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PRIMOLUT N

Active substance(s): NORETHISTERONE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Primolut N ®

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5 milligrams of norethisterone BP.
Excipient with known effect
Lactose
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Tablet.
White, uncoated tablets impressed with ‘AN’ in a regular hexagon on one side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Metropathia haemorrhagica. Premenstrual syndrome. Postponement of
menstruation. Endometriosis. Menorrhagia. Dysmenorrhoea.

4.2

Posology and method of administration
Posology
Not intended for use in children.
Metropathia haemorrhagica (dysfunctional uterine bleeding): 1 tablet 3 times daily
for 10 days. Bleeding is arrested usually within 1-3 days. A withdrawal bleeding
resembling normal menstruation occurs within 2-4 days after discontinuing treatment.
One tablet twice daily from the 19th to the 26th day of the two subsequent cycles
should be given to prevent recurrence of the condition.

To ensure treatment success, Primolut N must be taken for the full 10 days.
Occasionally, slight bleeding may occur after the initial suspension of bleeding.
Treatment should not be interrupted or suspended in these cases.
If vaginal bleeding does not stop, despite correct tablet intake, an organic cause or an
extra-genital factor (e.g. polyps, carcinoma of the cervix uteri or endometrium,
myoma, residua of abortion, extra-uterine pregnancy, or coagulation disorders) must
be considered so that other measures are then mostly required. This also applies to
cases where after an initial suspension of bleeding, fairly heavy bleeding reoccurs
during tablet intake.
Premenstrual syndrome (including premenstrual mastalgia): Premenstrual symptoms
such as headache, migraine, breast discomfort, water retention, tachycardia, and
psychological disturbances may be relieved by the administration of 1-3 tablets daily
from the 19th to the 26th day of the cycle. Treatment should be repeated for several
cycles. When treatment is stopped, the patient may remain symptom-free for a
number of months.
Postponement of menstruation: In cases of too frequent menstrual bleeding, and in
special circumstances (e.g. operations, travel, sports) the postponement of
menstruation is possible. The dosage is 1 tablet of Primolut N three times daily,
starting 3 days before the expected onset of menstruation and continuing for not
longer than 10 to 14 days. A normal period should occur 2-3 days after the patient has
stopped taking tablets. This method should be restricted to users who are not at risk
of pregnancy during the treatment cycle.
Endometriosis (pseudo-pregnancy therapy): Treatment should begin between the
first and 5th day of the cycle with 1 of tablet Primolut N twice daily. In the event of
spotting, the dose can be increased to 2 tablets twice daily. If bleeding ceases, dose
reduction to the initial dose should be considered. Treatment is to be continued for at
least 4 to 6 months. With uninterrupted daily intake, ovulation and menstruation do
not usually occur.
Menorrhagia (hypermenorrhoea): 1 tablet 2-3 times a day from the 19th to the 26th
day of the cycle (counting the first day of menstruation as day 1).
Dysmenorrhoea: Functional or primary dysmenorrhoea is almost invariably relieved
by the suppression of ovulation. 1 tablet three times daily for 20 days, starting on the
fifth day of the cycle (the first day of menstruation counting as day 1). Treatment
should be maintained for three to four cycles followed by treatment-free cycles. A
further course of therapy may be employed if symptoms return.
Method of administration
The tablets are to be swallowed whole with some liquid.

4.3

Contraindications
Primolut N should not be used in the presence of any of the conditions listed below.
Should any of the conditions appear during the use of Primolut N, the use of the
preparation must be discontinued immediately.
1.

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

2.

Known or suspected pregnancy.

3.

Lactation.

4.

Previous idiopathic or current venous thromboembolism (deep vein thrombosis,
pulmonary embolism).

5.

Active or recent arterial thromboembolic disease (e.g. angina, myocardial
infarction).

6.

Presence or a history of prodromi of a thrombosis (e.g. transient ischaemic
attack, angina pectoris).

7.

A high risk of venous or arterial thrombosis (see section 4.4)

8.

History of migraine with focal neurological symptoms.

9.

Diabetes mellitus with vascular involvement.

10. Presence or history of severe hepatic disease as long as liver function values
have not returned to normal.
11. Previous or existing liver tumours (benign or malignant).
12. Known, past or suspected sex hormone-dependent malignancies, including breast
cancer.
13. History during pregnancy of idiopathic jaundice or severe pruritus.
14. Undiagnosed genital bleeding.
15. Untreated endometrial hyperplasia.

4.4

Special warnings and precautions for use
Medical Examination
A complete personal and family medical history should be taken for each woman.
Physical examination should be guided by this and by the contraindications (section
4.3) and warnings (section 4.4) for this product. The frequency and nature of these
assessments should be based upon relevant guidelines which should be adapted to the
individual woman and should include measurement of blood pressure, and if judged
appropriate by the clinician, breast, abdominal and pelvic examination including
cervical cytology.
Therapy should be discontinued immediately if the following occur:
New onset of migraine-type headaches or more frequent occurrence of
unusually severe headaches
Sudden perceptual disorders (e.g. disturbances of vision or hearing)
First signs of thrombophlebitis or thromboembolic symptoms, feeling of pain
and tightness in the chest
Pending operations (six weeks beforehand), immobilisation (e.g. after
accidents)
Onset of jaundice or deterioration in liver function, anicteric hepatitis, general
pruritus
Significant increase in blood pressure
Pregnancy.

If any of the conditions/risk factors mentioned below is present or deteriorates while
using Primolut N, an individual risk-benefit analysis should be done before Primolut
N is started or continued.
• Circulatory disorders
It has been concluded from epidemiological surveys that the use of oral
oestrogen/progestogen containing ovulation inhibitors is associated by an increased
incidence of thromboembolic diseases. Therefore, one should keep the possibility of
an increased thromboembolic risk in mind, particularly where there is a history of
thromboembolic diseases.
A patient who develops symptoms suggestive of thromboembolic complications
should stop treatment immediately. The need for treatment should be reassessed
before continuing therapy.
Generally recognised risk factors for venous thromboembolism (VTE) include:
1. Positive personal or family history (VTE in a sibling or a parent at a relatively
early age)
2. Age
3. Obesity
4. Systemic lupus erythematous (SLE)
5. Prolonged immobilisation
6. Major surgery
7. Major trauma.
Patients with a history of VTE or known thrombophilic states have an increased risk
of VTE. The treatment with steroid hormone may add to this risk. Personal or strong
family history of thromboembolism or recurrent spontaneous abortion should be
investigated in order to exclude a thromboembolic predisposition. Until a thorough
evaluation of thrombophilic factors has been made or anticoagulant treatment
initiated, use of progestogens in these patients should be viewed as contraindicated.
Where a patient is already taking anticoagulants, the risk and benefits of progestogen
therapy should be carefully considered.
The risk of VTE may be temporarily increased with prolonged immobilisation, major
trauma or major surgery. As in all post-operative patients, scrupulous attention
should be given to prophylactic measures to prevent VTE. Where prolonged
immobilisation is likely to follow elective surgery, particularly abdominal or
orthopaedic surgery to the lower limbs, consideration should be given to stopping
progestogen therapy 4-6 weeks pre-operatively. Treatment should not be restarted
until the patient is fully remobilised.
There is no consensus about the possible role of varicose veins and superficial
thrombophlebitis in venous thromboembolism.
• Known Hyperlipidaemias
Women with hypertriglyceridemia, or a family history thereof, may be at increased
risk of pancreatitis when using COCs.
Women with hyperlipiaedmia are at increased risk of arterial disease (see section 4.4
“Circulatory disorders”). However, routine screening of women on COCs is not
appropriate.
• Tumours

In rare cases, benign liver tumours, and even more rarely, malignant liver tumours
have been reported in users of hormonal substances such as the one contained in
Primolut N. In isolated cases, these tumours have led to life-threatening intraabdominal haemorrhages. If severe upper abdominal complaints, liver enlargement
or signs of intra-abdominal haemorrhage occur, a liver tumour should be included in
the differential diagnosis and, if necessary, the preparation should be withdrawn.
• Other
Primolut-N can influence carbohydrate metabolism. Parameters of carbohydrate
metabolism should be examined carefully in all diabetics before and regularly during
treatment.
Chloasma may occasionally occur, especially in women with a history of chloasma
gravidarum. Women with a tendency to chloasma should minimise exposure to the
sun or ultraviolet radiation when taking Primolut N.
Patients who have a history of depression should be carefully observed and the drug
discontinued if the depression recurs to a serious degree.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose-galactose malabsorption should not take this medicine.
Any patient who develops an acute impairment of vision, proptosis, diplopia or
migraine headache should be carefully evaluated ophthalmologically to exclude
papilloedema or retinal lesions before continuing medication.
Progestogens may cause fluid retention. Special care should be taken when
prescribing norethisterone in patients with conditions which might be aggravated by
this factor:


Epilepsy



Migraine



Asthma



Cardiac dysfunction



Renal dysfunction.

If menstrual bleeding should fail to follow a course of Primolut N, or if the patient
wishes to postpone menstruation in special circumstances, the possibility of
pregnancy must be excluded before a further course is given.
Additional warnings based on the partial metabolisation of norethisterone to
ethinylestradiol
After oral administration, norethisterone is partly metabolised to ethinylestradiol
resulting in an equivalent dose of about 4-6 micrograms ethinylestradiol per 1
milligram of orally administered norethisterone or norethisterone acetate (see section
5.2)
Due to the partial conversion of norethisterone to ethinylestradiol, administration of
Primolut N is expected to result in similar pharmacological effects as seen with
COCs. Therefore, the following general warnings associated with the use of COCs
should also be considered:
• Circulatory disorders (thromboembolic events)
Venous thromboembolic events (VTE)
Epidemiological studies have shown that the incidence of venous thromboembolism
(VTE) in users of oral contraceptives with low oestrogen content (<50 µg

ethinylestradiol) ranges from about 20 to 40 cases per 100,000 women-years, but this
risk estimate varies according to the progestogen. This compares with 5 to 10 cases
per 100,000 women-years for non-users. The use of any combined oral contraceptive
carries an increased risk of VTE compared with no use. This increased risk is less
than the risk of VTE associated with pregnancy, which is estimated as 60 cases per
100,000 pregnancies. The excess risk of VTE is highest during the first year a woman
initially starts using a COC or when she restarts COC use after a pill-free interval of
at least a month.
VTE may be life-threatening or may have a fatal outcome (in 1-2 % of the cases).
VTE manifesting as deep venous thrombosis and/or pulmonary embolism, may occur
during the use of all COCs.
Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g.
hepatic, mesenteric, renal, cerebral 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.
Common signs/symptoms of VTE include:
• Severe pain in the calf of one leg; swelling of the lower leg
• Sudden breathlessness, chest pain.
Arterial thromboembolic related conditions
The use of a combined oral contraceptive may also increase the risk of conditions
such as stroke and myocardial infarction which are secondary to arterial
thromboembolic events.
Common signs/symptoms associated with arterial thromboembolism include:
• sudden severe pain in the chest, whether or not reaching to the left arm;
• sudden coughing for no apparent reason
• any unusual severe, prolonged headache, especially if it occurs for the first
time or gets progressively worse, or is associated with any of the following
symptoms:
o

sudden partial or complete loss of vision or diplopia;

o

aphasia;

o

vertigo;

o

collapse with or without focal epilepsy;

o

weakness or very marked numbness suddenly affecting one side or
one part of the body.

Risk Factors for Thromboembolic Events:


Age



Obesity (body mass index over 30 kg/m2)



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
known or suspected, the woman should be referred to a specialist for advice
before deciding about any COC use



Prolonged immobilisation, 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 remobilisation


Smoking (with heavier smoking and increasing age the risk further increases,
especially in women over 35 years of age)



Dyslipoproteinaemia



Hypertension



Migraine (An increase in frequency or severity of migraine during COC use
may be prodromal of a cerebrovascular event and therefore a reason for
immediate discontinuation of the COC).



Valvular heart disease



Atrial fibrillation

Other factors affecting circulatory events
Other medical conditions which have been associated with adverse circulatory events
include:


Diabetes mellitus



Systemic lupus erythematosus (SLE)



Haemolytic uremic syndrome



Chronic inflammatory bowel disease (Crohn’s disease/Ulcerative colitis)



Sickle cell disease.

Biochemical factors that may be indicative of hereditary or acquired predisposition
for venous or arterial thrombosis include:


Activated Protein C (APC) resistance



Hyperhomocysteinaemia



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 (<0.05 mg
ethinylestradiol).
• Tumours
Cervical Cancer
The most important risk factor for cervical cancer is persistent 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.
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 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 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.
Malignancies may be life-threatening or may have a fatal outcome.
• Other
Blood pressure
Although small increases in blood pressure have been reported in many women
taking COCs, clinically relevant increases are rare. 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.
Conditions which deteriorate in pregnancy or during previous COC use
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 (SLE)



haemolytic uremic 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
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.
Crohn’s disease and ulcerative colitis have been associated with COC use.

4.5

Interaction with other medicinal products and other forms of interaction
Drug interactions which result in an increased clearance of sex hormones can
lead to decreased therapeutic efficacy. This has been established with many

hepatic enzyme-inducing drugs (including phenytoin, barbiturates, primidone,
carbamazepine, rifampicin, oxcarbazepine and rifabutin); griseofulvin is also
suspected to interact leading to menstrual irregularities.
Herbal preparations containing St. Johns wort (Hypericum perforatum) may
induce the metabolism of progestogens.
Progestogens may interfere with the metabolism of other drugs. Accordingly,
plasma and tissue concentrations may be affected (e.g. ciclosporine
metabolism may be inhibited).
The use of progestogens may influence the results of certain laboratory tests
(e.g. tests for hepatic function, thyroid function and coagulation).
4.6

Fertility, pregnancy and lactation
Pregnancy
The administration of Primolut N during pregnancy is contraindicated.
Breast-feeding
Primolut N can pass into breast milk and therefore should be avoided during lactation.

4.7

Effects on ability to drive and use machines
None known.

4.8

Undesirable effects
Undesirable effects are more common during the first months after start of intake of
Primolut preparations, and subside with duration of treatment. The frequencies are
based on reporting rates from postmarketing experience and literature.

System Organ
Class

Very common
≥ 1/10

Common
≥ 1/100
< 1/10

Uncommon
to

Rare

Very rare

Frequency

≥ 1/1,000 to
< 1/100

≥ 1/10,000
to
< 1/1000

< 1/10,000

not known

Immune
system
disorders
Nervous
system
disorders

Hypersensitivity
reactions
Headache

Migraine

Dizziness

System Organ
Class

Very common
≥ 1/10

Common
≥ 1/100
< 1/10

Uncommon
to

Rare

Very rare

Frequency

≥ 1/1,000 to
< 1/100

≥ 1/10,000
to
< 1/1000

< 1/10,000

not known

Psychiatric
disorders

Depression
aggravated

Eye disorders

Visual
disturbances

Respiratory,
thoracic and
mediastinal
disorders

Dyspnoea

Nausea

Gastrointestinal
disorders

Abdominal
pain

Cholestasis

Hepato-biliary
disorders

Jaundice
Skin and
subcutaneous
tissue disorders
Reproductive
system and
breast
disorders

Urticaria
Rash
Uterine/
Vaginal
bleeding
including
Spotting*

Amenorrhoea*

Hypomenorrhoea*
Oedema

General
disorders and
administration
site conditions

* in the indication Endometriosis
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 ill-effects from overdosage and treatment is generally
unnecessary. There are no special antidotes, and treatment should be symptomatic.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: sex hormones and modulators of the genital system,
progestogens, ATC Code: G03DC02
Norethisterone has progestational actions similar to those of progesterone, but is a
more potent inhibitor of ovulation and has weak oestrogenic and androgenic
properties. It is used to treat a number of disorders of the menstrual cycle.

5.2

Pharmacokinetic properties
Norethisterone is absorbed from the gastro-intestinal tract and its effects last for at
least 24 hours. It is excreted in the urine.
Metabolism
Norethisterone is partly metabolized to ethinylestradiol after oral administration of
norethisterone or norethisterone acetate in humans. This conversion results in an
equivalent dose of about 4-6 µg ethinylestradiol per 1 mg orally administered
norethisterone / norethisterone acetate.

5.3

Preclinical safety data
Non-clinical data on norethisterone or its esters reveal no special risk for humans
based on conventional studies of repeated dose toxicity, genotoxicity and
carcinogenic potential which is not already included in other relevant sections.
However, it should be kept in mind that sexual steroids might stimulate the growth of
hormone-dependent tissues and tumours.
Reproduction toxicity studies showed the risk of masculinisation in female fetuses
when administered at high doses at the time of the development of the external
genitalia. Since epidemiological studies show that this effect is relevant in humans
after high doses, it must be stated that Primolut N may provoke signs of virilisation in
female fetuses if administered during the hormone-sensitive stage of somatic sexual
differentiation (from day 45 of pregnancy onwards). Apart from this, no indications
of teratogenic effects were obtained from the studies.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
lactose

maize starch
magnesium stearate

6.2

Incompatibilities
Not known.

6.3

Shelf life
5 years.

6.4

Special precautions for storage
Not applicable.

6.5

Nature and contents of container
Cardboard carton containing 3 blisters of 10 tablets.

6.6

Special precautions for disposal and other handling
Keep out of the sight and reach of children.

7

MARKETING AUTHORISATION HOLDER
Bayer plc
Bayer House
Strawberry Hill
Newbury
Berkshire

RG14 1JA

8

MARKETING AUTHORISATION NUMBER(S)
PL 00010/0553

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
23/11/2006

10

DATE OF REVISION OF THE TEXT
29/07/2015

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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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