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CILEST 35/250 MICROGRAMS FILM-COATED TABLETS

Active substance(s): ETHINYLESTRADIOL / NORGESTIMATE / ETHINYLESTRADIOL

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Transcript
SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Cilest 35/ 250 micrograms film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains norgestimate 0.25 mg and ethinylestradiol
0.035 mg.
Excipients with known effects:
Lactose monohydrate 57.065 mg, see section 4.4
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Film-coated tablet
Blue, round, biconvex, coated tablet, imprinted ‘0 250’ on one side and ‘35’ on the
other side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Contraception and the recognised indications for such oestrogen/progestogen
combinations.
The decision to prescribe Cilest should take into consideration the individual
woman’s current risk factors, particularly those for venous thromboembolism
(VTE), and how the risk of VTE with Cilest compares with other Combined
Hormonal Contraceptives (CHCs) (see sections 4.3 and 4.4).

4.2

Posology and method of administration
For oral administration.
4.2.1 Adults
How to take Cilest
One tablet is taken daily at the same time (preferably in the evening) without
interruption for 21 days, followed by a break of 7 tablet-free days. Each
subsequent pack is started after the 7 tablet-free days have elapsed. Additional
contraceptive precautions are not then required. During the tablet-free period,
bleeding can be expected, usually beginning 2 to 4 days after the last tablet.
Starting treatment
It is preferable that tablet intake from the first pack is started up to and including
day 5 of menstruation in which case no extra contraceptive precautions are
necessary.

Cilest can be started at any other time, if pregnancy can reasonably be excluded.
In this case additional contraceptive precautions must be taken for the first 7 days
of tablet taking
Switching from another contraceptive
Hormonal methods: Cilest can be started immediately if the patient has been
using the current hormonal method consistently and correctly, or if pregnancy
can reasonably be excluded. There is no need to wait for the next menstruation.
Additional contraceptive precautions are not required.
Non-hormonal methods: If Cilest is started after the first 5 days of menstruation,
additional contraceptive precautions are required for the next 7 days.
Post-partum administration
Following a vaginal delivery, oral contraceptive administration to non-breastfeeding mothers can be started 21 days post-partum provided the patient is fully
ambulant and there are no puerperal complications. No additional contraceptive
precautions are required. If post-partum administration begins more than 21 days
after delivery, additional contraceptive precautions are required for the first 7
days of pill-taking.
If intercourse has taken place post-partum, oral contraceptive use should be
delayed until the first day of the first menstrual period.
For information on breast-feeding mothers, see section 4.6.
Use after Abortion or Miscarriage
After an abortion or miscarriage that occurs prior to 24 weeks gestation, oral
contraceptives can be started immediately. An additional method of
contraception is not needed.
After an induced or spontaneous abortion that occurs at or after 24 weeks
gestation, hormonal contraceptives may be started either on Day 21 post-abortion
or on the first day of the first spontaneous menstruation, whichever comes first.
No additional contraceptive precautions are required.
To skip a period
To skip a period, a new pack of Cilest should be started on the day after finishing
the current pack (the patient skips the tablet-free days). Tablet-taking should be
continued in the usual way.
During the use of the second pack she may experience slight spotting or breakthrough bleeding but contraceptive protection will not be diminished provided
there are no tablet omissions.
The next pack of Cilest is started after the usual 7 tablet-free days, regardless of
whether the period has completely finished or not.
Reduced reliability
When Cilest is taken according to the directions for use, the occurrence of
pregnancy is highly unlikely. However, the reliability of oral contraceptives may
be reduced under the following circumstances:
(i) Missed tablets
If the patient forgets to take one tablet or if a new strip is started one day late, she
should take it as soon as she remembers and take the next one at the normal time.

This may mean that two tablets are taken in one day. No additional contraceptive
precautions are required. If more than one tablet is missed or if a new strip is
started more than one day late, she should take the last missed tablet as soon as
she remembers but leave the other missed tablets in the strip. She should
continue to take the rest of the strip as usual but must use extra precautions (e.g.
condom, diaphragm, plus spermicide) for the next 7 days.
If the tablets are missed:
• In week 1
If unprotected sex has taken place, the use of emergency contraception should
be considered. The usual 7-day break can be left before starting the next strip.
• In week 2
The usual 7-day break can be left before starting the next strip.
• In week 3
When the strip is finished the next strip should be started the next day without
a break. If withdrawal bleeding does not occur at the end of the second strip, a
pregnancy test should be performed.
(ii) Vomiting or diarrhoea
If a patient vomits within two hours of taking a tablet she should take another
tablet from a spare strip.
If severe vomiting or diarrhoea continues for more than one day, she should
follow the procedure for missed tablets (and continue taking the tablets if she
can).
4.2.2. Elderly:
Use of this product is not indicated in post-menopausal women.
4.2.3. Children:
Use of this product before menarche is not indicated.

4.3

Contraindications


Presence or risk of venous thromboembolism (VTE)
o Venous thromboembolism – current VTE (on anticoagulants) or history of
(e.g. deep venous thrombosis [DVT] or pulmonary embolism [PE])
o Known hereditary or acquired predisposition for venous thromboembolism,
such as APC-resistance, (including Factor V Leiden), antithrombin-IIIdeficiency, protein C deficiency, protein S deficiency (see section 4.4)
o Major surgery with prolonged immobilisation (see section 4.4)
o A high risk of venous thromboembolism due to the presence of multiple risk
factors (see section 4.4)



Presence or risk of arterial thromboembolism (ATE)
o Arterial thromboembolism – current arterial thromboembolism, history of
arterial thromboembolism (e.g. myocardial infarction) or prodromal condition
(e.g. angina pectoris)
o Cerebrovascular disease – current stroke, history of stroke or prodromal
condition (e.g. transient ischaemic attack, TIA)



o Known hereditary or acquired predisposition for arterial thromboembolism,
such as hyperhomocysteinaemia and antiphospholipid-antibodies
(anticardiolipin-antibodies, lupus anticoagulant)
o History of migraine with focal neurological symptoms
o A high risk of arterial thromboembolism due to multiple risk factors (see
section 4.4) or to the presence of one serious risk factor such as:
− diabetes mellitus with vascular symptoms
− severe hypertension
− severe dyslipoproteinaemia
Acute or chronic liver disease, including hepatitis (viral or non-viral) or severe
cirrhosis, or a history of these conditions until at least 3 months after abnormal liver
function tests have returned to normal; hepatic adenomas or carcinomas.



Known or suspected carcinoma of the breast.



Hypersensitivity to the active substances or to any of the excipients listed in section
6.1.



In patients receiving drug combinations with paritaprevir/ritonavir, ombitasvir,
and/or dasabuvir due to potential for ALT elevations (see section 4.5).

Should any of these conditions occur for the first time during use of Cilest, the tablets
should be discontinued immediately.

4.4

Special warnings and precautions for use
Warnings
If any of the conditions/risk factors mentioned below is present, the suitability
of Cilest should be discussed with the woman.
In the event of aggravation, or first appearance of any of these conditions or
risk factors, the woman should be advised to contact her doctor to determine
whether the use of Cilest should be discontinued.
Exclude likelihood of pregnancy before starting treatment.
Undiagnosed vaginal bleeding should be investigated further.
Serum folate levels may be depressed by oral contraceptive therapy. This may
be of clinical significance if a woman becomes pregnant shortly after
discontinuing oral contraceptives.
Medical examination/consultation
Prior to the initiation or reinstitution of Cilest a complete medical history
(including family history) should be taken and pregnancy must be ruled out.
Blood pressure should be measured and a physical examination should be
performed, guided by the contraindications (see section 4.3) and warnings (see
section 4.4).
It is important to draw a woman’s attention to the information on venous and
arterial thrombosis, including the risk of Cilest compared with other CHCs, the
symptoms of VTE and ATE, the known risk factors and what to do in the
event of a suspected thrombosis.

The woman should also be instructed to carefully read the user leaflet and to
adhere to the advice given.
The frequency and nature of examinations should be based upon established
practice guidelines and should be adapted to the individual woman.
Women should be advised that oral contraceptives DO NOT protect against
HIV infections (AIDS) or any other sexually transmitted disease.
Conditions requiring supervision
− The theoretical or proven risks usually outweigh the advantages of using
Combined Oral Contraceptives (COCs) in the conditions listed below.
Consequently the decision to prescribe the COC must be made with
specialist clinical judgement.
− Breast feeding (see section 4.6)
− Increased risk of venous thromboembolic disorders (See section 4.3 and
“Circulatory disorders” below)
− Adequately controlled hypertension (persistently elevated baseline systolic
values 140-159 mmHg or diastolic values 90-94 mmHg)
− Obesity (BMI ≥ 35kg/m2)
− History of cholestasis (related to COCs), current or medically treated gall
bladder disease, porphyria
− History of breast cancer, 5 years disease-free.
Circulatory disorders
Risk of Venous Thromboembolism (VTE)
The use of any CHCs increases the risk of venous thromboembolism (VTE)
compared with no use. Products that contain levonorgestrel, norgestimate
(including Cilest) or norethisterone are associated with the lowest risk of
VTE. The decision to use Cilest should be taken after a discussion with
the woman to ensure she understands the risk of VTE with Cilest, how
her current risk factors influence this risk, and that her VTE risk is
highest in the first ever year of use. There is also some evidence that the
risk is increased when a CHC is re-started after a break in use of 4 weeks
or more.
In women who do not use a CHC and are not pregnant, about 2 out of 10,000
will develop a VTE over the period of one year. However, in any individual
woman the risk may be far higher, depending on her underlying risk factors
(see below).
It is estimated that out of 10,000 women who use a CHC that contains
levonorgestrel, about 6 will develop a VTE in a year.
Current evidence suggests that the risk of VTE with use of norgestimatecontaining CHCs is similar to the risk with levonorgestrel-containing CHCs.
This number of VTEs per year is fewer than the number expected in women
during pregnancy or in the postpartum period.
VTE may be fatal in 1-2% of cases.

Number of VTE events per 10,000 women in one year

Extremely rarely, thrombosis has been reported to occur in CHC users in other
blood vessels, e.g. hepatic, mesenteric, renal or retinal veins and arteries.
Risk factors for VTE
The risk for venous thromboembolic complications in CHC users may
increase substantially in a woman with additional risk factors, particularly if
there are multiple risk factors (see table).
Cilest is contraindicated if a woman has multiple risk factors that put her at
high risk of venous thrombosis (see section 4.3). If a woman has more than
one risk factor, it is possible that the increase in risk is greater than the sum of
the individual factors – in this case her total risk of VTE should be considered.
If the balance of benefits and risks is considered to be negative a CHC should
not be prescribed (see section 4.3).
Table: Risk factors for VTE
Risk factor

Comment

Obesity (body mass index over
30kg/m²)

Risk increases substantially as BMI rises.

Prolonged immobilisation,
major surgery, any surgery to
the legs or pelvis, neurosurgery,
or major trauma

Particularly important to consider if other
risk factors also present.

In these situations it is advisable to
discontinue use of the Pill (in the case of
elective surgery at least four weeks in
advance) and not resume until two weeks
after complete remobilisation. Another
Note: temporary immobilisation method of contraception should be used to
avoid unintentional pregnancy.
including air travel >4 hours
can also be a risk factor for
Antithrombotic treatment should be
VTE, particularly in women
considered if Cilest has not been
with other risk factors
discontinued in advance.

Positive family history (venous
thromboembolism ever in a
sibling or parent especially at a
relatively early age e.g. before
50)

If a hereditary predisposition is suspected,
the woman should be referred to a specialist
for advice before deciding about any CHC
use.

Other medical conditions
associated with VTE

Cancer, systemic lupus erythematosus,
haemolytic uraemic syndrome, chronic
inflammatory bowel disease (Crohn's
disease or ulcerative colitis) and sickle cell
disease.

Increasing age

Particularly above 35 years old.

There is no consensus about the possible role of varicose veins and superficial
thrombophlebitis in the onset or progression of venous thrombosis.
The increased risk of thromboembolism in pregnancy, and particularly the 6
week period of the puerperium, must be considered (for information on
“Pregnancy and lactation” see section 4.6).
Symptoms of VTE (deep vein thrombosis and pulmonary embolism)
In the event of symptoms women should be advised to seek urgent medical
attention and to inform the healthcare professional that she is taking a CHC.
• Symptoms of deep vein thrombosis (DVT) can include:
− unilateral swelling of the leg and/or foot or along a vein in the leg
− pain or tenderness in the leg which may be felt only when standing or
walking
− increased warmth in the affected leg; red or discoloured skin on the leg.
• Symptoms of pulmonary embolism (PE) can include:
− sudden onset of unexplained shortness of breath or rapid breathing
− sudden coughing which may be associated with haemoptysis
− sharp chest pain
− severe light headedness or dizziness
− rapid or irregular heartbeat.
Some of these symptoms (e.g. shortness of breath, coughing) are non-specific
and might be misinterpreted as more common or less severe events (e.g.
respiratory tract infections).
Other signs of vascular occlusion can include: sudden pain, swelling and slight
blue discolouration of an extremity.
If the occlusion occurs in the eye symptoms can range from painless blurring
of vision which can progress to loss of vision. Sometimes loss of vision can
occur almost immediately.
Risk of arterial thromboembolism (ATE)
Epidemiological studies have associated the use of CHCs with an increased
risk for arterial thromboembolism (e.g. myocardial infarction) or for

cerebrovascular accident (e.g. transient ischaemic attack, stroke). Arterial
thromboembolic events may be fatal.
Risk factors for ATE
The risk of arterial thromboembolic complications or of a cerebrovascular
accident in CHC users increases in women with risk factors (see table). Cilest
is contraindicated if a woman has one serious or multiple risk factors for ATE
that puts her at high risk of arterial thrombosis (see section 4.3). If a woman
has more than one risk factor, it is possible that the increase in risk is greater
than the sum of the individual factors - in this case her total risk should be
considered. If the balance of benefits and risks is considered to be negative a
CHC should not be prescribed (see section 4.3).
Table: Risk factors for ATE
Risk factor

Comment

Increasing age

Particularly above 35 years old.

Smoking

Women should be advised not to smoke if
they wish to use a CHC. Women over 35
years old who continue to smoke should be
strongly advised to use a different method
of contraception.

Hypertension
Obesity (body mass index over
30kg/m2)

Risk increases substantially as BMI
increases.
Particularly important in women with
additional risk factors.

Positive family history (arterial
thromboembolism ever in a
sibling or parent especially at a
relatively early age e.g. below
50 years old).

If a hereditary predisposition is suspected,
the woman should be referred to a specialist
for advice before deciding about any CHC
use.

Migraine

An increase in frequency or severity of
migraine during CHC use (which may be
prodromal of a cerebrovascular event) may
be a reason for immediate discontinuation.

Other medical conditions
associated with adverse
vascular events

Diabetes mellitus, hyperhomocysteinaemia,
valvular heart disease and atrial fibrillation,
dyslipoproteinaemia and systemic lupus
erythematosus.

Symptoms of ATE
In the event of symptoms women should be advised to seek urgent medical
attention and to inform the healthcare professional that she is taking a CHC.
• Symptoms of a cerebrovascular accident can include:
− sudden numbness or weakness of the face, arm or leg, especially on one
side of the body

sudden trouble walking, dizziness, loss of balance or coordination
− sudden confusion, trouble speaking or understanding
− sudden trouble seeing in one or both eyes
− sudden, severe or prolonged headache with no known cause
− loss of consciousness or fainting with or without seizure.
Temporary symptoms suggest the event is a transient ischaemic attack
(TIA).


• Symptoms of myocardial infarction (MI) can include:
− pain, discomfort, pressure, heaviness, sensation of squeezing or fullness
in the chest, arm, or below the breastbone
− discomfort radiating to the back, jaw, throat, arm, stomach
− feeling of being full, having indigestion or choking
− sweating, nausea, vomiting or dizziness
− extreme weakness, anxiety, or shortness of breath
− rapid or irregular heartbeats.
Hepatic adenomas
Malignant hepatic tumours have been reported on rare occasions in long-term
users of oral contraceptives. Benign hepatic tumours have also been associated
with oral contraceptive usage. A hepatic tumour should be considered in the
differential diagnosis when upper abdominal pain, enlarged liver or signs of
intra-abdominal haemorrhage occur. In isolated cases, life-threatening intraabdominal haemorrhage may occur.
Breast cancer
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 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 additional breast
cancers diagnosed in current users of COCs or in women who have used
COCs in the last 10 years are more likely to be localised to the breast than
those in women who never used COCs.
Breast cancer is rare among women under 40 years of age whether or not they
take COCs. Whilst this background risk increases with age, the excess number
of breast cancer diagnoses in current and recent COC users is small in relation
to the overall risk of breast cancer (see bar chart).
The most important risk factor for breast cancer in COC users is the age
women discontinue the COC; the older the age at stopping, the more breast
cancers are diagnosed. Duration of use is less important and the excess risk
gradually disappears during the course of the 10 years after stopping COC use
such that by 10 years there appears to be no excess.
The possible increase in risk of breast cancer should be discussed with the user
and weighed against the benefits of COCs taking into account the evidence
that they offer substantial protection against the risk of developing certain
other cancers (e.g. ovarian and endometrial cancer).

Estimated cumulative numbers of breast cancers per 10,000 women
diagnosed in 5 years of use and up to 10 years after stopping COCs,
compared with numbers of breast cancers diagnosed in 10,000 women
who had never used COCs
300
262
250
230
200
Number of breast
cancers

181
160
150

Never took COCs
Used COCs for 5 years

100

111
100

44 48.7

50
16 17.5
0
Took the Pill at these ages:
Cancers found up to the age of:

4 4.5
Under 20
30

20-24

25-29

30-34

35

40

45

35-39
50

40-44
55

Cervical cancer
The most important risk factor for cervical cancer is persistent Human
Papilloma Virus (HPV) infection. Some epidemiological studies have
indicated that long-term use of COCs may further contribute to this increased
risk but there continues to be controversy about the extent to which this
finding is attributable to confounding effects, e.g. cervical screening and
sexual behaviour including use of barrier contraceptives.
There is some theoretical concern that COCs enhance progression of Cervical
Intraepithelial Neoplasia (CIN) to invasive disease. For women with
diagnosed cervical cancer, COCs may be used whilst awaiting treatment.
Other tumours
Numerous epidemiological studies have been reported on the risk of ovarian
and endometrial cancer in women using COCs. The evidence is clear that
COCs offer substantial protection against both ovarian and endometrial
cancer.
Bleeding irregularities
Breakthrough bleeding, spotting and/or absence of withdrawal flow may be
encountered in patients on oral contraceptives, especially during the first three
months of use.
If bleeding irregularities persist beyond three cycles or occur after previously
regular cycles, non-hormonal causes should be considered and adequate
diagnostic measures are indicated to exclude malignancy or pregnancy.
Some woman may experience post-Pill amenorrhoea or oligomenorrhoea,
especially when such a condition was pre-existing.
Laboratory tests
In the literature, at least a hundred different laboratory test parameters have
been reported to be possibly influenced by oral contraceptive use,
predominantly by the oestrogenic component. Among these are: biochemical
parameters of the liver, thyroid, adrenal and renal function, plasma levels of
(carrier) proteins and lipid/lipoprotein fractions and parameters of coagulation
and fibrinolysis.

Other conditions
In the following conditions the benefit of oral contraception generally
outweighs the theoretical or known risk. However, they may need to be
considered before prescribing to individual patients:
• Known hyperlipidaemias. A small proportion of women will have
persistent hypertriglyceridemia while on the Pill. Changes in serum
triglycerides and lipoprotein levels have been reported in oral contraceptive
users. However, routine screening of women with hypertriglyceridaemia is
not considered appropriate. Women with hypertriglyceridaemia, or a family
history thereof, may be at an increased risk of pancreatitis when using
COCs.
• Diabetes without vascular involvement (although all patients with diabetes
are at increased risk of arterial disease).
• Decreased glucose tolerance. The oestrogen component of Cilest may cause
a decrease in glucose tolerance, while the progestogens may increase
insulin secretion and create insulin resistance. Because of these
demonstrated effects, pre-diabetic and diabetic women in particular should
be carefully monitored while taking oral contraceptives.
• Asymptomatic gall bladder disease or cholecystectomy.
• Benign liver tumours (focal nodular hyperplasia). There is limited, direct
evidence that hormonal contraceptive use does not influence either
progression or regression of liver lesions among women with focal nodular
hyperplasia.
• Migraine without focal aura. The onset or exacerbation of migraine or
development of headache with a new pattern which is recurrent, persistent
or severe requires discontinuation of oral contraceptives and evaluation of
the cause.
• Crohn’s disease and ulcerative colitis have been associated with COC use.
If any of the following conditions developed or worsened during a prior
pregnancy or during previous COC use, they may occur while taking Cilest:
• elevated blood pressure
• cholestasis
• herpes gestationis
• otosclerosis
• SLE
• severe headaches
• haemolytic uraemic syndrome
• Sydenham’s chorea
Chloasma
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 whilst taking this preparation.
Chloasma is often not fully reversible.

Additional contraceptive precautions
When additional contraceptive precautions are required, the patient should be
advised either not to have sex, or to use a cap plus spermicide or for her
partner to use a condom. Rhythm methods should not be advised as the Pill
disrupts the usual cyclical changes associated with the natural menstrual cycle,
e.g. changes in temperature and cervical mucus.
Excipients
The tablets contain lactose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
should not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction
Potential Reduction in Contraceptive Effectiveness Associated With CoAdministration of Other Drugs:
Hepatic enzyme inducers
Drugs or herbal products that induce enzymes, especially CYP3A4, may decrease the
plasma concentrations of contraceptive hormones, and may decrease their
effectiveness and/or increase breakthrough bleeding. Enzyme induction may be
observed after a few days of treatment. Maximal enzyme induction is generally seen
within a few weeks, but may then be sustained for at least 4 weeks after the cessation
of medicinal product therapy.
Examples include:





barbiturates



bosentan



carbamazepine



eslicarbazepine acetate



felbamate



(fos)aprepitant



hydantoins



primidone



griseofulvin



some (combinations of) HIV protease inhibitors (e.g. nelfinavir, ritonavir,
ritonavir-boosted protease inhibitors)

some HCV protease inhibitors (e.g. boceprevir, telaprevir)


modafinil



some non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine)



oxcarbazepine



phenytoin



rifampicin and rifabutin



rufinamide



St. John’s Wort



topiramate

Drugs that affect absorption
Drugs that increase gastrointestinal motility, e.g. metoclopramide, may reduce
hormone absorption.
Treatment with activated charcoal will compromise absorption of steroid hormones.
Colesevelam, a bile acid sequestrant, given together with a combined oral hormonal
contraceptive, has been shown to significantly decrease the AUC of ethinylestradiol. No
interaction was seen when the contraceptive was given 4 hours before colesevelam.
Management
Long-term
For women on long-term treatment with drugs and herbal products that interact with
hormonal contraception, another reliable, non-hormonal method of contraception is
recommended.
Short-term
Women on short-term treatment with drugs and herbal products that interact with
hormonal contraception and may decrease plasma levels of contraceptive hormones
could have their contraceptive effectiveness reduced. They should be advised to use a
barrier contraceptive method (e.g. condoms, diaphragm) in addition to Cilest as
follows:


Women using liver enzyme-inducing drugs should temporarily use a barrier
contraceptive method in addition to Cilest during the time of concomitant
medicinal product administration and for 28 days after their discontinuation.



In the case of modafinil, use of a barrier contraceptive method should continue
for 56 days after discontinuation.

If discontinuation of the concomitant medicinal product occurs in week three or runs
beyond the end of the tablets in the strip, the next strip should be started without a
break.
Increase in Plasma Hormone Levels Associated With Co-administered Drugs:



etoricoxib

some HIV protease inhibitors (e.g. atazanavir, indinavir )

Changes in Plasma Levels of Co-Administered Drugs that may be of Clinical
Significance:
Combination hormonal contraceptives may also affect the pharmacokinetics of some
other drugs if used concomitantly.
Drugs whose plasma levels may be increased (due to CYP inhibition)
Examples include:


ciclosporin



prednisolone



selegiline



theophylline



tizanidine

Drugs whose plasma levels may be decreased (due to induction of glucuronidation)
Examples include:


lamotrigine

Contraindicated co-administration
Cilest should not be co-administered with drug combinations containing
paritaprevir/ritonavir, ombitasvir, and/or dasabuvir due to potential for ALT
elevations.
Management
Physicians are advised to consult the labelling of concurrently-used drugs to obtain
further information about interactions with hormonal contraceptives and the possible
need to adjust dosages.

4.6

Fertility, pregnancy and lactation
4.6.1. Use during pregnancy
Not indicated during pregnancy. Confirm suspected pregnancy before discontinuing
treatment.
The majority of recent studies do not indicate a teratogenic effect, particularly in so
far as cardiac anomalies and limb reduction defects are concerned, when taken
inadvertently during early pregnancy.
The increased risk of VTE during the postpartum period should be considered when
re-starting Cilest (see sections 4.2 and 4.4).
4.6.2. Use during lactation
Contraceptive steroids and/or their metabolites may be excreted in breast milk. In
addition, combination hormonal contraceptives given in the postpartum period may
interfere with lactation by decreasing the quantity and quality of breast milk. If
possible, the nursing mother should be advised not to use Cilest or other combination
hormonal contraceptives but to use other forms of contraception particularly in the
first 6 weeks post-partum.

4.7

Effects on ability to drive and use machines
Not applicable.

4.8

Undesirable effects
Description of selected adverse reactions

An increased risk of arterial and venous thrombotic and thromboembolic events,
including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis
and pulmonary embolism has been observed in women using CHCs. These are
discussed in more detail in section 4.4. These adverse reactions (ARs) require
immediate medical attention and/or cessation of oral contraceptive use.
The following ARs may also require immediate medical attention and/or cessation of
CHC use: retinal vein thrombosis, new onset of migraine-type headache, breast
cancer, hepatic tumours, adenomas, high blood pressure, angioedema, urticaria and
hypersensitivity.
Alternative non-hormonal methods of contraception should be used, while
appropriate diagnostic and therapeutic measures are undertaken.
Based on pooled safety data from 5 clinical trials, the most commonly reported
(≥10%) AR was headache (27.9%). The most commonly reported (≥10%) AR
identified during post-marketing experience was diarrhoea (11.8%).
The most common ARs (≥10%) reported in the first treatment cycle in clinical trials
were: dysmenorrhoea (40.4%); nausea (29.1%); metrorrhagia (26.3%);
gastrointestinal disorder [reported as nausea or vomiting] (24.6%) and abnormal
withdrawal bleeding (16.9%). The incidence of these ARs was highest in cycle 1 and
decreased over time with the exception dysmenorrhoea. The highest incidence of
vomiting occurred in cycle 12 (11.8%).
The 5 clinical trials (2 randomised active-controlled trials and 3 uncontrolled openlabel trials), which were used to evaluate the safety of Cilest, included 1,891 healthy
women of child bearing potential. In 3 trials, subjects were followed for up to 24
cycles and in the other 2 trials for up to 12 cycles. An additional uncontrolled study
(n=8,331) reported ARs by treatment cycle for up to 24 cycles. As the frequency of
ARs vary according to the cycle of treatment, the highest cycle incidence has been
used to assign the ADR to a frequency category.
The table below displays all ARs that have been reported with the use of Cilest in
clinical trials or from post marketing experiences with norgestimate and ethinyl
estradiol tablets.
The displayed frequency categories use the following convention: Very common
(>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare
(>1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated
from the available data).

Infections and infestations
Common

Urinary tract infection, vaginal infection

Neoplasms benign, malignant and unspecified (including cysts and polyps)
Uncommon

Cervical dysplasia

Rare

Breast cyst

Frequency not
known

Hepatic adenomas , breast cancer, benign breast neoplasm, focal
nodular hyperplasia, fibroadenoma of breast

Immune system disorders

Common

Hypersensitivity

Metabolism and nutrition disorders
Common

Fluid retention

Uncommon

Increase and decrease in appetite, weight fluctuation

Rare

Appetite disorder

Frequency not
known

Dyslipidaemia

Psychiatric disorders
Common

Mood altered, depression, nervousness, insomnia

Uncommon

Anxiety, libido disorder

Nervous system disorders
Very common

Headache

Common

Migraine, dizziness

Uncommon

Syncope, paraesthesia

Frequency not
known

Cerebrovascular accident, convulsion

Eye disorders
Uncommon

Visual impairment, dry eye

Frequency not
known

Intolerance to contact lenses, retinal vascular thrombosis*

Ear and labyrinth disorders
Rare

Vertigo

Cardiac disorders
Uncommon

Palpitations

Rare

Tachycardia

Frequency not
known

Myocardial infarction

Vascular disorders
Uncommon

Thrombosis, hypertension, hot flush

Rare

Venous thromboembolism, Arterial thromboembolism

Frequency not
known

Deep venous thrombosis*, Venous thrombosis**

Respiratory, thoracic and mediastinal disorders
Uncommon

Dyspnoea

Frequency not
known

Pulmonary embolism*

Gastrointestinal disorders
Very common

Gastrointestinal disorder, vomiting, diarrhoea, nausea

Common

Gastrointestinal pain, abdominal pain, abdominal distension,
constipation, flatulence

Rare

Pancreatitis

Hepato-biliary disorders
Rare

Hepatitis

Skin and subcutaneous tissue disorders
Common

Acne, rash

Uncommon

Alopecia, hirsutism, urticaria, pruritus, erythema, skin discolouration

Rare

Hyperhidrosis, photosensitivity reaction

Frequency not
known

Angioedema, erythema nodosum, night sweats

Musculoskeletal and connective tissue disorders
Common

Muscle spasms, pain in extremity, back pain

Uncommon

Myalgia

Reproductive system and breast disorders
Very common

Dysmenorrhoea, metrorrhagia, abnormal withdrawal bleeding

Common

Amenorrhoea, genital discharge, breast pain

Uncommon

Breast discharge, breast enlargement, ovarian cyst, vulvovaginal
dryness

Rare

Vaginal discharge

Frequency not
known

Suppressed lactation

General disorders and administration site conditions
Common

Chest pain, oedema, asthenic conditions

Investigations
Common

Weight increased

Uncommon

Weight decreased

* Not seen in clinical trials therefore frequency cannot be estimated. See section 4.4 for
frequency based on standard reporting rates for similar combined hormonal
contraceptives.

** The bundled terms for venous thrombosis include Budd Chiari Syndrome and
hepatic vein thrombosis.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9

Overdose
There have been no reports of serious ill-health from overdose. Symptoms that
may occur are nausea, vomiting and vaginal bleeding. There are no antidotes
and further treatment should be symptomatic.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic Group: Hormonal Contraceptives for Systemic Use;
Progestogens and oestrogens, fixed combinations
ATC Code: G03AA11
Cilest acts through the mechanism of gonadotrophin suppression by the
oestrogenic and progestational actions of ethinylestradiol and norgestimate.
The primary mechanism of action is inhibition of ovulation, but alterations to
the cervical mucus, the fallopian tube motility and to the endometrium may
also contribute to the efficacy of the product.

5.2

Pharmacokinetic properties
Absorption: Norgestimate and ethinyl estradiol are rapidly absorbed
following oral administration. Following single or multiple (three cycles)
administration of Cilest, serum concentrations of norgestimate remain below
the quantitation limit of the assay (0.1ng/mL) metabolites of norgestimate,
norelgestromin and norgestrel, are found in measurable concentrations in
circulation, reaching maximal serum levels approximately 1.5 hours post-dose.
Increase in Cmax and AUC for norelgestromin are proportional to dose after
administration of 0.180 to 0.250mg of norgestimate. Ethinyl estradiol serum
concentrations are measurable within 0.5 hours of dosing, reaching peak levels
approximately 1.2 hours post-dose.
Distribution: Norelgestromin and norgestrel are highly bound (>97%) to
serum proteins. Norelgestromin is bound to albumin but not to SHBG, while
norgestrel is bound primarily to SHBG and to a much lesser extent to albumin.
Ethinyl estradiol is extensively bound to serum albumin.
Studies have shown that the lack of binding of norelgestromin to SHBG is
unique when compared to other progestogens in oral contraceptives and plays

a key role in enhancing its biological activity. In contrast, norgestrel formed
from norgestimate is largely bound to SHBG, which limits its biological
activity.
Metabolism: Norgestimate is rapidly metabolised by first-pass (intestinal
and/or hepatic) mechanisms to norelgestromin (peak serum concentrations
observed within 2 hours) and norgestrel, both of which are pharmacologically
active progestogens. Ethinyl estradiol is metabolised to various hydroxylated
metabolites and their glucuronide and sulfate conjugates.
Elimination: Both norelgestromin and norgestrel, and ethinyl estradiol are
subsequently metabolised and their metabolites are eliminated by renal and
faecal pathways. Elimination half-life values at steady-state were 10 to 15
hours for ethinyl estradiol, 24.9 hours for norelgestromin and 45 hours for
norgestrel. Following administration of 14C-norgestimate, 47% of the
administered radioactivity was eliminated in the urine and 37% in the faeces.
Steady-State Pharmacokinetics: Following administration of 0.250mg
norgestimate /0.035mg ethinyl estradiol, the mean AUC 0-24h at steady-state,
based on non-SHBG bound serum levels, was 18.1 h ng/mL for
norelgestromin and 3.64 h ng/mL for norgestrel. The AUC for norgestrel
following administration of 0.250mg norgestimate /0.035mg ethinyl estradiol,
corresponds to the exposure after a levonorgestrel dose of approximately 30
micrograms in combination with ethinyl estradiol.

5.3

Preclinical safety data
The toxicology of norgestimate and ethinylestradiol has been extensively
investigated in animal studies and through long term clinical experience with
widespread use in contraceptives.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core:
Lactose monohydrate
Croscarmellose sodium
Magnesium stearate
Microcrystalline cellulose
Film coating:
Hypromellose
Carnauba wax
Polyethylene glycol
Polysorbate 80
Purified water

Titanium dioxide
F.D. & C. Blue No. 2 Aluminium Lake (E132)

6.2

Incompatibilities
Not applicable

6.3

Shelf life
24 months

6.4

Special precautions for storage
This medicinal product does not require any special temperature storage
conditions. Keep the strips in the outer carton in order to protect from light.

6.5

Nature and contents of container
Cartons containing 1 (Starter Pack), 3 and 6 PVC/foil blister strips of 21
tablets each.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Not applicable

7

MARKETING AUTHORISATION HOLDER
Janssen-Cilag Ltd
50 -100 Holmers Farm Way
High Wycombe
Buckinghamshire
HP12 4EG
UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 00242/0209

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
01/07/1995

/

07/01/2009

10

DATE OF REVISION OF THE TEXT
25/04/2017

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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