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LIZINNA 250 MICROGRAM/35 MICROGRAM TABLETS

Active substance(s): ETHINYLESTRADIOL / NORGESTIMATE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Lizinna 250 microgram /35 microgram Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Lizinna are tablets for oral administration.
Each tablet contains norgestimate 250 microgram and ethinylestradiol 35 microgram.
Excipient(s) of known effect:
Each uncoated tablet contains 89.357 mg of Lactose.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Tablet
Round, blue, uncoated, 6.4 mm uncoated flat beveled edge tablets with ‘146’
debossed on one side and the other side plain.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Oral contraception
The decision to prescribe Lizinna should take into consideration the individual
woman’s current risk factors, particularly those for venous thromboembolism (VTE),
and how the risk of VTE with Lizinna compares with other CHCs (see sections 4.3
and 4.4).

4.2

Posology and method of administration
For oral administration.
Posology
Paediatric population

Lizinna is contraindicated in girls that have not reached pubertal age - before
menarche (see section 4.3).
Adults
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.
Elderly
Use of this product is not indicated in post-menopausal women.

Method of administration
Starting treatment
Tablet intake is started on day 1 of the woman´s natural cycle (i.e. the first day
of her menstrual bleeding).
Switching from another contraceptive
Changing from a combined hormonal contraceptive (combined oral
contraceptive (COC), vaginal ring or transdermal patch)
The woman should start with Lizinna preferably on the day after the last active
tablet (the last tablet containing the active substances) of her previous COC,
but at the latest on the day following the usual tablet-free or placebo tablet
interval of her previous COC. In case a vaginal ring or transdermal patch has
been used the woman should start using Lizinna preferably on the day of
removal, but at the latest when the next application would have been due.
Changing from a progestogen-only-method (progestogen-only pill, injection,
implant) or from a progestogen-releasing intrauterine system (IUS)
The woman may switch any day from the progestogen-only pill (from an
implant or the IUS 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.
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 sections 4.3, 4.4 and 4.6.
Use after Abortion or Miscarriage
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
Women should be advised to start at day 21 to 28 after delivery or secondtrimester abortion. When starting later, the woman should be advised to
additionally use a barrier method for the first 7 days. 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.
For breastfeeding women see section 4.6.
To skip a period
To skip a period, a new pack of Lizinna 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 Lizinna is started after the usual 7 tablet-free days, regardless
of whether the period has completely finished or not.
Reduced reliability
When Lizinna 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:
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 4 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:
• Day 1-7
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.
• Day 8-14
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 she has missed
more than 1 tablet, the woman should be advised to use extra precautions
for 7 days.
• Day 15-21
The risk of reduced reliability is imminent because of the forthcoming 7
day 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, she should follow the first of these two options and 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 blister
pack must be started as soon as the current blister 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 blister, but she may
experience spotting or breakthrough bleeding on tablet-taking days.
2. The woman may also be advised to discontinue tablet-taking from
the current blister pack. She should then have a tablet-free interval
of up to 7 days, including the days she missed tablets and
subsequently continue with the next blister 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.
In case of severe gastro-intestinal disturbances (e.g., vomiting or diarrhoea),
absorption may not be complete and additional contraceptive measures should
be taken. If vomiting occurs within 3-4 hours after tablet-taking, a new
(replacement) tablet should be taken as soon as possible. The new tablet
should be taken within 12 hours of the usual time of tablet-taking if possible.
If more than 12 hours elapse, the advice concerning missed tablets, as given in
section 4.2 “Management of missed tablets”, is applicable. If the woman does

not want to change her normal tablet-taking schedule, she has to take the extra
tablet(s) from another blister pack.

4.3

Contraindications


Hypersensitivity to the active substance(s) or to any of the excipients listed in
section 6.1



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
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

Breast-feeding mothers less than 6 weeks post-partum.
The presence of serious or multiple risk factor(s) for the occurrence of arterial
thrombosis: moderate to severe hypertension (Persistent blood pressure values of
≥160 mm Hg systolic or ≥95 mm Hg diastolic)
Hereditary dyslipoproteinaemia
Hereditary or acquired predisposition for venous or arterial thrombosis, such as
activated protein C (APC-) resistance, antithrombin-III deficiency, protein C
deficiency, protein S deficiency, hyperhomocysteinaemia, and antiphospholipid
antibodies (anticardiolipin antibodies, lupus anticoagulant)
Carcinoma of the endometrium or other known or suspected oestrogen-dependent
neoplasia
Undiagnosed abnormal genital bleeding











Major surgery with prolonged immobilisation.
Complicated valvular and congenital heart disease (e.g. with pulmonary
hypertension, atrial fibrillation, history of subacute bacterial endocarditis)
Migraine with focal aura.
Diabetes with nephropathy/retinopathy/neuropathy or other vascular involvement
or > 20 years' duration.
Smoking 15 or more cigarettes per day in patients aged 35 years or more.
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.
Pancreatitis or a history thereof if associated with severe hypertriglyceridemia
Lizinna is contraindicated in girls that have not reached pubertal age - before
menarche.

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

4.4

Special warnings and precautions for use
If any of the conditions or risk factors mentioned below is present, the suitability of
Lizinna 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 Lizinna should be discontinued.
Risk of venous thromboembolism (VTE)
The use of any combined hormonal contraceptive (CHC) increases the risk of venous
thromboembolism (VTE) compared with no use. Products that contain
levonorgestrel, norgestimate (including Lizinna) or norethisterone are associated
with the lowest risk of VTE. The decision to use Lizinna should be taken after a
discussion with the woman to ensure she understands the risk of VTE with
Lizinna, 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 61 will develop a VTE in a year.
Current evidence suggests that the risk of VTE with use of norgestimate-containing
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.

Mid-point of range of 5-7 per 10,000 WY, based on a relative risk for CHCs containing levonorgestrel versus non-use of
approximately 2.3 to 3.6

1

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).
Lizinna 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
Obesity (body mass index over 30 kg/m²)

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

Comment
Risk increases substantially as BMI rises.
Particularly important to consider if other
risk factors also present.
In these situations it is advisable to
discontinue use of the patch/pill/ring (in
the case of elective surgery at least four
weeks in advance) and not resume until
two weeks after complete remobilisation.
Another method of contraception should
be used to avoid unintentional
pregnancy.

Note:
temporary
immobilisation
including air travel >4 hours can also be a
risk factor for VTE, particularly in
Antithrombotic treatment should be
women with other risk factors
considered if Lizinna has not been
discontinued in advance.
Positive
family
history
(venous If a hereditary predisposition is
thromboembolism ever in a sibling or suspected, the woman should be referred
parent especially at a relatively early age to a specialist for advice before deciding
e.g. before 50).
about any CHC use
Other medical conditions associated with Cancer, systemic lupus erythematosus,
VTE
haemolytic uraemic syndrome, chronic
inflammatory bowel disease (Crohn’s
disease or ulcerative colitis) and sickle
cell disease
Increasing age
Particularly above 35 years
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
discoloration 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 (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). Lizinna 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
Increasing age
Smoking

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

Hypertension
Obesity (body mass index over 30 Risk increases substantially as BMI
kg/m2)
increases.

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

Other medical conditions associated with
adverse vascular events

Particularly important in women with
additional risk factors
If a hereditary predisposition is suspected,
the woman should be referred to a
specialist for advice before deciding about
any CHC use
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
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.
Medical examination/consultation
Prior to the initiation or reinstitution of Lizinna 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
contra-indications (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 Lizinna 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 on
established practice guidelines and be adapted to the individual woman.
Women should be advised that hormonal contraceptives do not protect against HIV
infections (AIDS) and other sexually transmitted diseases.

Tumours
An increased risk of cervical cancer in long-term users of COCs (> 5 years) has been
reported in some epidemiological studies, but there continues to be controversy about
the extent to which this finding is attributable to the compounding effects of sexual
behaviour and other factors such as human papilloma virus (HPV).
A meta-analysis of 54 epidemiological studies reported that there is a slightly
increased risk (RR = 1.24) of having breast cancer diagnosed in women who are

currently using COCs. The excess 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 overall risk of breast cancer. These studies do not
provide evidence for causation. The breast cancers diagnosed in ever-users tend to be
less advanced clinically than the cancers diagnosed in never-users. 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.
In rare cases, benign liver tumours, and even more rarely, malignant liver tumours
have been reported in users of COCs. In isolated cases, these tumours have led to lifethreatening intra-abdominal haemorrhages. Therefore a hepatic tumour should be
considered in the differential diagnosis when severe upper abdominal pain, liver
enlargement or signs of intra-abdominal haemorrhage occur in women using COCs.
With the use of the higher-dosed COCs (50 μg ethinylestradiol) the risk of
endometrial and ovarian cancer is reduced. Whether this also applies to lower-dosed
COCs remains to be confirmed.
Other conditions
Contraceptive efficacy may be reduced in women weighing equal or greater than 90
kg.
Women with hypertriglyceridaemia, or a family history thereof, may be at an
increased risk of pancreatitis when using combination hormonal contraceptives.
Although small increases of blood pressure have been reported in many women using
hormonal contraceptives, clinically relevant increases are rare. Only in these rare
cases an immediate discontinuation of COC use is justified. If, during the use of a
combination hormonal contraceptive in pre-existing hypertension, constantly elevated
blood pressure values or a significant increase in blood pressure do not respond
adequately to antihypertensive treatment, the combination hormonal contraceptive
must be withdrawn. Combination hormonal contraceptive 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; gallstones; porphyria;
systemic lupus erythaematosus; haemolytic ureamic syndrome; Sydenham’s chorea;
herpes gestationis; otosclerosis-related hearing loss.
In women with hereditary angioedema exogenous estrogens may induce or exacerbate
symptoms of angioedema.
Acute or chronic disturbances of liver function may necessitate the discontinuation of
combination hormonal contraceptives until markers of liver function return to normal.
Recurrence of cholestatic-related pruritus, which occurred during a previous
pregnancy or previous use of sex steroids, necessitates the discontinuation of
combination hormonal contraceptives.
Although combined hormonal contraceptives 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 low-dose COCs (containing < 0.05 mg

ethinylestradiol).. However, diabetic women should be carefully observed,
particularly in the early stage of COCs use.
Worsening of endogenous depression, of epilepsy, of Crohn’s disease and of
ulcerative colitis has been reported during COC use.
Chloasma may occasionally occur, especially in users with a history of chloasma
gravidarum. Users with a tendency to chloasma should avoid exposure to the sun or
ultraviolet radiation while using COCs. Chloasma is often not fully reversible.
Medical examination/consultation
Prior to the initiation or reinstitution of Norgestimate/Ethinylestradiol a complete
medical history (including family history) should be taken and pregnancy should 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). The woman should also be instructed to carefully read the package leaflet and to
adhere to the advice given.
The frequency and nature of subsequent examinations should be based on established
guidelines and be adapted to the individual woman on the basis of clinical impression.
Women should be advised that hormonal contraceptives do not protect against HIV
infections (AIDS) and other sexually transmitted diseases.
Reduced efficacy
The efficacy of COCs may be reduced in the event of e.g. missed active tablets (see
section 4.2), gastro-intestinal disturbances during active tablet taking (see section 4.2)
or concomitant medication (see section 4.5).
Reduced cycle control
With all combination hormonal contraceptives, irregular blood loss (spotting or
breakthrough bleeding) can occur, especially during the initial months of usage. For
this reason, a medical opinion on irregular blood loss will only be useful after an
adjustment period of approximately three cycles. If breakthrough bleeding persists, or
breakthrough bleeding occurs after previously regular cycles, while the COC has been
used according the recommended regimen, a cause other than COCs should be
considered. Non-hormonal causes should be considered and, if necessary, adequate
diagnostic measures taken to rule out organic disease or pregnancy. This may include
curettage.
In some women withdrawal bleeding may not occur during this pill free period. 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 COCs use is continued.
Some users may experience amenorrhoea or oligomenorrhoea after discontinuing
hormonal contraception, especially when such a condition was pre-existent.
Herbal preparations containing St John’s Wort (Hypericum perforatum) should not be
used while taking Norgestimate/Ethinylestradiol (see section 4.5)
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. Examples include:
• barbiturates
• bosentan
• carbamazepine
• felbamate
• hydantoins
• primidone
• griseofulvin
• some HIV protease inhibitors (e.g. ritonavir)
• modafinil
• some non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine)
• oxcarbazepine
• phenytoin
• rifampicin and rifabutin
• St. John's Wort
• topiramate
Antibacterial drugs that are not enzyme inducers
There have been reports of pregnancy while taking hormonal contraceptives and
antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of
antibiotics (eg ampicillin and tetracyclines) on plasma concentrations of synthetic
steroids.
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.
Management
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.
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 Lizinna as
follows:




Women using liver enzyme-inducing drugs should temporarily use a barrier
contraceptive method in addition to Lizinna 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.
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
• theophylline
Drugs whose plasma levels may be decreased (due to induction of glucuronidation).
Examples include:
• lamotrigine
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.
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

Fertility, pregnancy and lactation
Pregnancy
Not indicated during pregnancy. Confirm suspected pregnancy before discontinuing
treatment.
The increased risk of VTE during the postpartum period should be considered when
re-starting Lizinna (see section 4.2 and 4.4).

Breastfeeding
Contraceptive steroids and/or their metabolites may be excreted in breast milk.

The use of COCs is contraindicated for breast-feeding mothers less than 6 weeks
post-partum (see section 4.3) and should be used with clinical judgement for breastfeeding mothers between 6 weeks and 6 months post-partum (see section 4.4).
Mothers who are breast-feeding should be advised not to use the combined pill since
this may reduce the amount of breast-milk, but may be advised instead to use a
progestogen-only pill (POP).
Fertility

Norgestimate, alone and in combination with ethinyl estradiol, is an effective
antiovulatory agent. After discontinuing oral contraceptive therapy, the patient
should delay pregnancy until at least one normal spontaneous cycle has
occurred in order to date the pregnancy. An alternative contraceptive method
should be used during this time.
Norgestimate and Ethinyl Estradiol combination resulted in a dose-related
suppression of fertility, decreased implantation efficiency and litter size and an
increased fetal resorption in the female rats at all dose levels. It is moderately
potent in the standard in vivo progestational assay which measures
endometrial proliferation in rabbits, and it effectively blocks ovulation in rats,
hamsters and rabbits.
4.7

Effects on ability to drive and use machines
Not applicable.

4.8

Undesirable effects
Certain adverse drug reactions (ADRs) that have been associated with oral
contraceptive use may require immediate medical attention and/or cessation of oral
contraceptive use. These ADRs include: myocardial infarction, deep venous
thrombosis, pulmonary embolism, cerebrovascular accidents, 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%) ADR was headache (27.9%). The most commonly reported ( 10%) ADR
identified during post-marketing experience was diarrhoea (11.8%).
The most common ADRs ( 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 ADRs 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 Norgestimate /
Ethinylestradiol, 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 ADRs by treatment cycle for up
to 24 cycles. As the frequency of ADRs 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 ADRs that have been reported with the use of
Norgestimate / Ethinylestradiol 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).
Description of selected adverse reactions
An increased risk of arterial and venous thrombotic and thrombo-embolic events,
including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis
and pulmonary embolism has been observed in women using CHCs, which are
discussed in more detail in section 4.4.
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
Rare
Loss of libido
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
VTE or ATE
Respiratory, Thoracic and Mediastinal Disorders
Uncommon
Dyspnoea
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.

4.9

Overdose
There have been no reports of serious ill-health from overdosage. 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
Progestogens and estrogens, fixed combinations

for

Systemic

Use;

ATC Code: G03AA11
Norgestimate / Ethinylestradiol 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
Norgestimate / Ethinylestradiol, serum concentrations of norgestimate remain below
the quantitation limit of the assay (0.1 ng/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
0.250 mg 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 sulphate 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 0.250 mg
norgestimate /0.035 mg 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 0.250 mg
norgestimate /0.035 mg ethinyl estradiol corresponds to the exposure after a

levonorgestrel dose of approximately 30 micrograms in combination with ethinyl
estradiol.

5.3

Preclinical safety data
Non-clinical studies reveal no special hazard for humans additional to those already
mentioned in other sections of the SmPC. Among others, these studies have included
single and repeated dose toxicity, genotoxicity, carcinogenicity and reproductive
toxicity studies conducted with the combination of norgestimate with ethinylestradiol.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Lactose, Anhydrous
Lactose, Monohydrate
Povidone K-25
dl-a-tocopherol
Microcrystalline cellulose
Croscarmellose sodium
Starch, Pregelatinised (starch 1500)
Magnesium Stearate
Indigo carmine aluminium lake (E 132)

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
2 years

6.4

Special precautions for storage
Store in the original package to protect from light.

6.5

Nature and contents of container
PVC/PVdC- Aluminium blister strips of 21 tablets. Each blister is packed in a
trilaminated pouch.

Packs containing
21, 63, 126 tablets
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Not applicable.

7

MARKETING AUTHORISATION HOLDER
MORNINGSIDE HEALTHCARE LIMITED
115 NARBOROUGH ROAD
LEICESTER
LE3 0PA
UNITED KINGDOM

8

MARKETING AUTHORISATION NUMBER(S)
PL 20117/0220

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
07/11/2012

10

DATE OF REVISION OF THE TEXT
21/07/2014

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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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