Consumer medicine information

Primolut N

Norethisterone

BRAND INFORMATION

Brand name

Primolut N

Active ingredient

Norethisterone

Schedule

SUMMARY CMI

PRIMOLUT^® N

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I taking PRIMOLUT N?

PRIMOLUT N contains the active ingredient norethisterone. PRIMOLUT N is used to treat: irregular menstrual periods with heavy and/or persistent bleeding that has no identified cause; lack of menstrual bleeding; premenstrual complaints (premenstrual syndrome); menopausal complaints in combination with estrogen as part of hormone replacement therapy; endometriosis (a disease caused by womb-lining tissue growing outside the womb).

For more information, see Section 1. Why am I taking PRIMOLUT N? in the full CMI.

2. What should I know before I take PRIMOLUT N?

Do not use if you have ever had an allergic reaction to norethisterone or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I take PRIMOLUT N? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with PRIMOLUT N and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take PRIMOLUT N?

Your doctor will advise you about how many tablets to take but this can vary from 1 to 4 tablets daily depending on the condition being treated.
Swallow each tablet whole with a glass of water. It does not matter if you take the tablets before or after food.

More instructions can be found in Section 4. How do I take PRIMOLUT N? in the full CMI.

5. What should I know while taking PRIMOLUT N?

Things you should do	Remind any doctor, dentist or pharmacist or surgeon and anaesthetist (if having surgery) you visit that you are taking PRIMOLUT N. Monitor for potential signs of blood clots and situations such as surgery or immobilisation (including air travel greater than 4 hours) that might increase the risk of blood clots.
Things you should not do	Do not stop taking this medicine or change the dosage without checking with your doctor. Do not take to treat other conditions unless advised by your doctor.
Driving or using machines	Adverse effects of PRIMOLUT N include visual disturbances, dizziness and somnolence, which could affect a person's ability to drive or use machines.
Drinking alcohol	n/a
Looking after your medicine	Keep your tablets in a cool dry place where the temperature stays below 30°C

For more information, see Section 5. What should I know while taking PRIMOLUT N? in the full CMI.

6. Are there any side effects?

Common side effects include nausea, headache (including migraines), fluid retention, shortness of breath, hypersensitivity reactions (e.g. rash, hives), abnormal vision. Serious side effects include severe allergy like reactions characterized by difficulty breathing, swollen tongue, feeling of tightness in the throat and blood clots such as thrombophlebitis and pulmonary embolism.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

PRIMOLUT^® N (PREE moe loot)

Active ingredient(s): norethisterone

Consumer Medicine Information (CMI)

This leaflet provides important information about using PRIMOLUT N. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using PRIMOLUT N.

Where to find information in this leaflet:

1. Why am I taking PRIMOLUT N?
2. What should I know before I take PRIMOLUT N?
3. What if I am taking other medicines?
4. How do I take PRIMOLUT N?
5. What should I know while taking PRIMOLUT N?
6. Are there any side effects?
7. Product details

1. Why am I taking PRIMOLUT N?

PRIMOLUT N contains the active ingredient norethisterone. PRIMOLUT N is a type of hormone similar to the natural female hormone progesterone. Some of the active ingredient in PRIMOLUT N is converted to estrogen in the body.

PRIMOLUT N is used to treat irregular menstrual periods with heavy and/or persistent bleeding that has no identified cause; lack of menstrual bleeding; premenstrual complaints (premenstrual syndrome); menopausal complaints in combination with estrogen as part of hormone replacement therapy; endometriosis (a disease caused by womb-lining tissue growing outside the womb).

PRIMOLUT N is not to be used as a contraceptive.

2. What should I know before I take PRIMOLUT N?

Warnings

Do not take PRIMOLUT N if:

you are allergic to norethisterone, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.
you have or have had a blood clot in: the blood vessels of the legs (deep vein thrombosis); the lungs (pulmonary embolism); the heart (heart attack); the brain (stroke); or other parts of the body
you are concerned about an increased risk of blood clots. Blood clots are rare. Very occasionally blood clots may cause serious permanent disabilities, or may even be fatal. You are at an increased risk of having a blood clot when you take hormonal medicines such as PRIMOLUT N.
you are concerned about an increased risk of blood clots because of age or smoking. The risk of having a heart attack or stroke increases as you get older. It also increases if you smoke.
you are taking antiviral medicines which contain ombitasvir, paritaprevir, or dasabuvir, and combinations of these. These antiviral medicines are used to treat chronic (long-term) hepatitis C (an infectious disease that affects the liver, caused by the hepatitis C virus).
you have or have had angina (chest pain)
you have or have had a mini stroke (also known as a TIA or transient ischaemic attack)
you have or have had high risk of blood clots due to conditions such as diabetes with blood vessel damage, severe high blood pressure
you have or have had migraine, where you have also had problems with seeing, speaking or had weakness or numbness in any part of your body
you have or have had severe liver disease and your liver function values have not returned to normal
you have or have had a benign or malignant liver tumour
you have or have had cancer that may grow under the influence of sex hormones (e.g. of the breast or the genital organs)
you have or have had a condition causing an increase in the breakdown of red blood cells in the body (Dubin-Johnson syndrome or Rotor syndrome)
you have or have had vaginal bleeding or blood in your urine for which a cause has not been identified
you have or have had breast disease for which a cause has not been identified
you have or have had a missed miscarriage.

If any of these conditions appear for the first time while taking PRIMOLUT N, stop taking it at once and tell your doctor.

Check with your doctor if you:

have diabetes
have high blood pressure
have liver disease or a liver tumour
have a history of depression with hallucinations, delusions
have epilepsy
have migraines
have asthma
have kidney disease
have heart disease
smoke
or anyone in your immediate family has had blood clots in the legs (DVT) or lungs (PE), a heart attack, a stroke, breast cancer or high cholesterol
are overweight
have any hereditary or acquired conditions that may make it more likely for you to get blood clots
have liver disease
have jaundice (yellowing of the skin) and/or pruritus (itching of the skin) related to cholestasis (condition in which the flow of bile from the liver stops or slows)
have gall bladder disease
have Crohn's disease or ulcerative colitis (chronic inflammatory bowel disease)
have high cholesterol or triglycerides
have systemic lupus erythematosus (SLE – a disease affecting the skin all over the body)
have haemolytic uraemic syndrome (HUS – a disorder of blood coagulation causing failure of the kidneys)
have sickle cell disease
have a condition that occurred for the first time, or worsened during pregnancy or previous use of sex hormones (e.g. hearing loss, a metabolic disease called porphyria, a skin disease called herpes gestationis, a neurological disease called Sydenham's chorea)
have chloasma (yellowish-brown pigmentation patches on the skin, particularly of the face) – if so, avoid the sun or ultraviolet radiation
have hereditary angio-oedema, such as swollen face, tongue and/or pharynx and/or difficulty swallowing, or hives together with difficulty in breathing.

If any of the above conditions appear for the first time, recur or worsen while taking PRIMOLUT N, you should talk to your doctor.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. Do not take this medicine if you are pregnant or think you might be pregnant. It may affect your developing baby if you take it during pregnancy.

Talk to your doctor if you are breastfeeding or intend to breastfeed. Do not breastfeed if you are taking this medicine. The active ingredient in PRIMOLUT N passes into breast milk and there is a possibility that your baby may be affected.

Do not give this medicine to a child.

Do not take this medicine if the packaging is torn or shows signs of tampering. If the packaging is damaged, return it to your pharmacist for disposal.

Do not take this medicine after the expiry date printed on the pack and blister. The expiry date is printed on the carton and on each blister after “EXP” (e.g. 11 18 refers to November 2018). The expiry date refers to the last day of that month. If it has expired return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with PRIMOLUT N and affect how it works. These include:

medicines used to treat epilepsy such as primidone, phenytoin, barbiturates, carbamazepine, oxcarbazepine, topiramate, felbamate, lamotrigine
medicines used to treat tuberculosis such as rifampicin
medicines used to treat fungal infections such as griseofulvin, ketoconazole
medicines used to treat HIV, such as ritonavir or nevirapine
some medicines used to treat Hepatitis C Virus (HCV) such as ombitasvir, paritaprevir, or dasabuvir or combinations of these
etoricoxib, an anti-inflammatory medicine used to treat pain
tizanidine, melatonin or midazolam which are medicines that relax the body
theophylline, a medicine that helps with breathing
medicines used to treat high blood pressure, chest pain and/or irregular heartbeats such as diltiazem, verapamil
macrolide antibiotics (e.g. clarithromycin, erythromycin)
herbal medicines containing St John's wort
cyclosporin, a medicine used to suppress the immune system
grapefruit juice

These medicines may be affected by PRIMOLUT N or may affect how well it works. Your doctor may need to alter the dose of these medicine, or prescribe a different medicine.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect PRIMOLUT N.

4. How do I take PRIMOLUT N?

How much to take

PRIMOLUT N is used to treat a number of different conditions. The dosage will vary depending on why you have been given this medicine.
The recommended dosage can range between 1 tablet daily in some conditions, up to 4 tablets daily in other conditions. Your doctor will advise you on how to take your tablets.
If you do not understand the instructions printed on the pharmacist label, talk to your doctor or pharmacist.

When to take PRIMOLUT N

PRIMOLUT N tablets should be swallowed whole with a glass of water. It does not matter if you take it before or after food.
Depending on your condition you may be prescribed to take PRIMOLUT N for 10 days, or for up to 6 months. Follow the advice of your doctor carefully. Continue taking your medicine for as long as your doctor tells you.
There are no specific withdrawal symptoms if you stop PRIMOLUT N but there is the possibility that the original complaints might re-occur.

If you forget to take PRIMOLUT N

PRIMOLUT N should be used regularly at the same time each day. If you miss your dose at the usual time, only take the last missed tablet as soon as you remember and then continue taking your tablet at your usual time on the next day.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

The efficacy of PRIMOLUT N could be reduced if you forget to take a tablet as directed.

If you take too much PRIMOLUT N

If you think that you have taken too much PRIMOLUT N, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while taking PRIMOLUT N?

Things you should do

Call your doctor straight away if you:

become pregnant while taking this medicine
feel a lump in your breast
are immobilised (e.g. due to an accident or you have your leg(s) in a splint/plaster)
are to have surgery (consult your doctor at least six weeks in advance)
have unusual, heavy vaginal bleeding
have been experiencing unusually severe headaches
develop high blood pressure
are experiencing abnormal vision
have severe stomach pain
are about to be started on any new medicine, remind your doctor and pharmacist that you are taking PRIMOLUT N.

Remind any doctor, dentist or pharmacist, surgeon and anaesthetist (if you are going to have surgery) you visit that you are using PRIMOLUT N.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Keep all of your doctor's appointments so that your progress can be checked.

The risk of having blood clots is temporarily increased as a result of major surgery, any surgery to the legs or pelvis, neurosurgery or major trauma. In women who take PRIMOLUT N, the risk may be higher.

In women at risk of prolonged immobilisation (including major surgery, any surgery to the legs and pelvis, neurosurgery, or major trauma), your doctor may tell you to stop taking (in the case of elective surgery at least 4 weeks in advance) and not resume until two weeks after complete remobilisation. Your doctor may prescribe other treatment (e.g. treatment for blood clots) if PRIMOLUT N has not been discontinued in advance.

Other risk factors for blood clotting include temporary immobilisation including air travel of greater than 4 hours, particularly in women with other risk factors. Consult your doctor if you plan to air travel for greater than 4 hours.

Stop taking PRIMOLUT N and see your doctor immediately if you notice the following signs:

one-sided 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
sudden onset of unexplained shortness of breath or rapid breathing
sudden coughing or coughing up of blood
sharp chest pain or sudden severe pain in the chest which may increase with deep breathing
severe light headedness or dizziness
rapid or irregular heartbeat
sudden pain, swelling and slight blue discoloration of an extremity
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, slurred speech or aphasia; sudden partial or complete loss of vision, double vision, painless blurring of vision which can progress to loss of vision
sudden, severe or prolonged headache with no known cause
loss of consciousness or fainting with or without seizure
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
extreme weakness and anxiety.

If you have sexual intercourse, you should use non-hormonal methods of contraception (e.g. barrier methods such as condoms or diaphragm). If you think you might have fallen pregnant despite such protective measures, stop taking the tablets and see your doctor immediately.

Things you should not do

Do not take PRIMOLUT N to treat any other conditions unless your doctor tells you to.
Do not give your medicine to anyone else, even if they have the same condition as you.
Do not stop taking your medicine or change the dosage without checking with your doctor. If you stop taking it suddenly, your condition may worsen or you may have unwanted effects.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how PRIMOLUT N affects you.

Adverse effects of PRIMOLUT N include visual disturbances, dizziness and somnolence, which could affect a person's ability to drive or use machines.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they may not keep well.
Keep your tablets in a cool dry place where the temperature stays below 30°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Side effects are more common during the first month after starting PRIMOLUT N, and they should subside with duration of treatment.

When used for endometriosis, changes in bleeding pattern including irregular bleeding, scanty bleeding and absence of bleeding may occur.

Less serious side effects

Less serious side effects

What to do

nausea
headache, including migraines
fluid retention
shortness of breath
hypersensitivity reactions (e.g. rash, hives)
abnormal vision

Progestogen effects:

severe allergic like reactions characterised by difficulty breathing, swollen tongue, feeling of tightness in the throat
thrombophlebitis (blood clot in a vein)
pulmonary embolism (blood clot in the lung)
nervousness
difficulty sleeping
drowsiness, tiredness
depression
shaking movements in one or more parts of the body
pre-menstrual type depression
hives, rash, itchiness
acne
hirsutism
hair loss
sweating
irregular uterine bleeding
spotting and lack of period
breast tenderness and discharge
changes in cervical excretions and secretions
high fever
fatty hump between the shoulders, rounded face and pink or purple stretch marks (Cushing's syndrome)
weight gain

Speak to your doctor if you have any of these less serious side effects and they worry you.

Specific side effects

Blood clots and PRIMOLUT N

Blood clots may block blood vessels in your body. This type of blood clot is also called thrombosis.

Blood clots sometimes occur in the deep veins of the legs (deep venous thrombosis, DVT). If this blood clot breaks away from the veins where it is formed, it may reach and block the arteries of the lungs, causing a so-called pulmonary embolism (PE).

Blood clots can also occur in the blood vessels of the heart (causing a heart attack) or the brain (causing a stroke).

Blood clots are a rare occurrence and can develop whether or not you are taking PRIMOLUT N.

If you notice signs of a blood clot, stop taking PRIMOLUT N and consult your doctor immediately.

Cancer and PRIMOLUT N

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. These tumours may lead to internal bleeding.

Contact your doctor immediately if you have severe pain in your abdomen.

Breast cancer has been diagnosed slightly more often in women who take hormonal substances similar to PRIMOLUT N than in women of the same age who do not take these medicines.

It is not known whether the difference is caused by these medicines. It may be that these women were examined more often, so that the breast cancer was noticed earlier.

It is important that you check your breasts regularly and contact your doctor if you feel any lumps.

Cervical cancer has been reported to occur more often in women who have been taking hormonal medicines for a long time. It is not certain if this is caused by hormonal medicines.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What PRIMOLUT N contains

Active ingredient (main ingredient)	Norethisterone 5 mg
Other ingredients (inactive ingredients)	Lactose monohydrate, maize starch, magnesium stearate
Potential allergens	n/a

Do not take this medicine if you are allergic to any of these ingredients.

Tablets do not contain sucrose or gluten. Tablets also do not contain tartrazine or any other azo dyes.

What PRIMOLUT N looks like

PRIMOLUT N comes in a box containing 3 blister strips. Each blister strip contains 10 white tablets marked with “AN” inside a hexagon (AUST R 134491).

Who distributes PRIMOLUT N

Bayer Australia Ltd
ABN 22 000 138 714
875 Pacific Highway
Pymble NSW 2073

This leaflet was prepared in September 2023.

See TGA website (www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information.

^® Registered Trademark of the Bayer Group, Germany

Published by MIMS February 2025

BRAND INFORMATION

Brand name

Primolut N

Active ingredient

Norethisterone

Schedule

1 Name of Medicine

Primolut N (norethisterone).

2 Qualitative and Quantitative Composition

Each tablet of Primolut N contains 5 mg norethisterone.
List of excipients with known effect: Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablet.

Tablets are round and white, quarter scored on one side, with the letters ‘AN’ in a regular hexagon on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Dysfunctional bleeding, primary and secondary amenorrhoea, premenstrual syndrome, delay of menstrual period, endometriosis, adjunct to estrogen hormone replacement therapy.

4.2 Dose and Method of Administration

The tablets are to be swallowed whole with some liquid.
The efficacy of Primolut N could be reduced if the user forgets to take a tablet as directed. The woman should take only the last missed tablet as soon as she remembers and then continue tablet intake at her usual time on the next day.
If contraceptive protection is required, additional nonhormonal contraceptive methods should be used.

Dysfunctional bleeding.

Primolut N 1 tablet is to be taken 3 times daily for 10 days. In the majority of cases this will arrest uterine bleeding that is not associated with organic lesions within 1 to 3 days, nevertheless, to ensure treatment success Primolut N must be taken for the full 10 days. About 2 to 4 days after completion of the treatment, withdrawal bleeding will occur with the intensity and duration of normal menstruation.
Occasionally, slight bleeding may occur after the initial suspension of bleeding. Also in these cases tablet intake should not be interrupted or stopped.
If vaginal bleeding does not stop, despite correct tablet intake, an organic cause or an extragenital factor (e.g. polyps, carcinoma of the cervix uteri or endometrium, myoma, residua of abortion, extrauterine 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.
To prevent dysfunctional bleeding recurrence in patients with anovulatory cycles Primolut N can be administered prophylactically (1 tablet 1 to 2 times daily from the 16th to the 25th day of the cycle (1st day of the cycle = 1st day of the last bleeding). Withdrawal bleeding occurs a few days after the last tablet intake.

Primary and secondary amenorrhoea.

Hormone treatment of secondary amenorrhoea can be carried out only after the exclusion of pregnancy. Before treatment of primary or secondary amenorrhoea is commenced the presence of a prolactin producing pituitary tumour should be excluded. The possibility cannot be ruled out that macroadenomas increase in size when exposed to high doses of estrogen for prolonged periods of time.
Endometrial priming with an estrogen must be carried out (e.g. for 14 days) before beginning treatment with Primolut N. Thereafter 1 tablet of Primolut N is given 1 to 2 times daily for 10 days. Withdrawal bleeding occurs within a few days after intake of the last tablet.
In patients in whom sufficient endogenous estrogen production has been achieved, an attempt can be made to stop the estrogen treatment and to induce cyclical bleeding by administering 1 tablet of Primolut N twice daily from the 16th to the 25th day of the cycle.

Premenstrual syndrome.

One tablet of Primolut N taken 1 to 3 times daily during the luteal phase of the cycle may relieve or improve premenstrual symptoms such as headaches, depressive moods, water retention and a feeling of tension in the breasts.

Timing of menstruation.

Monthly menstrual bleeding can be postponed with administration of Primolut N. However, this method should be restricted to users who are not at risk of pregnancy during the treatment cycle.
Dosage: 1 tablet Primolut N 2 to 3 times daily for not longer than 10-14 days, beginning about 3 days before the expected menstruation. Bleeding will occur 2-3 days after having stopped medication.

Endometriosis.

Treatment should begin between the first and 5th day of the cycle with 1 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. After discontinuation of hormone treatment withdrawal bleeding will occur.

4.3 Contraindications

Primolut N should not be used in the presence of any of the conditions listed below, which are derived also from information on progestogen only products and combined oral contraceptives (COCs). Should any of the conditions appear during the use of Primolut N, the product should be stopped immediately.
Known or suspected pregnancy.
Lactation.
Presence or a history of venous or arterial thrombotic/ thromboembolic events (e.g. deep venous thrombosis, pulmonary embolism, myocardial infarction) or of a cerebrovascular accident.
Presence or a history of prodromi of a thrombosis (e.g. transient ischaemic attack, angina pectoris).
A high risk of venous or arterial thrombosis (see Section 4.4 Special Warnings and Precautions for Use).
History of migraine with focal neurological symptoms.
Diabetes mellitus with vascular involvement.
Presence or history of severe hepatic disease as long as liver function values have not returned to normal.
Use of direct-acting antiviral (DAA) medicinal products containing ombitasvir, paritaprevir, or dasabuvir and combination of these (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Presence or history of liver tumours (benign or malignant).
Known or suspected sex hormone dependent malignancies (e.g. of the genital organs or the breasts).
Hypersensitivity to the active substances or to any of the excipients.
Dubin-Johnson syndrome.
Rotor syndrome.
Missed abortion.
Undiagnosed vaginal or urinary bleeding.
Undiagnosed breast pathology.

4.4 Special Warnings and Precautions for Use

If any of the conditions/risk factors mentioned below is present or deteriorates, 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 estrogen/progestogen containing ovulation inhibitors is attended by an increased incidence of thromboembolic diseases (see Section 5.2 Pharmacokinetic Properties, Metabolism). Therefore, one should keep the possibility of an increased thromboembolic risk in mind, particularly where there is a history of thromboembolic diseases. Generally recognised risk factors for venous thromboembolism (VTE) include a positive personal or family history (VTE in a sibling or a parent at a relatively early age), age, obesity, prolonged immobilisation, major surgery or major trauma.
The increased risk of thromboembolism in the puerperium must be considered (see Section 4.6 Fertility, Pregnancy and Lactation).
Treatment should be stopped at once if there are symptoms of an arterial or venous thrombotic event or suspicion thereof.

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 intra-abdominal haemorrhages. 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 taking Primolut N.

Other.

Strict medical supervision is necessary if the patient suffers from diabetes.
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 when taking Primolut N.
Patients who have a history of psychic depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.
Because this drug may cause some degree of fluid retention, conditions which might be influenced by this factor, such as epilepsy, migraine, asthma or cardiac or renal dysfunction, require careful observation.
Breakthrough bleeding is likely to occur in patients being treated for endometriosis. No other hormonal intervention is recommended for managing this bleeding. Nonfunctional causes should also be borne in mind and, in cases of undiagnosed vaginal bleeding, adequate diagnostic measures are indicated.
A decrease in glucose tolerance has been observed in some patients on progestogens. The mechanism of this decrease is obscure. This fact should be borne in mind when treating all patients and for this reason diabetic patients should be carefully observed while receiving progestogen therapy. The age of the patient constitutes no absolute limiting factor although treatment with progestogens may mask the onset of the climacteric.
The pathologist should be advised of progestogen therapy when relevant specimens are submitted.
Weight gain may be associated with the use of the medication. Caution should, therefore, be exercised in treating any patient with a pre-existing condition that may be adversely affected by weight gain.
Primolut N tablets are not to be used as a test for pregnancy or where pregnancy is suspected.
In perimenopausal patients where the endometrium is still proliferative, persistence of the endometrial proliferation may occur during administration of hormone replacement therapy (HRT). An endometrial biopsy may be performed at the discretion of the attending doctor.
Additional precautions applicable to other progestogen products may also apply.

Medical examination.

A complete medical history should be taken and a physical and gynaecological examination should be performed prior to the initiation or reinstitution of the use of Primolut N, see Section 4.3 Contraindications and Section 4.4 Special Warnings and Precautions for Use, and these should be repeated during the use of Primolut N. The frequency and nature of these assessments should be adapted to the individual woman but should generally include special reference to blood pressure, breasts, abdomen and pelvic organs, and should also include cervical cytology.

Additional warnings based on the partial metabolism of norethisterone to ethinylestradiol.

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 (see Section 5.2 Pharmacokinetic Properties). Therefore the following general warnings associated with the use of COCs should be considered in addition, when assessing the individual risk benefit for using Primolut N.

Circulatory disorders.

The risk of venous thromboembolism (VTE) is highest during the first year of use of a COC. This increased risk is present after initially starting, or restarting (following a 4 week or greater pill free interval) the same or a different COC. Data from a large, prospective 3 armed cohort study suggest that this increased risk is mainly present during the first 3 months.
Overall the risk for VTE in users of low estrogen dose (< 50 microgram ethinylestradiol) COCs is two to threefold higher than for nonusers of COCs who are not pregnant and remains lower than the risk associated with pregnancy and delivery.
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.
Symptoms of venous (includes pulmonary embolism (PE) and deep venous thrombosis (DVT) or arterial thrombotic/ thromboembolic (includes myocardial infarction (MI), vascular occlusion and cerebrovascular accident) events can include: unilateral leg pain and/or swelling; 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; sudden severe pain in the chest which may increase with deep breathing; 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; rapid or irregular heartbeat; sudden onset of unexplained shortness of breath or rapid breathing; sudden onset of coughing which may bring up blood; sudden, severe, prolonged headache with no known cause; sudden partial or complete loss of vision; diplopia; sense of anxiety; dizziness; slurred speech or aphasia; sudden confusion; vertigo; collapse with or without focal seizure; weakness or very marked numbness suddenly affecting one side or one part of the body; motor disturbances; ‘acute’ abdomen; fullness, indigestion or choking feeling; sweating; nausea; vomiting.
Some of these symptoms (e.g. "shortness of breath", "coughing") are nonspecific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections).
Arterial thromboembolic events may be life-threatening or may have a fatal outcome.
The potential for an increased synergistic risk of thrombosis should be considered in women who possess a combination of risk factors or exhibit a greater severity of an individual risk factor. This increased risk may be greater than a simple cumulative risk of the factors. Primolut N should not be prescribed in case of a negative risk benefit assessment (see Section 4.3 Contraindications).
The risk of venous or arterial thrombotic/ thromboembolic events or of a cerebrovascular accident increases with:
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 treatment.
Prolonged immobilisation, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue treatment (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.
Valvular heart disease.
Atrial fibrillation.
There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in VTE.
Other medical conditions which have been associated with adverse circulatory events include diabetes mellitus, systemic lupus erythematosus, haemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease.
An increase in frequency or severity of migraine during treatment (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the medicine.
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).

Tumours.

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.
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 (see Section 5.3 Preclinical Safety Data, Carcinogenicity).

Other conditions.

Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when taking COCs.
Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare.
If sustained clinically significant hypertension develops during the treatment then it is prudent for the physician to withdraw the medicine and treat the hypertension. Where considered appropriate, treatment 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 or Primolut N use is currently inconclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; 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 treatment 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 treatment.
Crohn's disease and ulcerative colitis have been associated with COC use.

Reasons for immediate discontinuation of the tablets.

Occurrence for the first time of migrainous 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 (for example unusual pains in or swelling of the legs, stabbing pains on breathing or coughing for no apparent reason), a feeling of pain and tightness in the chest, pending operations (six weeks beforehand), immobilisation (for instance following accidents), onset of jaundice, onset of anicteric hepatitis, generalised pruritus, significant rise in blood pressure, pregnancy.

Paediatric use.

Primolut N is only indicated after menarche.

Effect on laboratory tests.

The use of progestogens 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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Note.

The following interactions have been reported for combined oral contraceptives in the literature and may be relevant for Primolut N as well. The prescribing information of concomitant medications should be consulted to identify potential interactions.

Effects of other medicinal products on Primolut N.

Interactions can occur with medicines that induce microsomal enzymes, which can result in increased clearance of sex hormones and which may lead to changes in the uterine bleeding profile and/or reduction of the therapeutic efficacy.
Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After the cessation of drug therapy enzyme induction may be sustained for about 4 weeks.

Substances increasing the clearance of sex hormones (diminished efficacy by enzyme-induction) e.g.

Phenytoin, barbiturates, primidone, carbamazepine, rifampicin and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St John’s wort.

Substances with variable effects on the clearance of sex hormones.

When co-administered with COCs, many human immunodeficiency virus (HIV)/hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of estrogen or progestin. These changes may be clinically relevant in some cases.

Substances decreasing the clearance of sex hormones (enzyme inhibitors).

Strong and moderate CYP 3A4 inhibitors like azole antifungals (e.g. ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice can increase plasma concentrations of the estrogen or the progestogen or both.
Etoricoxib doses of 60 to 120 mg/day have been shown to increase plasma concentrations of ethinylestradiol by 1.4 to 1.6-fold respectively, when taken concomitantly with a combined hormonal medicinal product containing 35 microgram ethinylestradiol.

Effects of Primolut N on other medicinal products.

Progestogens may interfere with the metabolism of other drugs. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) or decrease (e.g. lamotrigine).
In clinical studies, administration of a hormonal contraceptive containing ethinylestradiol led to no, or weak increase in CYP3A4 substrates (e.g. midazolam) and a weak (e.g. theophylline) to moderate (e.g. melatonin and tizanidine) increase in CYP1A2.

Pharmacodynamic interactions.

Co-administration of ethinylestradiol-containing medicinal products with direct-acting antiviral (DAA) medicinal products containing ombitasvir, paritaprevir or dasabuvir and combinations of these has been shown to be associated with increases in alanine aminotransferase (ALT) levels to greater than 20 times the upper limit of normal in healthy female subjects and HCV infected women (see Section 4.3 Contraindications).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category D*)
The use of Primolut N during pregnancy is contraindicated.
Studies on reproduction toxicology performed with norethisterone acetate as well as norethisterone enantate led to signs of masculinisation in female fetuses when administered in high doses at the time of the development of the external genitalia. Since epidemiological studies show that this effect is relevant for humans after high dosages, it is to 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.
In animal studies, maternal administration of high doses of synthetic estrogens produced urogenital malformations in the offspring.
* Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
Primolut N should not be used during lactation.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person’s ability to drive and use machines were not assessed as part of its registration.
However, adverse effects of this medicine include visual disturbances, dizziness and somnolence, which could affect the ability to drive or use machines (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Undesirable effects are more common during the first months after start of intake of Primolut N, and subside with duration of treatment. In addition to the adverse effects listed (see Section 4.4 Special Warnings and Precautions for Use), the following undesirable effects have been reported in users of Primolut N although a causal relationship could not always be confirmed.
In the indication of endometriosis, changes in bleeding pattern, including irregular bleeding, scanty bleeding and amenorrhoea may occur.
Other side effects that have been reported in users of Primolut N but for which the association has been neither confirmed nor refuted are seen in Table 1:
The following events, listed in order of seriousness rather than frequency of occurrence, have been associated with the use of progestogens:

Hypersensitivity.

Anaphylaxis and anaphylactoid-like reactions.

Thromboembolic disease.

Thrombophlebitis and pulmonary embolism.

Central nervous system.

Nervousness, insomnia, somnolence, fatigue, depression, dizziness and tremor. Some patients may complain of premenstrual type depression.

Dermatological.

Urticaria, pruritus, rash, acne, hirsutism, alopecia and sweating.

Genitourinary.

Irregular uterine bleeding, spotting and amenorrhoea.

Breast.

Tenderness and galactorrhoea.

Cervix.

Changes in excretions and secretions.

Other.

Hyperpyrexia, Cushing's syndrome, weight gain. Moderate elevation of blood pressure, transient elevation of alkaline phosphatase and/or serum transaminase activities, elevations of serum calcium and potassium levels, and increases in white cell and platelet counts.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Acute toxicity studies performed with norethisterone acetate did not indicate a risk of acute adverse effects in case of inadvertent intake of a multiple of the daily therapeutic dose.
For information on the management of overdose, contact Poisons Information Centre 131126.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Norethisterone is a progestogen with negligible androgenic effects. Complete transformation of the endometrium from a proliferative to a secretory state was achieved in estrogen primed castrated or climacteric women who were administered oral doses of 100-150 mg norethisterone per cycle. The progestogenic effects of norethisterone on the endometrium is the basis of the treatment of dysfunctional bleeding, primary and secondary amenorrhoea and endometriosis with Primolut N.
Gonadotropin secretion inhibition and anovulation can be achieved with a daily intake of 0.5 mg of norethisterone. Positive effects of Primolut N on premenstrual symptoms can be traced back to suppression of ovarian function.
Due to the stabilising effects of norethisterone on the endometrium, administration of Primolut N can be used to shift the timing of menstruation.
Like progesterone, norethisterone is thermogenic and alters the basal body temperature.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

In a single oral dose pharmacokinetic study in 24 healthy postmenopausal women different progesterone preparations were studied. Peak serum concentration after administration of 5 mg Primolut N were 16 ± 5 nanogram/mL; t_max was 1.5 ± 0.6 hours. In a study of 6 women aged 21-23 years, the bioavailability of a single dose of 1 mg norethisterone compared to an equivalent intravenous dose ranged from 47% to 73%, suggesting a significant first pass effect. This study showed that the disposition of norethisterone follows a biexponential pattern with half-lives of 0.4-2.6 and 5-13 hours, respectively. The apparent volume of disposition was 4.28 ± 0.56 L/kg.

Distribution.

Norethisterone is bound to serum albumin and to sex hormone binding globulin (SHBG). Only about 3-4% of the total serum drug concentrations are present as free steroid, about 35% and 61% are bound to SHBG and albumin, respectively. The apparent volume of distribution of norethisterone is 4.4 ± 1.3 L/kg. Following oral administration, the drug serum level time course follows a biphasic pattern.
Both phases are characterised by half-lives of 1-2 and about 5-13 hours, respectively.
Norethisterone is transferred into milk and the drug levels in breast milk were found to be about 10% of those found in maternal plasma.

Metabolism.

Norethisterone is mainly metabolised by saturation of the double bond in ring A and the reduction of the 3-keto group to a hydroxyl group followed by conjugation to the corresponding sulfates and glucuronides. Some of these metabolites are eliminated slowly from plasma, building approximately to a peak at the midpoint of the treatment cycle and rapidly dropping to near baseline levels when treatment is stopped. Norethisterone is partly metabolised to ethinylestradiol after oral administration of norethisterone in humans. This conversion results in an equivalent dose of about 4 microgram ethinylestradiol per 1 mg orally administered norethisterone.

Excretion.

Norethisterone is not excreted unchanged to a significant extent. Predominantly A-ring reduced and hydroxylated metabolites as well as their conjugates (glucuronides and sulfates) are excreted via urine and feces. In a study of radiolabelled norethisterone in 7 women, 37.4% to 80% of the orally administered dose was excreted in the urine over 5 days with a half-life of about 19 hours.

Steady-state conditions.

During multiple dose daily administration with norethisterone, an accumulation of the drug is unlikely because of the relatively short half-life of the drug. If, however, SHBG inducing agents such as ethinylestradiol are coadministered, an increase in norethisterone serum levels can occur because of the binding of norethisterone to SHBG.

5.3 Preclinical Safety Data

Genotoxicity.

The genotoxic potential of norethisterone has not been fully investigated, although it was shown to be negative in the Ames test for reverse gene mutations and in assays for DNA adduct formation and unscheduled DNA synthesis.
There is limited evidence available in the literature suggesting that estrogens may be weakly genotoxic at high doses. Ethinylestradiol was negative in studies for DNA adduct formation in cultured human liver slices and in assays for gene mutations (bacterial or mammalian cells in vitro) and gave equivocal results in assays for chromosomal damage (clastogenic effects were not consistently seen and occurred at high concentrations). In vivo studies did not confirm these results.

Carcinogenicity.

No study has been conducted to examine the carcinogenicity of Primolut N.
Benign hepatic adenomas have been found to be associated with the use of oral contraceptives containing sex hormones such as norethisterone. Although benign, hepatic adenomas may rupture and cause death through intra-abdominal haemorrhage.
It must also be borne in mind that sexual steroids can promote the growth of certain hormone dependent tissues and tumours. Women with a strong family history of breast cancer or who have breast nodules, fibrocystic disease or abnormal mammograms should be monitored with particular care (also see Section 4.4 Special Warnings and Precautions for Use).
Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis and liver. The clinical relevance of these findings is uncertain.

6 Pharmaceutical Particulars

6.1 List of Excipients

Primolut N also contains the inactive excipients lactose monohydrate, maize starch, magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Primolut N tablets are available in PVC/Al blister packs of 30 or 100 tablets.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Norethisterone is 17 β-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one. C₂₀H₂₆O₂. MW=298.4. Norethisterone is a white or yellowish-white odourless crystalline powder. It is practically insoluble in water; slightly to sparingly soluble in alcohol; soluble in chloroform and in dioxan; slightly soluble in ether.

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Primolut N Tablets 5 mg