-use: 3.0 (1.5–5.7)
** 3rd gen vs. non-use: 0.8 (0.3–2.3)
*** 3rd gen vs. 2nd-gen: 0.3 (0.1–0.9)
Non-use
Fig. 17: Transnational study – case-control analysis
Risk of acute myocardial infarction
(Lewis et al 1997)
The Danish case-control analysis (Lidegaard 1997) is
consistent with an increased risk of AMI in users of secondgeneration
OCs and an absence of such risk in thirdgeneration
OC users, but the difference was not statistically
significant between OC types.
Findings on AMI were also published by Jick and colleagues
(1996), as well as the WHO Collaborative Group (1997). They
both observed a lower risk of AMI with the third-generation
OCs compared to the second-generation OCs, but the
difference was not significant, probably as a result of the small
size of these analyses. The study of Dunn and colleagues
(MICA) is the only study not showing a benefit with third
generation OCs. This study was done retrospectively and
showed signs of being affected by recall bias influenced by the
awareness created by the Pill scare of 1995.
Although the importance of HDL in arterial disease has been
established in almost every type of population, these new
epidemiological studies may be the first indication that an OCinduced
increase in HDL would also be beneficial.
37

Safety aspects
Influence of
adjustment for
bias
Conclusion
It is probable that the prescribing bias and ‘healthy user’
effect that influenced the VTE studies have also affected the
stroke and AMI studies. Both phenomena induce an unequal
distribution of women at risk of cardiovascular disease over
the different OCs. The effect of adjustment for these biases
would be that the risk of VTE, stroke and AMI would go down
in users of third-generation OCs, but increase in users of
second-generation OCs. The difference in VTE risk would
therefore disappear (as evidenced by the studies of Farmer et
al 1997, 1998, 1999; Lewis et al 1999; Lidegaard et al
1998; Suissa et al 1997, 2000), whereas a beneficial effect of
third-generation OCs regarding stroke may be masked and the
beneficial effect of third-generation OCs regarding AMI would
become even more prominent.
Gracial has been shown to have favorable effects on lipid
metabolism and minimal effects on carbohydrate metabolism,
both factors that are known to play a role in the etiology of
cardiovascular disease. The data on stroke are not fully
consistent, but suggest that there is no difference in the risk of
stroke between Pill generations. The risk of myocardial
infarction in users of newer Pills is the same as in non-users of
oral contraception and seems to be lower than the risk in
users of second-generation Pills.
7.3 Gynecological cancer
Concern about a possible association between oral
contraceptive use and increased risk of gynecological cancer
has been present virtually since the introduction of the Pill.
However, epidemiological data indicate that the risk of
endometrial and ovarian cancer is actually reduced in OC
users compared to ‘never-users’ (Stanford 1991; Vessey and
Painter 1995). Although the odds ratio for breast cancer is
slightly higher in current OC users, the breast cancer was more
likely to be diagnosed at an earlier stage and less likely to
have spread beyond the breast than in never-users
(Collaborative Group on Hormonal Factors in Breast Cancer
1996). The association between cervical cancer and OC use
remains inconclusive (Brinton 1991; Zondervan et al 1996).
38

Safety aspects
Breast cancer
In the mid-1980s, preliminary results from early
epidemiological studies suggested that the use of combined
oral contraceptives was associated with an increase in the risk
of breast cancer. However, in the last two decades, numerous
epidemiological studies have been published, and the
consensus has been that OC use has no overall effect on the
risk of breast cancer, except perhaps in certain subgroups of
women.
The Collaborative Group on Hormonal Factors in Breast
Cancer (1996) carried out a meta-analysis of 54
epidemiological studies involving over 50,000 women with
breast cancer, mainly published between 1980 and 1995.
From this meta-analysis, it emerged that:
OC use and
breast cancer
1. Compared to non-users, current users of OCs have a
slightly increased risk of having breast cancer diagnosed
(relative risk 1.24). This risk disappears after 10 years of
discontinuation.
2. The risk of breast cancer is not associated with the
duration of use or dose or type of hormone in the
combined OC. There is no synergism with other risk factors
for breast cancer (e.g. family history).
3. Breast cancer in ‘ever-users’ of OCs was more likely to be
diagnosed at an earlier stage and less likely to have spread
beyond the breast than in ‘never-users’.
39

Safety aspects
On balance, this study is very reassuring. The finding that use
of the Pill does not increase the overall lifetime risk of breast
cancer is very positive, as is the fact that breast cancer in
users or former users of OCs is less likely to have metastasized
at the time of diagnosis. The risk of having breast cancer
diagnosed is slightly increased in current users of the Pill, but
not in those who used an OC 10 years ago. This suggests that
the Pill does not initiate cancer of the breast because the risk
of cancer following exposure to known carcinogens depends
upon the amount and overall duration of exposure and not
upon the length of time elapsed since exposure. It has been
hypothesized that the increased risk of breast cancer in
current users could reflect a higher likelihood of diagnosis as a
result of more frequent professional surveillance and selfexamination
in Pill users. Alternatively, the Pill may be acting
as a promoter of pre-existing breast cancer, thereby advancing
the time at which it becomes clinically detectable (but
conversely reducing its tendency to metastasize). It is not
possible to infer from these epidemiological data whether the
observed relation between breast-cancer risk and OCs is due
to an earlier diagnosis of breast cancer in ever-users, the
biological effects of OCs or a combination of reasons.
Confirmation from experimental studies is necessary.
OC use and
cervical cancer
OC use and
ovarian cancer
Cervical, ovarian and endometrial cancer
The relationship between cervical cancer and OC use is still
inconclusive. Although a slightly elevated risk of cervical
cancer has been reported with OC use (Brinton 1991;
Zondervan et al 1996), it is difficult to adjust for the
confounder of sexual activity, as having multiple partners is a
known risk factor for cervical cancer.
A study by Stanford (1991), investigating the risk of epithelial
ovarian cancer with OC use, showed that in women who have
ever used an oral contraceptive, the risk of ovarian cancer was
reduced by 30%. In addition, five or more years of use was
associated with a 50% reduction in risk. This protective effect
persisted for ten years or more after beginning use of OCs.
A second investigation confirmed this finding (Vessey and
Painter 1995). In comparison with never-users, the relative
risk of ovarian and endometrial cancer in users of OCs was
0.4 (95% CI 0.2–0.8) and 0.1 (95% CI 0.0–0.7), respectively.
There was also a strong negative relationship between the
duration of oral contraceptive use and ovarian-cancer risk, i.e.
in comparison with never-users, the relative risk in users of
40

Safety aspects
OCs decreased as the duration of use increased. The
beneficial effects of OCs on the risk of ovarian and
endometrial cancer are thought to be related to ovulation
inhibition and the reduction of endometrial stimulation,
respectively.
A recent case-control study (Ness 2000) in 767 women aged
20–69 with a diagnosis of ovarian cancer and 1,367
community controls indicated that the protection afforded by
oral contraceptives against epithelial ovarian cancer is
independent of the dose of estrogen or
progestogen. The data from this study also indicate that the
reduced risk continues for 30 or more years after
discontinuation of OC use.
Conclusion
In summary, women who are currently using combined OCs, or
who have used them in the past 10 years, are at a slightly
increased risk of having breast cancer diagnosed. However, the
cancer diagnosed tends to be in a clinically less advanced
stage and is less likely to have spread beyond the breast. In
addition, use of the Pill does not increase the overall lifetime
risk for breast cancer. Furthermore, the incidences of ovarian
and endometrial cancer are substantially reduced by OC use.
The longer OCs are used, the lower the associated risk. The
relationship between cervical cancer and OC use has not yet
been substantiated.
41

8. Summary
The most recent area of contraceptive research focuses on the
development of extensions to the existing range of Pills, each
with different characteristics specially tailored to a specific
subgroup of women. Gracial is a Pill which is particularly
suitable for women who wish to switch to a different OC
because they experience irregular bleeding. Gracial is a
combined oral contraceptive with a unique combiphasic
regimen: a relatively estrogenic first phase of seven tablets
followed by a relatively progestogenic phase during the
remaining 15 days of the cycle. In Gracial, the combination of
EE with the highly selective progestogen desogestrel in a
22-day regimen has permitted a major reduction in the total
cycle progestogen dose with a total estrogen dose comparable
to that of many combined OCs.
Clinical evidence confirms that:
• Gracial is a very reliable oral contraceptive
• Gracial provides excellent cycle control with a low level of
subjective side effects
• Gracial has beneficial effects on mild to moderate acne
• Gracial has mainly minimal or beneficial effects on
metabolic parameters.
The clinical profile of Gracial makes it eminently suitable for
those women who wish to switch from their first-prescribed
Pill, in particular, for reasons to do with cycle control.
42

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thromboembolic disease amongst German women using oral contraceptives: a
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Farmer RDT, Lawrenson RA, Todd JC, Williams TJ, MacRae KD et al. A
comparison of the risk of venous thromboembolic disease in association with
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of progestogens, and bioavailability of testosterone during treatment with
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1984; 42: 44–51
Hasenack HG, Bosch AMG, Käär K. Serum levels of 3-ketodesogestrel after
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Could preferential prescribing and referral behaviour of physicians explain the
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contraceptives Pharmacoepidemiol Drug Saf 1996; 5: 285–94
Heinemann LAJ, Lewis MA, Thorogood M, Spitzer WO, Guggenmoos-
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the increased risk of venous thromboembolism among users of third generation
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contraceptives (OCs). Contraception 1996; 54: 55–6
Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of idiopathic
cardiovascular death and non-fatal venous thromboembolism in women using
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Jick H, Jick SS, Myers MW. Risk of acute myocardial infarction and low-dose
combined oral contraceptives (letter). Br Med J 1996; 347: 627–8
Juchem M, Pollow K. Binding of oral contraceptive progestogens to serum
proteins and cytoplasmic receptor. Am J Obstet Gynecol 1990; 163: 2171–83
Jung-Hoffmann C, Storch A, Kuhl H. Serum concentrations of ethinylestradiol,
3-keto-desogestrel, SHBG, CBG and gonadotropins during treatment with a
biphasic oral contraceptive containing desogestrel. Horm Res 1992; 38: 184–9
Kloosterboer HJ, van Wayjen RGA, van den Ende A. Effects of three low-dose
oral contraceptives on sex hormone binding globulin, corticosteroid binding
globulin and antithrombin III activity in healthy women. Acta Obstet Gynecol
Scand 1987;Suppl 144:41–4
Kloosterboer HJ, Vonk-Noordegraaf CA, Turpijn EW. Selectivity of
progesterone and androgen receptor binding of progestagens used in oral
contraceptives. Contraception 1988; 38: 325–32
Kuhl H. Pharmacokinetics of oestrogens and progestogens. Maturitas 1990;
2: 171–197
Kuhl W, März W, Jung-Hoffmann C, Weber J, Siekmeier R, Gross W. Effect on
lipid metabolism of a biphasic desogestrel-containing oral contraceptive:
divergent changes in apolipoprotein B and E and transitory decrease in Lp(a)
levels. Contraception 1993; 47: 69–83
Kuhl H, Jung-Hoffmann C, Weber J, Boehm BO. The effects of a biphasic
desogestrel-containing oral contraceptive on carbohydrate metabolism and
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Lewis MA, Heinemann LAJ, MacRae KD, Bruppacher R, Spitzer WO. The
increased risk of venous thromboembolism and the use of third generation
progestagens: role of bias in observational research. Contraception 1996; 54:
5–13
Lewis MA, Heinemann LAJ, Spitzer WO, MacRae KD, Bruppacher R. The use
of oral contraceptives and the concurrence of acute myocardial infarction in
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47

10. Summary of product characteristics
1. NAME OF THE MEDICINAL
PRODUCT
Gracial®.
2. QUALITATIVE AND QUANTITATIVE
COMPOSITION
Gracial® is a combiphasic oral contraceptive of
which:
• each blue tablet contains 25 mcg desogestrel
(DSG) and 40 mcg ethinylestradiol (EE).
• each white tablet contains 125 mcg DSG and
30 mcg EE.
3. PHARMACEUTICAL FORM
Tablets for oral use.
4. CLINICAL PARTICULARS
4.1 Therapeutic Indications
Contraception.
4.2 Posology and method of
administration
4.2.1 How to take Gracial®
Tablets must be taken in the order directed on the
package every day at about the same time with
some liquid as needed. One tablet is to be taken
daily for 22 consecutive days. Each subsequent
pack is started after a 6-day tablet-free interval,
during which time a withdrawal bleed usually
occurs. This usually starts on day 2–3 after the
last tablet and may not have finished before the
next pack is started.
4.2.2 How to start Gracial®
No preceding hormonal contraceptive use [in the
past month]
Tablet-taking has to start on day 1 of the woman’s
natural cycle (i.e. the first day of her menstrual
bleeding). Starting on days 2–5 is allowed, but
during the first cycle a barrier method is
recommended in addition for the first 7 days of
tablet-taking.
Changing from another combined oral
contraceptive (COC)
The woman should start with Gracial® preferably
on the day after the last active tablet of her
previous COC, but at the latest on the day
following the usual tablet-free or placebo tablet
interval of her previous COC.
Changing from a progestagen-only method
(minipill, injection, implant)
The woman may switch any day from the minipill
(from an implant on the day of its removal, from
an injectable when the next injection would be
due), but should in all of these cases be advised to
additionally use a barrier method for the first
7 days of tablet-taking.
Following first-trimester abortion
The woman may start immediately. When doing
so, she need not take additional contraceptive
measures.
Following delivery or second-trimester abortion
For breast-feeding women see Section 4.6
Women should be advised to start at day 21 to 28
after delivery or second-trimester abortion. When
starting later, the woman should be advised to
additionally use a barrier method for the first 7
days of tablet-taking. However, if intercourse has
already occurred, pregnancy should be excluded
before the actual start of COC use or the woman
has to wait for her first menstrual period.
4.2.3 Management of missed tablets
If the user is less than 12 hours late in taking any
tablet, contraceptive protection is not reduced.
The woman should take the tablet as soon as she
remembers and should take further tablets at the
usual time.
If she is more than 12 hours late in taking any
tablet, contraceptive protection may be reduced.
The management of missed tablets can be guided
by the following two basic rules:
1. tablet-taking must never be discontinued for
longer than 6 days.
2. 7 days of uninterrupted tablet-taking are
required to attain adequate suppression of the
hypothalamic-pituitary-ovarian-axis.
Accordingly, the following advice can be given in
daily practice:
• Week 1
The user should take the last missed tablet as
soon as she remembers, even if this means
taking two tablets at the same time. She then
continues to take tablets at her usual time. In
addition, a barrier method such as a condom
should be used for the next 7 days. If
intercourse took place in the preceding 7 days,
the possibility of a pregnancy should be
considered. The more tablets are missed and
the closer they are to the regular tablet-free
interval, the higher the risk of a pregnancy.
48

Summary of product characteristics
• Week 2
The user should take the last missed tablet as
soon as she remembers, even if this means
taking two tablets at the same time. She then
continues to take tablets at her usual time.
Provided that the woman has taken her tablets
correctly in the 7 days preceding the first
missed tablet, there is no need to use extra
contraceptive precautions. However, if this is not
the case, or if she missed more than 1 tablet,
the woman should be advised to use extra
precautions for 7 days.
• Week 3
The risk of reduced reliability is imminent
because of the forthcoming tablet-free interval.
However, by adjusting the tablet-intake
schedule, reduced contraceptive protection can
still be prevented. By adhering to either of the
following two options, there is therefore no need
to use extra contraceptive precautions, provided
that in the 7 days preceding the first missed
tablet the woman has taken all tablets correctly.
If this is not the case, the woman should be
advised to follow the first of these two options
and to use extra precautions for the next 7 days
as well.
1. The user should take the last missed tablet as
soon as she remembers, even if this means
taking two tablets at the same time. She then
continues to take tablets at her usual time.
The next pack must be started as soon as the
current pack is finished, i.e., no gap should be
left between packs. The user is unlikely to
have a withdrawal bleed until the end of the
second pack, but she may experience
spotting or breakthrough bleeding on tablettaking
days.
2. The woman may also be advised to
discontinue tablet-taking from the current
pack. She should then have a tablet-free
interval of up to 6 days, including the days
she missed tablets, and subsequently
continue with the next pack.
If the woman missed tablets and subsequently has
no withdrawal bleed in the first normal tablet-free
interval, the possibility of a pregnancy should be
considered.
4.2.4 Advice in case of vomiting
If vomiting occurs within 3–4 hours after tablettaking,
absorption may not be complete. In such
an event, the advice concerning missed tablets, as
given in Section 4.2.3, is applicable. If the woman
does not want to change her normal tablet-taking
schedule, she has to take the extra tablet(s)
needed from another pack.
4.2.5 How to shift periods or how to delay a
period
To delay a period, the woman should continue with
the white tablets in another pack of Gracial®
without a tablet-free interval. The extension can be
carried on for as long as wished until the end of
the second pack (maximally 15 days). During the
extension the woman may experience
breakthrough bleeding or spotting. Regular intake
of Gracial® is then resumed after the usual 6-day
tablet-free interval.
To shift her period to another day of the week than
the woman is used to with her current scheme, she
can be advised to shorten her forthcoming tabletfree
interval by as many days as she likes. The
shorter the interval, the higher the risk that she
does not have a withdrawal bleed and will
experience breakthrough bleeding and spotting
during the second pack (just as when delaying a
period).
4.3 Contraindications
Combined oral contraceptives (COCs) should not
be used in the presence of any of the conditions
listed below. Should any of the conditions appear
for the first time during COC use, the product
should be stopped immediately.
• Thrombosis (venous or arterial) present or in
history (e.g. deep venous thrombosis, pulmonary
embolism, myocardial infarction,
cerebrovascular accident).
• Presence or history of prodromi of a thrombosis
(e.g. transient ischemic attack, angina pectoris).
• Diabetes mellitus with vascular involvement.
• The presence of a severe or multiple risk
factor(s) for venous or arterial thrombosis may
also constitute a contraindication (see under
‘Special Warnings and Special Precautions for
Use’).
• Presence or history of severe hepatic disease as
long as liver function values have not returned to
normal.
• Known or suspected malignant conditions of the
genital organs or the breasts, if sex steroid
influenced.
• Presence or history of liver tumors (benign or
malignant).
• Undiagnosed vaginal bleeding.
• Known or suspected pregnancy.
• Hypersensitivity to any of the components of
Gracial®.
49

Summary of product characteristics
4.4 Special warnings and special
precautions for use
4.4.1. Warnings
If any of the conditions/risk factors mentioned
below is present, the benefits of COC use should
be weighed against the possible risks for each
individual case and discussed with the woman
before she decides to start using it. In the event of
aggravation, exacerbation or first appearance of
any of these conditions or risk factors, the woman
should contact her physician. The physician should
then decide on whether its use should be
discontinued.
1. Circulatory Disorders
• Epidemiological studies have suggested an
association between the use of COCs and an
increased risk of arterial and venous thrombotic
and thromboembolic diseases such as
myocardial infarction, stroke, deep venous
thrombosis, and pulmonary embolism. These
events occur rarely.
• Venous thromboembolism (VTE), manifesting as
deep venous thrombosis and/or pulmonary
embolism, may occur during the use of all COCs.
The approximate incidence of VTE in users of
low-estrogen-dose (< 50 mcg EE) OCs is up to 4
per 10 000 woman years compared to 0.5–3
per 10 000 woman years in non-OC users.
However, the incidence of VTE occurring during
COC use is substantially less than the incidence
associated with pregnancy (i.e. 6 per 10,000
pregnant woman years).
• Extremely rarely, thrombosis has been reported
to occur in other blood vessels, e.g. hepatic,
mesenteric, renal or retinal veins and arteries, in
COC users. There is no consensus as to whether
the occurrence of these events is associated
with the use of COCs.
• Symptoms of venous or arterial thrombosis can
include: unilateral leg pain and/or swelling;
sudden severe pain in the chest, whether or not
it radiates to the left arm; sudden
breathlessness; sudden onset of coughing; any
unusual, severe, prolonged headache; sudden
partial or complete loss of vision; diplopia;
slurred speech or aphasia; vertigo; collapse with
or without focal seizure; weakness or very
marked numbness suddenly affecting one side
or one part of the body; motor disturbances;
‘acute’ abdomen.
• The risk of thromboembolism (venous and/or
arterial) increases with:
• age;
• smoking (with heavier smoking and increasing
age the risk further increases, especially in
women over 35 years of age);
• a positive family history (i.e. venous or arterial
thromboembolism ever in a sibling or parent
at a relatively early age). If a hereditary
predisposition is suspected, the woman
should be referred to a specialist for advice
before deciding about any COC use;
• obesity (body mass index over 30 kg/m 2 );
• dyslipoproteinemia;
• hypertension;
• valvular heart disease;
• atrial fibrillation;
• prolonged immobilization, major surgery, any
surgery to the legs, or major trauma. In these
situations it is advisable to discontinue COC
use (in the case of elective surgery at least
four weeks in advance) and not to resume
until two weeks after complete remobilization.
• There is no consensus about the possible role of
varicose veins and superficial thrombophlebitis
in venous thromboembolism.
• The increased risk of thromboembolism in the
puerperium must be considered (for information
on “Pregnancy and Lactation” see Section 4.6).
• Other medical conditions which have been
associated with adverse circulatory events
include diabetes mellitus, systemic lupus
erythematosus, hemolytic uremic syndrome and
chronic inflammatory bowel disease (Crohn's
disease or ulcerative colitis) and sickle cell
disease.
• An increase in frequency or severity of migraine
during COC use (which may be prodromal of a
cerebrovascular event) may be a reason for
immediate discontinuation of the COC.
• Biochemical factors that may be indicative of
hereditary or acquired predisposition for venous
or arterial thrombosis include Activated Protein
C (APC) resistance, hyperhomocysteinemia,
antithrombin-III deficiency, protein C deficiency,
protein S deficiency, antiphospholipid antibodies
(anticardiolipin antibodies, lupus anticoagulant).
• When considering risk/benefit, the physician
should take into account that adequate
treatment of a condition may reduce the
associated risk of thrombosis and that the risk
associated with pregnancy is higher than that
associated with COC use.
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Summary of product characteristics
2. Tumors
• An increased risk of cervical cancer in long-term
users of COCs has been reported in some
epidemiological studies, but there continues to
be controversy about the extent to which this
finding is attributable to the confounding effects
of sexual behavior and other factors such as
human papilloma virus (HPV).
• A meta-analysis from 54 epidemiological studies
reported that there is a slightly increased
relative risk (RR = 1.24) of having breast cancer
diagnosed in women who are currently using
COCs. The increased risk gradually disappears
during the course of the 10 years after cessation
of COC use. Because breast cancer is rare in
women under 40 years of age, the excess
number of breast cancer diagnoses in current
and recent COC users is small in relation to the
lifetime risk of breast cancer. These studies do
not provide evidence for causation. The
observed pattern of increased risk may be due
to an earlier diagnosis of breast cancer in COC
users, the biological effects of COCs or a
combination of both. The breast cancers
diagnosed in ever-users tend to be less
advanced clinically than the cancers diagnosed
in never-users.
• In rare cases, benign liver tumors, and even
more rarely, malignant liver tumors have been
reported in users of COCs. In isolated cases,
these tumors have led to life-threatening intraabdominal
hemorrhages. A hepatic tumor
should be considered in the differential
diagnosis when severe upper abdominal pain,
liver enlargement or signs of intra-abdominal
hemorrhage occur in women taking COCs.
3. Other conditions
• Women with hypertriglyceridemia, or a family
history thereof, may be at an increased risk of
pancreatitis when using COCs.
• Although small increases in blood pressure have
been reported in many women taking COCs,
clinically relevant increases are rare. A
relationship between COC use and clinical
hypertension has not been established.
However, if a sustained clinically significant
hypertension develops during the use of a COC
then it is prudent for the physician to withdraw
the COC and treat the hypertension. Where
considered appropriate, COC use may be
resumed if normotensive values can be achieved
with antihypertensive therapy.
• The following conditions have been reported to
occur or deteriorate with both pregnancy and
COC use, but the evidence of an association
with COC use is inconclusive: jaundice and/or
pruritus related to cholestasis; gallstone
formation; porphyria; systemic lupus
erythematosus; hemolytic uremic syndrome;
Sydenham’s chorea; herpes gestationis;
otosclerosis-related hearing loss.
• Acute or chronic disturbances of liver function
may necessitate the discontinuation of COC use
until markers of liver function return to normal.
Recurrence of cholestatic jaundice which
occurred first during pregnancy or previous use
of sex steroids necessitates the discontinuation
of COCs.
• Although COCs may have an effect on peripheral
insulin resistance and glucose tolerance, there is
no evidence for a need to alter the therapeutic
regimen in diabetics using COCs. However,
diabetic women should be carefully observed
while taking COCs.
• Crohn’ s disease and ulcerative colitis have been
associated with COC use.
• Chloasma may occasionally occur, especially in
women with a history of chloasma gravidarum.
Women with a tendency to chloasma should
avoid exposure to the sun or ultraviolet radiation
while taking COCs.
4.4.2. Medical examination/consultation
A complete medical history and physical
examination should be taken prior to the initiation
or reinstitution of COC use, guided by the
contraindications (Section 4.3) and warnings
(Section 4.4.1), and should be repeated at least
annually during the use of COCs. Periodic medical
assessment is also of importance because
contraindications (e.g. a transient ischemic attack,
etc.) or risk factors (e.g. a family history of venous
or arterial thrombosis) may appear for the first
time during the use of a COC. The frequency and
nature of these assessments should be adapted to
the individual woman but should generally include
special reference to blood pressure, breasts,
abdomen and pelvic organs, including cervical
cytology, and relevant laboratory tests.
Women should be advised that oral contraceptives
do not protect against HIV infections (AIDS) and
other sexually transmissible diseases.
4.4.3 Reduced efficacy
The efficacy of COCs may be reduced in the event
of missed tablets (Section 4.2.3), vomiting (Section
4.2.4) or concomitant medication (Section 4.5.1).
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Summary of product characteristics
4.4.4 Reduced cycle control
With all COCs, irregular bleeding (spotting or
breakthrough bleeding) may occur, especially
during the first months of use. Therefore, the
evaluation of any irregular bleeding is only
meaningful after an adaptation interval of about
three cycles.
If bleeding irregularities persist or occur after
previously regular cycles, then non-hormonal
causes should be considered and adequate
diagnostic measures are indicated to exclude
malignancy or pregnancy. These may include
curettage.
In some women, withdrawal bleeding may not
occur during the tablet-free interval. If the COC has
been taken according to the directions described
in Section 4.2, it is unlikely that the woman is
pregnant. However, if the COC has not been taken
according to these directions prior to the first
missed withdrawal bleed or if two withdrawal
bleeds are missed, pregnancy must be ruled out
before COC use is continued.
4.5 Interaction with other medicinal
products and other forms of interaction
4.5.1 Interactions
Drug interactions which result in an increased
clearance of sex hormones can lead to
breakthrough bleeding and oral contraceptive
failure. This has been established with hydantoins,
barbiturates, primidone, carbamazepine and
rifampicin; oxcarbazepine, topiramate and
griseofulvin are also suspected. The mechanism of
this interaction appears to be based on the
hepatic enzyme-inducing properties of these drugs.
Maximal enzyme induction is generally not seen
for 2–3 weeks but may then be sustained for at
least 4 weeks after the cessation of drug therapy.
Contraceptive failures have also been reported
with antibiotics, such as ampicillins and
tetracyclines. The mechanism of this effect has not
been elucidated.
Women on short-term treatment with any of the
above-mentioned classes of drugs or individual
drugs should temporarily use a barrier method in
addition to the COC, i.e. during the time of
concomitant drug administration and for 7 days
after their discontinuation. For women on
rifampicin a barrier method should be used in
addition to the COC during the time of rifampicin
administration and for 28 days after its
discontinuation. If concomitant drug administration
runs beyond the end of the tablets in the COC
pack, the next COC pack should be started
without the usual tablet-free interval.
In women on long-term treatment with hepatic
enzyme-inducing drugs, experts have
recommended to increase the contraceptive
steroid doses. If a high contraceptive dosage is not
desirable or appears to be unsatisfactory or
unreliable, e.g. in the case of irregular bleeding,
another method of contraception should be
advised.
4.5.2 Laboratory tests
The use of contraceptive steroids may influence
the results of certain laboratory tests, including
biochemical parameters of liver, thyroid, adrenal
and renal function, plasma levels of (carrier)
proteins, e.g. corticosteroid binding globulin and
lipid/lipoprotein fractions, parameters of
carbohydrate metabolism and parameters of
coagulation and fibrinolysis. Changes generally
remain within the normal laboratory range.
4.6 Use during pregnancy and lactation
Extensive epidemiological studies have revealed
neither an increased risk of birth defects in
children born to women who used COCs prior to
pregnancy, nor a teratogenic effect when COCs
were taken inadvertently during early pregnancy.
See also Contraindications.
Lactation may be influenced by COCs as they may
reduce the quantity and change the composition
of breast milk, therefore, the use of COCs should
generally not be recommended until the nursing
mother has completely weaned her child. Small
amounts of the contraceptive steroids and/or their
metabolites may be excreted with the milk but
there is no evidence that this adversely affects
infant health.
4.7 Effects on ability to drive and use
machines
No observed effects.
4.8 Undesirable effects
4.8.1 Serious undesirable effects
See Section 4.4.1.
4.8.2 Other possible undesirable effects
The following undesirable effects have been
reported in users of COCs and the association has
been neither confirmed nor refuted:
Breast tenderness, pain, secretion; headache;
migraine; changes in libido; depressive moods;
contact lens intolerance; nausea; vomiting;
changes in vaginal secretion; various skin
disorders; fluid retention; change in body weight;
hypersensitivity reaction.
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Summary of product characteristics
4.9 Overdose
There have been no reports of serious deleterious
effects from overdose. Symptoms that may occur
in this case are: nausea, vomiting and, in young
girls, slight vaginal bleeding. There are no
antidotes and further treatment should be
symptomatic.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Gracial® is a combiphasic OC containing DSG as
the progestagen component. The combiphasic
concept stands for a low and stepwise increased
progestagen dosage while at the same time the
estrogen dose is reduced. With this concept, cycle
control can be improved as compared to
monophasic OCs while maintaining their high
contraceptive efficacy. The contraceptive effect of
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. As well as protection against
pregnancy, COCs have several positive properties
which, next to the negative properties (see
Warnings, Undesirable effects), can be useful when
deciding on a 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. Apart from this, with the higher-dosed
COCs (50 mg ethinylestradiol), there is evidence of
a reduced risk of fibrocystic tumours of the
breasts, ovarian cysts, pelvic inflammatory disease,
ectopic pregnancy and endometrial and ovarian
cancer. Whether this also applies to lower-dosed
COCs remains to be confirmed.
5.2 Pharmacokinetic properties
Desogestrel
ABSORPTION
Orally administered desogestrel is rapidly and
completely absorbed and converted to
etonogestrel. Peak serum concentrations of
approximately 0.3 (day 7) to 1.6 ng/ml (day 22)
are reached at about 1.5 hours after ingestion.
Bioavailability is 62–81%.
DISTRIBUTION
Etonogestrel is bound to serum albumin and to sex
hormone binding globulin (SHBG). Only 2–4% of
the total serum drug concentrations are present as
free steroid, 40–70% are specifically bound to
SHBG. The ethinylestradiol-induced increase in
SHBG influences the distribution over the serum
proteins, causing an increase in the SHBG-bound
fraction and a decrease in the albumin-bound
fraction. The apparent volume of distribution of
desogestrel is 1.5 l/kg.
METABOLISM
Etonogestrel is completely metabolized by the
known pathways of steroid metabolism. The
metabolic clearance rate from serum is about
2 ml/min/kg. No interaction was found with the
co-administered ethinylestradiol.
ELIMINATION
Etonogestrel serum levels decrease in two phases.
The terminal disposition phase is characterized by
a half-life of approximately 30 hours. Desogestrel
and its metabolites are excreted at a urinary to
biliary ratio of about 6:4.
STEADY-STATE CONDITIONS
Etonogestrel pharmacokinetics are influenced by
SHBG levels, which are increased threefold by
ethinylestradiol. Following daily ingestion, drug
serum levels increase about two- to three-fold,
reaching steady-state conditions during the second
half of the treatment cycle.
Ethinylestradiol
ABSORPTION
Orally administered ethinylestradiol is rapidly and
completely absorbed. Peak serum concentrations
of about 80–100 pg/ml are reached within 1–2
hours. Absolute bioavailability as a result of
presystemic conjugation and first-pass metabolism
is approximately 60%.
DISTRIBUTION
Ethinylestradiol is highly but non-specifically
bound to serum albumin (approximately 98.5%)
and induces an increase in the serum
concentrations of SHBG. An apparent volume of
distribution of about 5 l/kg was determined.
METABOLISM
Ethinylestradiol is subject to presystemic
conjugation in both small bowel mucosa and the
liver. Ethinylestradiol 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 metabolic clearance rate is about 5 ml/min/kg.
53

Summary of product characteristics
ELIMINATION
Ethinylestradiol serum levels decrease in two
phases, the terminal disposition phase is
characterized by a half-life of approximately
24 hours. Unchanged drug is not excreted,
ethinylestradiol metabolites are excreted at a
urinary to biliary ratio of 4:6. The half-life of
metabolite excretion is about 1 day.
STEADY-STATE CONDITIONS
Steady-state concentrations are reached after
3–4 days when serum drug levels are higher by
30–40% as compared to single dose.
5.3 Preclinical safety data
Animal toxicity studies for human risk estimation
were performed for both components of the
preparation, ethinylestradiol and desogestrel, and
the combination.
No effects which might indicate an unexpected risk
to humans were observed during systemic
tolerance studies after repeated administration.
Long-term repeated dose toxicity studies did not
indicate a tumorigenic potential. However, it must
be borne in mind that sex steroids can promote
the growth of certain hormone-dependent tissues
and tumors.
Studies on embryotoxicity and teratogenicity and
the evaluation of the effects of both components
on the fertility of parent animals, fetal
development, lactation and reproductive
performance of the offspring gave no indication of
a risk of adverse effects in humans after
recommended use of the preparation.
In vitro and in vivo studies gave no indication of a
mutagenic potential.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Blue tablets:
Colloidal silicon dioxide; lactose; potato starch;
povidone; stearic acid; dl-alpha-tocopherol;
indigotin (E132).
White tablets:
Colloidal silicon dioxide; lactose; potato starch;
povidone; stearic acid; dl-alpha-tocopherol.
The daily amount of lactose (< 100 mg) is such
that women with an intolerance to lactose are
highly unlikely to experience a problem.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Shelf life of the tablets is as indicated on the box,
if stored according to the directions in Section 6.4.
6.4 Special precautions for storage
Store at 2°C to 30°C.
6.5 Nature and contents of container
Push-through packs with 7 blue and 15 white
tablets. Tablets are round, flat and 6 mm in
diameter. Tablets are coded on one side with
Organon* and on the reverse side with TR8 (white
tablets) or TR9 (blue tablets).
The pack is a PVC/Al blister consisting of
aluminium foil with a heat-seal coating and a PVC
film. Each blister is packed in a printed aluminium
pouch. The pouch is packed in a printed
cardboard box together with the package leaflet.
6.6 Instructions for use/handling and
disposal (if appropriate)
Store all drugs properly and keep them out of
reach of children.
7. MARKETING AUTHORIZATION
HOLDER
N.V. Organon
P.O. Box 20
5340 BH Oss
The Netherlands
8. NUMBERS IN THE COMMUNITY
REGISTER OF MEDICINAL
PRODUCTS
9. DATE OF FIRST AUTHORIZATION
[Market-specific information must be included in
this section where applicable].
10. DATE OF REVISION OF TEXT
February 1998.
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