Consumer medicine information

Primolut N

Norethisterone

BRAND INFORMATION

Brand name

Primolut N

Active ingredient

Norethisterone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Primolut N.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Primolut N. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Primolut N against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist for more advice.

Keep this leaflet with the medicine. You may need to read it again.

WHAT PRIMOLUT N IS USED FOR

Primolut N contains a hormone, norethisterone. This type of hormone is similar to the natural female hormone progesterone. Some of the information in this leaflet is based on experience with estrogen containing oral contraceptives as some of the active ingredient in Primolut N is converted to estrogen in the body.

However, Primolut N is not to be used as a contraceptive 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)

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

BEFORE YOU TAKE PRIMOLUT N

When you must not take it

Do not take Primolut N if you have an allergy to:

  • norethisterone, the active ingredient in Primolut N
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

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.

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 Primolut N if 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)
  • other parts of the body

Do not take Primolut N if 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.

Do not take Primolut N if 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.

Do not take Primolut N if 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).

Do not take Primolut N if you have or have had:

  • angina (chest pain)
  • mini stroke (also known as a TIA or transient ischaemic attack)
  • high risk of blood clots due to conditions such as diabetes with blood vessel damage, severe high blood pressure
  • migraine, where you have also had problems with seeing, speaking or had weakness or numbness in any part of your body
  • severe liver disease and your liver function values have not returned to normal
  • a benign or malignant liver tumour.
  • cancer that may grow under the influence of sex hormones (e.g. of the breast or the genital organs)
  • a condition causing an increase in the breakdown of red blood cells in the body (Dubin-Johnson syndrome or Rotor syndrome)
  • vaginal bleeding or blood in your urine for which a cause has not been identified
  • breast disease for which a cause has not been identified.
  • 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.

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.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if:

  • you smoke
  • you 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.

Tell your doctor if you have or have had any of the following medical conditions:

  • diabetes
  • high blood pressure
  • liver disease or a liver tumour you have a history of depression with hallucinations, delusions
  • epilepsy
  • migraine
  • asthma
  • kidney disease
  • heart disease.

Ask your doctor to check if you:

  • 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 – you should see your doctor immediately if you experience symptoms of 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 tell your doctor.

If you have not told your doctor about any of the above, tell him/her before you start taking Primolut N.

What happens once you stop taking Primolut N

There are no specific withdrawal symptoms if you stop Primolut N but there is the possibility that the original complaints might re-occur.

Taking other medicines

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

Some medicines and Primolut N may interfere with each other. 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 medicines, or prescribe a different medicine.

Your doctor and pharmacist have more information on medicines that you need to be careful with or avoid while taking this medicine.

HOW TO TAKE PRIMOLUT N

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the pack ask your doctor or pharmacist for help.

How to take it

Swallow each tablet whole with a glass of water. It does not matter if you take it before or after food.

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.

How long to take it

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.

If you forget to take it

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

Do not take a double dose to make up for forgotten individual doses.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (Australia: 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Primolut N.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

WHILE YOU ARE TAKING PRIMOLUT N

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Primolut N. Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. 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 or pelvis, neurosurgery, or major trauma), your doctor may tell you to stop taking (in the case of elective surgery at least four 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 become pregnant while taking this medicine, tell your doctor immediately.

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.

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.

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

Contact your doctor as soon as possible if you:

  • 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.

Things you must 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 side effects.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Primolut N.

This medicine helps most people, but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

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 the absence of bleeding may occur.

Tell your doctor if you notice any of the following and they worry you:

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

The following events have been associated with the use of progestogens:

  • severe allergy 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
  • dizziness
  • 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

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

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 occurence and can develop whether or not you are taking Primolut N.

If you notice possible 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.

AFTER TAKING PRIMOLUT N

Storage

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.

Do not store it or any other medicine in the bathroom, near a sink, or on a window-sill. Do not leave it in the car. Heat and damp can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a half metres above the ground is a good place to store medicines.

Disposal

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.

Return any unused medicine to your pharmacist.

PRODUCT DESCRIPTION

What it looks like

Primolut N comes in a box containing 3 blister packs. Each blister pack contains 10 white tablets marked with “AN” inside a hexagon.

Ingredients

Active ingredients per tablet:

  • 5 mg of norethisterone

Inactive ingredients:

  • lactose monohydrate
  • maize starch
  • magnesium stearate

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

Supplier

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

Australian registration number

Primolut N (blisters) – AUST R 134491

Date of Preparation

June 2018

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

® Registered Trademark of the Bayer Group, Germany
© Bayer Australia Ltd
All rights reserved.

Published by MIMS March 2019

BRAND INFORMATION

Brand name

Primolut N

Active ingredient

Norethisterone

Schedule

S4

 

1 Name of Medicine

Primolut N (norethisterone).

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.

Chemical structure.


CAS number.

CAS 68-22-4.

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.

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; tmax 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.

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.

4.3 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.

4.8 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.

4.2 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.

4.7 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)).

4.9 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.

7 Medicine Schedule (Poisons Standard)

S4.

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.

Summary Table of Changes