Consumer medicine information

Brevinor 28 Day

Ethinylestradiol; Norethisterone

BRAND INFORMATION

Brand name

Brevinor, Brevinor-1

Active ingredient

Ethinylestradiol; Norethisterone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Brevinor 28 Day.

What is in this leaflet

This leaflet answers some common questions about Brevinor 28 Day tablets.

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 Brevinor against the benefits it is expected to have for you.

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

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

What Brevinor is used for

Brevinor is a combined oral contraceptive, commonly known as a "birth control pill" or "the Pill". It contains both an oestrogen (ethinylestradiol) and progestogen (norethisterone) hormone.

Oral contraceptives belonging to this group produce their birth control (or contraceptive) effect by preventing ovulation (the release of an egg from the ovary) during each menstrual cycle. Combined oral contraceptives also cause changes to the mucus of the cervix and the lining of the womb which contribute to the contraceptive action.

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

Brevinor is only available on a prescription from your doctor.

This medicine is not expected to affect your ability to drive a car or operate machinery.

Before you start to take Brevinor

When you must not take it

Do not take Brevinor if you have an allergy to:

  • any medicine containing ethinylestradiol or norethisterone
  • any of the ingredients listed at the end of this leaflet
  • any other similar medicines (such as other oral contraceptives).

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 Brevinor if you have or have had any of the following medical conditions:

  • venous thromboembolism (VTE) and are on medicines called anticoagulants which are used to "thin the blood"
  • blood clots or a history of blood clots in the:
    - legs (thrombophlebitis or deep vein thrombosis (DVT)),
    - lungs (pulmonary embolism)
    - eyes.
  • hereditary or an acquired disposition for venous thromboembolism
  • multiple risk factors VTE including obesity, age above 35 years, smoking, high cholestrol
  • major surgery and have been confined to bed for long periods of time
  • arterial thromboembolism (ATE) or a past history of these that include:
    - stroke
    - angina
    - transient ischaemic attack or "mini stroke".
  • hereditary or an acquired disposition for ATE
  • history of migraine, accompanied by blurred vision, difficulty in speaking, muscle weakness, or increased sensitivity to light, sound, or noise
  • multiple risk factors for ATE or a serious risk factor for ATE that include:
    - uncontrolled high blood pressure
    - diabetes with blood vessel damage
    - severe lipid disease
    - sickle cell anaemia.
  • disease in any blood vessel(s)
  • inflammation of the pancreas which is associated with very high blood levels of triglycerides (fatty substances)
  • liver disease (including tumours of any type), a history of jaundice or cholestatic jaundice of pregnancy, or severe generalised itch in the body during pregnancy, Dubin-Johnson Syndrome or Rotor Syndrome
  • vaginal bleeding, the cause of which is unknown
  • pregnant or suspect that you may be pregnant
  • cancer or suspected cancer of the breast or sex organs (e.g. cervix, vagina, ovaries, endometrium, womb) and known or suspected oestrogen-dependent tumours
  • a family history of breast nodules, fibrocystic disease or have had an abnormal mammograph
  • a history of herpes of pregnancy
  • otosclerosis (an ear disorder) which worsened in past pregnancies.

If you are not certain whether these may apply to you, or you are worried by anything in this list, tell your doctor.

Do not take this medicine if you are taking anti-viral hepatitis C virus (HCV) medicinal products containing ombitasvir/ paritaprevir/ritonavir and dasabuvir with or without ribavirin. If you are not sure about your anti-HCV medication, tell your doctor.

Tell your doctor about any existing medical condition as this may be affected by taking the birth control pill.

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

Before you start to take it

You must have a thorough medical check-up, including a Pap smear, breast check, blood pressure check and urine test.

You must tell your doctor if you or anyone in your immediate family has, or has had blood clots in the legs or lungs. Blood clots are a rare occurrence when taking an oral contraceptive.

The risk of a blood clot is highest during the first year of taking an oral contraceptive for the first time or if you are re-starting the "pill" after a break of 4 weeks or more.

The risk of having a blood clot is higher in oral contraceptive users than in non-users, but is not as high as during pregnancy.

Tell your doctor about any of the following conditions as these are risk factors for developing blood clots:

  • cancer
  • systemic lupus erythematosus (SLE)
  • haemolytic uraemic syndrome (HUS) - a disorder of blood coagulation causing failure of the kidneys)
  • Crohn's disease or ulcerative colitis (chronic inflammatory bowel disease)
  • sickle cell disease
  • smoking particularly if you are heavy smoker (15 or more cigarettes per day) and are aged over 35 years
  • have had any recent surgery or trauma
  • are pregnant
  • had major surgery and have been confined to bed for long periods of time
  • also tell your doctor if you are planning a long haul plane flight (greater than 4 hours).

You must tell your doctor if you or anyone in your immediate family has, or has had a stroke or heart attack. Taking oral contraceptives is linked with an increased risk of having a heart attack, angina, stroke or a "mini stroke".

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

  • heart disease including heart valve disorders or certain heart rhythm disorders
  • high blood pressure
  • high cholesterol
  • Hepatitis C
  • diabetes
  • migraine or other headaches
  • hyperhomocysteinemia.

Tell your doctor if over 35 years of age or are overweight. If you are not certain whether any of the above may apply to you, check with your doctor.

Tell your doctor if you have the following conditions:

  • Breast lumps, abnormal breast X-ray or mammogram
  • gallbladder disease
  • liver, kidney or heart disease
  • epilepsy
  • asthma
  • experience a change in vision or intolerance to your contact lenses. Your doctor may refer you to an eye specialist
  • depression
  • Hereditary angioedema.

If you have any of these conditions you should have regular check-ups with your doctor to make sure that taking Brevinor is not making the conditions worse.

Tell your doctor if you plan to become pregnant or are breastfeeding. Your doctor can discuss the risks and benefits involved with you.

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

Brevinor contains lactose. If you know that you are intolerant to some sugars, or your doctor has told you so, speak to your doctor before taking it.

Tell your doctor if you are allergic to any foods, dyes, preservatives or any other medicines.

Taking other medicines

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

Some medicines may interfere with the effectiveness of Brevinor. These include medicines such as:

  • anti-viral hepatitis C virus (HCV) medicines such as ombitasvir, paritaprevir, ritonavir and dasabuvir
  • rifampicin and rifabutin for the treatment of tuberculosis
  • antibiotics such as ampicillin, oxacillin, tetracyclines, sulfamethoxazole and trimethoprim
  • anti-fungal agents such as griseofulvin
  • barbiturates (medicines prescribed for epilepsy, such as phenobarbitone)
  • medicines for epilepsy such as phenytoin, primidone, carbamazepine and topiramate
  • Ritonavir for the treatment of HIV infection
  • Modafinil used to treat excessive daytime sleepiness
  • Corticosteroids such as dexamethasone.
  • St John's wort, an ingredient found in medicines you can purchase without a prescription from a pharmacy, supermarket or health food shop.

While you are taking these medicines, and for seven days after stopping them, you must use a non-hormonal method of contraception (such as condoms or a diaphragm, but not the rhythm or temperature methods). If the seven days extend into the inactive orange tablet section, then you should start a new pack on the next day after having taken the last blue active tablet from the current pack. Skip the 7 orange tablets.

This is particularly important if you need to take antibiotics or medicines for epilepsy.

Ask your doctor or pharmacist about how long you need to use additional non-hormonal contraception.

Tell your doctor or pharmacist if you are taking any of the following:

  • Atorvastatin used to treat high cholesterol
  • Indinavir for the treatment of HIV infection
  • Anti-fungal medicines such as itraconazole and fluconazole
  • Paracetamol and ascorbic acid (Vitamin C)
  • Cyclosporin used to prevent organ rejection
  • Theophyllines used for asthma and other breathing difficulties
  • Corticosteroids
  • Lamotrigine for seizures.

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking Brevinor. Your doctor and pharmacist have more information on medicines to be careful with or avoid while you are taking this medicine.

How to take Brevinor

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 box, ask your doctor or pharmacist for help.

How to take it

Swallow one Brevinor tablet with a glass of water.

When to take Brevinor

You must take Brevinor every day, regardless of how often you have sex.

Brevinor will work best if you do not miss any tablets and take it at the same time each day. Taking Brevinor at the same time each day will also help you remember when to take your tablets.

If you are concerned about this, please speak to your doctor or pharmacist.

Starting a hormonal contraceptive for the first time

  • To begin Brevinor 28 Day, take your first tablet on the first day of your next period, that is, the day your bleeding starts.
  • Take your first tablet from the top row of the green section of the strip (i.e. the section which contains all the blue tablets). Take the tablet which corresponds to the appropriate day of the week. For example, if your first day of bleeding is on TUESDAY, take the blue tablet marked "TUE" from the top row of the green section of the strip.
  • Continue to take one tablet every day, following the arrows around the strip, until you finish all 21 blue tablets in the green section of the strip.
  • Then take one orange tablet daily for the next 7 days, following the arrows so that you are taking the correct tablet for the day of the week. Taking these orange tablets helps you to remember to take a tablet every day.
    You can expect your period during the week that you are taking these orange inactive tablets. Your protection continues during this week.
  • On the day after your last orange tablet, begin the next strip with a blue tablet from the top row of the green section that matches the day of the week. Do this even if you are still bleeding.
  • You should start your tablets the same day of the week every 4 weeks.
  • Repeat this sequence of tablet taking for as long as birth control is required.

This product is effective from the first day if taken as directed above.

Although spotting and break-through bleeding may occur in some women, these tend to disappear in the majority of patients after the first three to four cycles.

Make sure you always have a new strip of tablets available, so that you can continue to take the tablets without interruption.

Changing from a different oral contraceptive

If you are switching to Brevinor 28 Day from another 21 or 28 Day oral contraceptive, follow the instructions below carefully.

If switching from a 21 day oral contraceptive:

  • Stop taking your current oral contraceptive after you have taken the last active tablet.
  • Leave 7 tablet-free days.
  • Start the new Brevinor 28 Day pack on the eighth day by taking a blue active tablet from the top row of the green section which corresponds to the day of the week.
  • Continue to take one tablet every day, following the arrows around the strip until you finish all 21 blue tablets in the green section of the strip.
  • Then take one orange tablet daily for the next 7 days, before starting your new strip.

You must use an additional, non-hormonal method of contraception (such as condoms or a diaphragm, but not the rhythm or temperature methods) until a blue tablet has been taken daily for 7 days without a break.

If switching from a 28 day oral contraceptive:

  • Stop taking your current oral contraceptive after you have taken the last inactive tablet in the strip.
  • Start the new Brevinor 28 Day pack on the next day by taking a blue active tablet from the top row which corresponds to the day of the week.
  • Continue to take one tablet every day, following the arrows around the strip until you finish all 21 blue tablets in the green section of the strip.
  • Then take one orange tablet daily for the next 7 days, before starting your new strip.

You must use an additional, non-hormonal method of contraception (such as condoms or a diaphragm, but not the rhythm or temperature methods) until a blue tablet has been taken daily for 7 days without a break.

If you vomit or have diarrhoea after taking Brevinor

If you suffer from a stomach upset which results in vomiting or diarrhoea, the effectiveness of Brevinor may be reduced.

During any period of vomiting or diarrhoea, continue taking Brevinor tablets. Also use a non-hormonal method of contraception (such as condoms or a diaphragm, but not the rhythm or temperature methods), and continue for seven days following the episode of vomiting or diarrhoea. If these seven days extend into the inactive orange tablet section you should start a new pack on the next day after having taken the last active blue tablet from the green section of the current pack (i.e. skip the orange inactive tablets).

You may not have a period until you finish the second pack.

If you have vomiting or diarrhoea after taking an orange tablet, do not worry.

If you forget to take a tablet

If you forget to take Brevinor it may not work as well in protecting you from becoming pregnant.

Do not try to make up for missed doses by taking more than one tablet at a time.

If you miss a blue active tablet:

If you are less than 12 hours late in taking your tablet, you should take that tablet at once and then take the next one at your usual time.

If you are more than 12 hours late in taking your tablet, do not take it.

Take the next day's tablet at the usual time and use an additional, non-hormonal method of contraception for the next seven days (such as condoms or a diaphragm, but not the rhythm or temperature methods).

If the seven days extend into the inactive orange tablet section, start a new pack on the day after taking the last blue active tablet from the current pack. Take your first tablet from the top row of the new strip, then repeat the sequence of tablet taking for as long as birth control is required. This will mean that you will not have a period until you finish the second pack.

If you miss more than one blue tablet, contact you doctor for advice on what to do.

If you miss an orange inactive tablet, take it as soon as you remember and continue on as before. Additional birth control method is not necessary in this case.

If your doctor told you to take Brevinor differently, or you are unclear about the above directions, discuss this with him or her.

If you have trouble remembering to take Brevinor, ask your pharmacist for some hints.

If you miss a period

If you have missed a period you may be pregnant.

Contact your doctor to check if you are pregnant.

If you take too much (overdose)

Immediately telephone your doctor or pharmacist or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital if you think you or anyone else may have taken too much Brevinor. Do this even if there are no signs of discomfort or poisoning.

Serious ill effects have not been reported in young children who have taken large doses of birth control pills.

Overdosage may cause nausea. This may be followed by vaginal bleeding in some women.

While you are taking Brevinor

Things you must do

Tell all doctors, dentists and pharmacists who are treating you that you are taking Brevinor.

Tell the hospital doctor that you are taking Brevinor birth control pills if you need to have an operation, or go to hospital in an emergency.

If you are about to be started on any new medicine, tell your doctor or dentist and your pharmacist that you are taking Brevinor.

If you become pregnant while taking Brevinor, see your doctor immediately.

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

Visit your doctor regularly for check-ups, including a Pap smear. A pap smear can detect any abnormal cells from the cervix, which may develop into cancer. Cervical cancer has been reported to occur more frequently in women who use oral contraceptives.

Your doctor will advise you of the type and frequency of any tests required.

Perform regular breast self-examination Examining your breasts for lumps or any changes in size or shape can help you find a breast cancer early. Breast cancer has been found more frequently in women who use oral contraceptives. It is not known whether this increase is caused by the use of oral contraceptives, or if it is due to the fact that users were examined more often, and therefore the breast cancer was detected earlier.

If you are unsure, ask your doctor about breast self-examination.

Tell your doctor you are taking Brevinor at least 4 weeks before any planned hospitalisation or surgery. Your doctor may tell you to stop taking Brevinor several weeks before surgery or at the time of immobilisation. Your doctor will tell you when you can start taking Brevinor after you are back on your feet.

To avoid pregnancy during this time you must use a non-hormonal method of contraception such as condoms or a diaphragm.

If you are worried about contracting a sexually transmitted disease (STD) use a barrier contraceptive method. Brevinor does not protect against the transmission of STDs such as HIV-AIDS, chlamydia, genital herpes and warts, gonorrhoea, hepatitis B or human papilloma virus. To protect against STDs ask your partner to wear a condom when having sexual intercourse with you.

Tell your doctor if you feel depressed, think you are retaining water, experience headaches, experience persistent or recurrent irregular bleeding or your eyes are uncomfortable whilst wearing contact lenses. Your doctor will make an assessment of your condition and advise whether or not you should continue to take Brevinor.

Things you must not do

Do not take Brevinor to treat any other complaints 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 Brevinor, or change the dosage, without checking with your doctor. If you stop taking Brevinor or do not take a tablet every day, without using another form of contraception, you may become pregnant.

Things to be careful of

Slight breast tenderness or a feeling of sickness may occur in the first few months of use. This usually improves or stops with continued use.

If vaginal irritation or discharge occurs, it may be an indication of yeast infection for which treatment is available from your doctor.

Side effects

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

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

It can be difficult to tell whether side effects are the result of taking Brevinor or are side effects of another medicine you are taking.

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

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

Tell your doctor if...

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

  • changes in bleeding patterns, including break-through bleeding
  • spotting
  • Painful periods
  • absence of periods, but if you have not taken Brevinor as directed you should check whether you are pregnant
  • gastric or stomach discomforts including abdominal pain, cramps, bloating, nausea, vomiting and diarrhoea
  • change in menstrual flow
  • change in cervical secretions
  • change in weight
  • Swelling of the hands, ankles or feet
  • dark discolouration of the skin
  • blotchy discolouration on the face or limbs (which may persist after the tablets have been stopped)
  • breast changes (tenderness, enlargement and secretion)
  • headache, including migraines
  • nervousness, dizziness
  • mood change, including depression
  • fatigue or tiredness
  • hair growth or loss of scalp hair
  • increase in body hair
  • acne, rashes, itching
  • leg cramps
  • back ache
  • change in sexual drive
  • vaginal thrush(Candida), vaginal irritation, change in mucus from the vagina
  • pre-menstrual-like symptoms
  • suppression of milk production
  • contact lenses becoming uncomfortable to wear
  • change in appetite.

The above list includes the more common side effects of your medicine.

Tell your doctor as soon as possible if...

Tell your doctor as soon as possible if you notice any worsening of conditions that you may already have such as:

  • Chorea (involuntary muscle spasm)
  • Porphyria
  • Systemic lupus erythematosus (Lupus)
  • Varicose veins
  • gallbladder disease
  • kidney disease
  • hereditary angioedema (swelling of the face lips, mouth tongue or throat.

Go to hospital if...

Tell your doctor immediately, or go to accident and emergency at your nearest hospital if you notice any of the following:

  • unexplained or persistent pains in the head, chest, arm or below the breastbone
  • severe pain, swelling or discolouration in either of your legs
  • shortness of breath
  • rapid or irregular heartbeat
  • blurred or double vision
  • partial or complete loss of sight
  • eye protrusion, swelling of the eye or eye lesions
  • dizziness or fainting, sometimes with loss of balance
  • sweating, nausea or vomiting
  • an unusual cough
  • weakness or numbness in any part of your body
  • discomfort radiating to the back, jaw, throat or stomach
  • confusion, trouble speaking or understanding
  • bloody diarrhoea
  • abdominal pain
  • fever
  • feeling of indigestion or choking
  • rectal bleeding
  • feeling tired
  • lose your appetite or lose weight
  • migraine headaches for the first time
  • more frequent or severe migraines if you already suffer from them
  • breast lumps
  • jaundice or a yellowing of the skin or eyes, often with fever, fatigue, loss of appetite, dark coloured urine, nausea and vomiting. Taking oral contraceptives may be associated with liver disease including liver cancer
  • rise in blood pressure. You may experience headache, blurred vision or palpitations. Sometimes your blood pressure may rise without you experiencing any of these symptoms. It is important to keep your routine doctor's appointments so that your blood pressure can be checked
  • swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing.

Whilst these side effects are rare, they are serious. You may need urgent medical attention or hospitalisation.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

After stopping Brevinor

Delays in becoming pregnant may occur after Brevinor therapy is stopped. This is more likely to occur in women whose periods were irregular before using birth control pills.

See your doctor if you continue to experience difficulties in falling pregnant.

After taking Brevinor

Storage

Keep your tablets in a safe place away from the sight and reach of children. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep your Brevinor tablets in a dry place, at a temperature below 25°C. Do not keep your tablets in the refrigerator.

Do not store Brevinor or any other medicine in the bathroom or near a sink. Do not leave it in the car on hot days or on window sills. Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking Brevinor or if the tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

Brevinor 28 Day is available in calendar packs consisting of four strips of tablets (4 months' supply) each with 21 blue active tablets marked "SEARLE" on one side and "BX" on the other, and 7 orange inactive tablets.

Ingredients

Each blue tablet contains

  • norethisterone 500 micrograms (mcg)
  • ethinylestradiol 35 micrograms (mcg)
  • magnesium stearate
  • povidone
  • maize starch
  • lactose monohydrate
  • indigo carmine CI 73015.

The orange inactive tablets contain

  • magnesium stearate
  • cellulose microcrystalline
  • lactose
  • sunset yellow FCF (CI No. 15985).

Brevinor contains lactose.

Brevinor does not contain sucrose, gluten or tartrazine.

Australian Registration Number

AUST R 62132

Supplier

Pfizer Australia Pty Ltd
Sydney, NSW
Toll Free number: 1800 675 229
www.pfizer.com.au

Date of preparation

This leaflet was prepared in January 2020.

®Registered trademark.

Published by MIMS March 2020

BRAND INFORMATION

Brand name

Brevinor, Brevinor-1

Active ingredient

Ethinylestradiol; Norethisterone

Schedule

S4

 

1 Name of Medicine

Norethisterone and ethinylestradiol.

6.7 Physicochemical Properties

Norethisterone is a progestogen. It is a white to creamy-white odourless crystalline powder with a slightly bitter taste, insoluble in water and sensitive to light.
Ethinylestradiol is an estrogen. It is a fine, white odourless, crystalline powder almost insoluble in water and sensitive to light.

Chemical structure.


CAS number.

Norethisterone: 68-22-4; Ethinylestradiol: 57-63-6.

2 Qualitative and Quantitative Composition

Brevinor 28 day tablets.

Each blue active tablet contains norethisterone 500 microgram and ethinylestradiol 35 microgram. Each orange tablet is a placebo tablet.

Brevinor-1 28 day.

Each white active tablet contains norethisterone 1 mg and ethinylestradiol 35 microgram.
Each orange tablet is a placebo tablet.

Excipients with known effect.

Brevinor 28 day tablets.

Blue tablets: Lactose monohydrate.
Orange tablets: Lactose, lactose monohydrate.

Brevinor-1 28 day.

White tablets: Lactose monohydrate.
Orange tablets: Lactose, lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablet.

Brevinor 28 day.

Each blister contains 21 blue active tablets and 7 orange placebo tablets.

Brevinor-1 28 day.

Each blister contains 21 white active tablets and 7 orange placebo tablets.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pharmacological class: synthetic steroidal combination oral contraceptives (COC).
Estrogenic, progestational and antigonadotrophic characteristics are revealed by the endocrine profile of these combinations.
Like other combination type pills (estrogen and progestogen combination), Brevinor and Brevinor-1 produce a contraceptive effect primarily by suppressing the hypothalamic pituitary system resulting in prevention of ovulation. The estrogenic compound, ethinylestradiol acts by suppressing secretion of follicle stimulating hormone (FSH), resulting in prevention of follicle development and the rise of plasma estradiol which is thought to be the stimulus for releasing luteinising hormone (LH). The progestogenic compound, norethisterone, primarily acts by inhibiting the preovulatory rise of LH. Long-term administration of combination type oral contraceptives may also produce a direct effect on ovarian steroidogenesis or the response of the ovary to gonadotrophins. Although the primary mechanism of action is inhibition of ovulation, alterations in the genital tract including changes in the cervical mucus (which increase the difficulty of sperm penetration) and the endometrium (which reduce the likelihood of implantation) may also contribute to contraceptive effectiveness.

Clinical trials.

Different pregnancy and adverse reaction rates have been reported with the use of each oral contraceptive. In as much as these rates are usually derived from separate studies conducted by different investigators in several population groups, they cannot be compared with precision. Furthermore, pregnancy and adverse reaction rates tend to be lower as clinical experience is expanded, possibly due to retention in the clinical study of those patients who accept the treatment regimen and did not discontinue due to adverse reactions or pregnancy.
In clinical trials with Brevinor tablets, 1,168 patients completed 16,345 cycles of use, and a total of three pregnancies were reported. In each case, the tablets were not taken as directed. This represents a pregnancy rate of 0.22 per 100 women years. In clinical trials with Brevinor-1 tablets, 940 patients completed 14,366 cycles of use and a total of two pregnancies were reported. In each case, the tablets were not taken as directed. This represents a pregnancy rate of 0.17 per 100 women years.

5.2 Pharmacokinetic Properties

Absorption.

Studies using 14C labelled compounds have shown that both norethisterone and ethinylestradiol are rapidly absorbed from the gastrointestinal tract.

Metabolism/excretion.

Following oral administration, metabolites of both compounds appear in the urine as conjugated glucuronides and sulfates, with unconjugated metabolites appearing in the faeces.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

4 Clinical Particulars

4.1 Therapeutic Indications

Contraception.

4.3 Contraindications

Brevinor or Brevinor-1 should not be used in the presence of any of the conditions listed below. Should any of the conditions appear for the first time during Brevinor or Brevinor-1 use, the product should be stopped immediately.
Presence or risk of venous thromboembolism (VTE) (see Section 4.4 Special Warnings and Precautions for Use):
current VTE (on anticoagulants) or history of deep venous thrombosis (DVT) or pulmonary embolism (PE) or other thrombotic disorder;
known hereditary or acquired predisposition for venous thromboembolism, such as APC resistance (including factor V Leiden), antithrombin-III deficiency, protein C deficiency, protein S deficiency;
major surgery with prolonged immobilisation;
a high risk of venous thromboembolism due to the presence of multiple risk factors.
Presence or risk of arterial thromboembolism (ATE) (see Section 4.4 Special Warnings and Precautions for Use):
current ATE or history of ATE (e.g. myocardial infarction or stroke) or prodromal condition (e.g. angina pectoris or transient ischaemic attack (TIA));
known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid antibodies (e.g. anticardiolipin antibodies and lupus anticoagulant);
headaches with focal neurological symptoms (such as aura) including haemiplegic migraine;
a high risk of arterial thromboembolism due to multiple risk factors or to the presence of one serious risk factor such as diabetes mellitus with vascular symptoms, uncontrolled hypertension, severe dyslipoproteinaemia, sickle cell anaemia.
Pancreatitis or a history thereof if associated with severe hypertriglyceridemia.
Presence or history of active hepatic disease as long as liver function values have not returned to normal, history of cholestatic jaundice or pruritus in pregnancy, jaundice with oral contraceptive use, Dubin-Johnson syndrome, Rotor syndrome.
Presence or history of liver tumours (benign or malignant).
Known or suspected sex steroid influenced malignancies (e.g. of the genital organs or the breasts).
Undiagnosed vaginal bleeding.
Known or suspected pregnancy.
History of herpes in pregnancy, history of otosclerosis with exacerbations in pregnancy.
Combined oral contraceptives (COCs) are contraindicated for concomitant use with certain anti-viral hepatitis C virus (HCV) medicinal products such as ombitasvir, paritaprevir, ritonavir and dasabuvir (see Section 4.4 Special Warnings and Precautions for Use, Hepatic neoplasia/liver disease/hepatitis C; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Hypersensitivity to any of the ingredients contained in Brevinor or Brevinor-1.

4.4 Special Warnings and Precautions for Use

If any of the conditions/ risk factors mentioned below are present, the benefits of Brevinor or Brevinor-1 should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start taking it. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her doctor. The doctor should then decide whether Brevinor or Brevinor-1 should be discontinued.

Circulatory disorders.

Epidemiological studies have suggested an association between the use of COCs containing ethinylestradiol and an increased risk of venous and arterial thrombotic and thromboembolic events, such as myocardial infarction, stroke, deep venous thrombosis, and pulmonary embolism. These events occur rarely in average-risk women.
For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient.

Venous thrombosis and thromboembolism.

The physician should be alert to the earliest manifestations of those disorders (e.g. pulmonary embolism, cerebrovascular insufficiency, cerebral haemorrhage, cerebral thrombosis, coronary occlusion, retinal thrombosis, mesenteric thrombosis). Should any of these occur or be suspected; the medicine should be discontinued immediately.

Risk of venous thromboembolism (VTE).

The use of any COC increases the risk of VTE compared with no use. The women considering using Brevinor or Brevinor-1 should be advised that her VTE risk is highest in the first ever year of use and that there is some evidence that the risk is increased when a COC is restarted after a break in use of 4 weeks or more.
It is important that women understand that VTE associated with COC use is rare in average risk women. The risk in pregnancy (5-20 per 10,000 women over 9 months) and the risk in the postpartum period (45-65 per 10,000 women over 12 weeks) is higher than that associated with COC use. The risk of VTE with the COC is greatest for products containing over 50 microgram of ethinylestradiol. There is less risk for products such as Brevinor or Brevinor-1 containing less than 35 microgram ethinylestradiol. Products that contain the progestagen norethisterone are associated with the lowest risk of VTE. The lowest dose of norethisterone tolerated should be prescribed.
The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with COCs, and how her current risk factors influence this risk. (See Table 1.)
The increased risk of VTE during the postpartum period must be considered if restarting Brevinor or Brevinor-1 at this time.
VTE is a serious condition and may be fatal in 1-2% of cases. Extremely rarely, thrombosis has been reported to occur in COC users in other blood vessels, e.g. hepatic, mesenteric, renal or retinal veins and arteries.
The risk for venous thromboembolic complications in COC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see list below).
Brevinor or Brevinor-1 is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis. If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors, in this case her total risk of VTE should be considered. If the balance of benefits and risks is considered to be negative a COC should not be prescribed.

Risk factors for VTE.

The risk of venous thrombotic and thromboembolic events is further increased in women with conditions predisposing for venous thrombosis and thromboembolism. Examples of predisposing conditions for venous thrombosis and thromboembolism are:
Obesity (body mass index over 30 kg/m2). Risk increases substantially as BMI rises.
Prolonged immobilisation, major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma.
Temporary immobilisation including air travel > 4 hours can also be a risk factor for VTE, particularly in women with other risk factors.
Positive family history (venous thromboembolism ever in a sibling or parent especially at a relatively early age, e.g. before 50).
Biochemical factors activated protein C (APC) resistance (including factor V Leiden), antithrombin-III deficiency, protein C deficiency, protein S deficiency.
Other medical conditions associated with VTE: cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis), sickle cell disease.
Increasing age, particularly above 35 years.
Smoking.
Recent delivery or second trimester abortion.
In women at risk of prolonged immobilisation (including major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma), it is advisable to discontinue use of Brevinor or Brevinor-1 (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Another method of contraception should be used to avoid unintentional pregnancy. Antithrombotic treatment should be considered if Brevinor or Brevinor-1 has not been discontinued in advance.
If a hereditary predisposition to VTE is suspected, the woman should be referred to a specialist for advice before deciding about any COC use.
The increased risk of VTE during the postpartum period should be considered if re-starting Brevinor or Brevinor-1. Since the immediate post-partum period is associated with an increased risk of thromboembolism, combined oral contraceptives should be started no earlier than day 28 after delivery in a non-lactating woman, or second-trimester abortion.
There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism.

Symptoms of VTE (deep vein thrombosis and pulmonary embolism).

Women should be informed of the symptoms of VTE and be advised to seek urgent medical attention if VTE symptoms develop and to inform the healthcare professional that she is taking a COC.
Symptoms of deep vein thrombosis (DVT) can include:
unilateral swelling of the leg and/or foot or along a vein in the leg;
pain or tenderness in the leg which may be felt only when standing or walking;
increased warmth in the affected leg; red or discoloured skin on the leg.
Symptoms of pulmonary embolism (PE) can include:
sudden onset of unexplained shortness of breath or rapid breathing;
sudden coughing which may be associated with haemoptysis;
sharp chest pain;
severe light headedness or dizziness;
rapid or irregular heartbeat.
Some of these symptoms (e.g. “shortness of breath”, “coughing”) are nonspecific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections).
Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity.
If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately.

Risk of arterial thromboembolism (ATE).

Epidemiological studies have associated the use of COCs with an increased risk for arterial thrombotic and thromboembolic events (e.g. myocardial infarction, angina pectoris, and cerebrovascular events, such as ischaemic and haemorrhagic stroke or TIA). Arterial thromboembolic events may be fatal.
The risk of arterial thrombotic and thromboembolic complications in COC users further increases in women with risk factors. Brevinor or Brevinor-1 is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis. If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors, in this case her total risk should be considered. If the balance of benefits and risks is considered to be negative a COC should not be prescribed.

Risk factors for ATE.

Caution must be exercised when prescribing COCs for women with risk factors for arterial thrombotic and thromboembolic events, such as:
Increasing age, particularly above 35 years.
Smoking.
Hypertension.
Hyperlipidaemias.
Obesity.
Positive family history (arterial thromboembolism ever in a sibling or parent especially at relatively early age, e.g. below 50).
Biochemical factors: hyperhomocysteinaemia and antiphospholipid antibodies (e.g. anticardiolipin antibodies, and lupus anticoagulant).
Migraine.
Other medical conditions associated with adverse vascular events: diabetes mellitus, hyperhomocysteinaemia, valvular heart disease, atrial fibrillation, dyslipoproteinaemia, systemic lupus erythematosus.
History of pre-eclamptic toxaemia.
Cigarette smoking increases the risk of serious cardiovascular adverse reactions from COC use. This risk increases with age and with the extent of smoking (in epidemiology studies, smoking 15 or more cigarettes per day was associated with a significantly increased risk), and is quite marked in women over 35 years of age. Women should be advised not to smoke if they wish to use a COC. Women over 35 years of age who continue to smoke should be strongly advised to use a different method of contraception.
If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any COC use.
An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation.

Symptoms of ATE.

Women should be informed of the symptoms of ATE and be advised to seek urgent medical attention if ATE symptoms develop and to inform the healthcare professional that she is taking a COC.
Symptoms of a stroke can include:
sudden numbness or weakness of the face, arm or leg, especially on one side of the body;
sudden trouble walking, dizziness, loss of balance or coordination;
sudden confusion, trouble speaking or understanding;
sudden trouble seeing in one or both eyes;
sudden, severe or prolonged headache with no known cause;
loss of consciousness or fainting with or without seizure.
Temporary symptoms suggest the event is a transient ischaemic attack (TIA).
Symptoms of myocardial infarction (MI) can include:
pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone;
discomfort radiating to the back, jaw, throat, arm, stomach;
feeling of being full, having indigestion or choking;
sweating, nausea, vomiting or dizziness;
extreme weakness, anxiety, or shortness of breath;
rapid or irregular heartbeats.

Persistence of risk of vascular disease.

There are three studies which have shown persistence of risk of vascular disease for ever users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40-49 years who had used oral contraceptives for 5 or more years, but this increased risk was not demonstrated in other age groups. In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small. Subarachnoid haemorrhage also has a significantly increased relative risk after termination of use of oral contraceptives. However, these studies were performed with oral contraceptive formulations containing 0.05 mg or higher of estrogen.

Estimates of mortality from contraceptive use.

One study gathered data from a variety of sources which have estimated the mortality rates associated with different methods of contraception at different ages. These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth. The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970's but not reported in the U.S. until 1983. However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this document.
Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. The committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy nonsmoking women (even with the newer low dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception.
Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy nonsmoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective.

Carcinoma of the reproductive organs.

Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian and cervical cancer in women using oral contraceptives.

Cervical cancer.

The most important risk factor for cervical cancer is persistent human papillomavirus infection.
Several epidemiological studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia or invasive cervical cancer. It is not known whether the use of oral contraceptives is causative but an independent association has been consistently shown. The studies suggest that there is an “ever used” effect in addition to the duration of use. These findings must be balanced against evidence of significant effects attributable to sexual behaviour, smoking, the presence of human papilloma virus and other factors. In view of the above, periodical cervical smears should form part of the routine follow-up of women who have previously used oral contraceptives. As part of the routine counselling, advice that hormonal contraception does not protect against the transmission of sexually transmittable diseases, including human papilloma virus, should be made clear. Patients may not be aware that barrier contraceptive measures are necessary to reduce the risk of transmission of human papilloma virus.
In cases of undiagnosed abnormal genital bleeding, adequate diagnostic measures are indicated.

Breast cancer.

A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using combined oral contraceptives. The excess risk gradually disappears during the course of the ten years after cessation of combined oral contraceptive use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent combined oral contraceptives 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 combined oral contraceptives users, the biological effects of combined oral contraceptives 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.
Established risk factors for the development of breast cancer include increasing age, family history, obesity, nulliparity, and late age for first full-term pregnancy.
In spite of many studies of the relationship between oral contraceptive use and breast or cervical cancers, a cause and effect relationship has not been established.

Hepatic neoplasia/liver disease/hepatitis C.

In very rare cases, hepatic adenomas, and in extremely rare cases, hepatocellular carcinoma may be associated with COC use. The risk appears to increase with duration of COC use. Rupture of hepatic adenomas may cause death through intra-abdominal haemorrhage.
Indirect calculations have estimated the attributable risk of hepatic adenomas to be in the range of 3.3 cases per 100,000 for users, a risk that increases after 4 or more years of use.
Studies in the United States and Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) oral contraceptive users. However, these cancers are extremely rare in the United States and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users is less than 1 per 1,000,000 users.
Women with a history of COC-related cholestasis and women who develop cholestasis during pregnancy are more likely to develop cholestasis with COC use. Such patients who use COCs should be carefully monitored, and COC use should be discontinued if cholestasis recurs.
Hepatocellular injury has been reported with COC use. Early identification of drug-related hepatocellular injury can decrease the severity of hepatotoxicity when the drug is discontinued. If hepatocellular injury is diagnosed, patients should stop their COC, use a non-hormonal form of birth control, and consult their doctor.
Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until liver function has returned to normal.

Hepatitis C.

During clinical trials with patients treated for HCV infections with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN) occurred significantly more frequently in women using ethinylestradiol-containing medications such as COCs (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Ocular lesions.

With use of combined oral contraceptives, there have been clinical case reports of retinal thrombosis, which may lead to partial or complete loss of vision. Discontinue oral contraceptives and institute appropriate diagnostic and therapeutic measures if there is unexplained, gradual or sudden, partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or any evidence of retinal vascular lesions or optic neuritis.

Gallbladder disease.

Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogen. More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal. The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogen and progestogens.

Carbohydrate and lipid metabolic effects.

Oral contraceptives have been shown to impair oral glucose tolerance. Oral contraceptives containing greater than 0.075 mg of estrogen cause glucose intolerance with impaired insulin secretion, while lower doses of estrogen may produce less glucose intolerance. Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives. Some women may develop persistent hypertriglyceridemia while on the pill. Glucose intolerance has been reported in COC users. Women with impaired glucose tolerance or diabetes mellitus who use COCs should be carefully monitored (see Section 4.3 Contraindications).
A small proportion of women will have adverse lipid changes while taking COCs. Non-hormonal birth control should be considered in women with uncontrolled dyslipidemias. Persistent hypertriglyceridemia may occur in a small proportion of COC users. Elevations of plasma triglycerides in COC users may lead to pancreatitis and other complications.
Estrogens increase serum high-density lipoproteins (HDL cholesterol), whereas a decline in serum HDL cholesterol has been reported with many progestational agents. Some progestins may elevate low-density lipoprotein (LDL) levels and may render the control of hyperlipidaemias more difficult. The net effect of a COC depends on the balance achieved between doses of estrogen and progestin and the nature and absolute amount of progestins used in the contraceptive. The amount of both hormones should be considered in the choice of a COC.
Women who are being treated for hyperlipidaemias should be followed closely if they elect to use COCs.

Elevated blood pressure.

An increase in blood pressure has been reported in women taking oral contraceptives. The incidence of risk also was reported to increase with continued use and among older women. Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing concentrations of progestogens.
Women with a history of hypertension or hypertension-related diseases or renal disease should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives and there is no difference in the occurrence of hypertension among ever- and never-users.
COC use is contraindicated in women with uncontrolled hypertension (see Section 4.3 Contraindications).

Migraine/headache.

The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent or severe requires discontinuation of oral contraceptives and evaluation of the cause.
Women with migraine (particularly migraine with aura) who take COCs may be at increased risk of stroke.

Angioedema.

Exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema.

Genital bleeding.

In some women withdrawal bleeding may not occur during the inactive-tablet interval. If the COC has not been taken according to directions prior to the first missed withdrawal bleed, or if two consecutive withdrawal bleeds are missed, tablet taking should be discontinued and a non-hormonal back-up method of birth control should be used until the possibility of pregnancy is excluded.
Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first 3 months of use. Non-hormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea pregnancy should be ruled out.
Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was pre-existent.

Sexually transmitted diseases.

This product (like all oral contraceptives) is intended to prevent pregnancy. Patients should be counselled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Vomiting and/or diarrhoea.

Diarrhoea and/or vomiting may reduce hormone absorption resulting in decreased serum concentrations (see Section 4.2 Dose and Method of Administration).

General.

i. Physical examination and follow-up.

It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. A Papanicolaou (Pap) smear should be performed if the patient has been sexually active or if it is otherwise indicated. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.

ii. Lipid disorders.

Women who are being treated for hyperlipidaemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult.

iii. Liver function.

If jaundice develops in any woman receiving oral contraceptives the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.

iv. Fluid retention.

Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.

v. Emotional disorders.

Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree. Patients becoming significantly depressed while taking COCs should stop the medication and use an alternative method of birth control in an attempt to determine whether the symptom is drug-related.

vi. Contact lenses.

Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

vii.

Pre-existing uterine fibromyomata may increase in size.

viii.

Other conditions such as epilepsy, migraine, asthma, cardiac or renal dysfunction may be influenced by oral contraceptive therapy.

ix.

Because estrogens may hasten epiphyseal closure, oral contraceptives should be used judiciously in young patients in whom bone growth is not complete.

x.

Patients should be advised that vulvovaginal candidiasis may occur, in which case they should return for appropriate therapy.

Ectopic pregnancy.

Ectopic as well as intrauterine pregnancy may occur in contraceptive failures. However, in oral contraceptive failures, the ratio of ectopic to intrauterine pregnancies is higher than in women who are not receiving oral contraceptives, since the drugs are more effective in preventing intrauterine than ectopic pregnancies. The higher ectopic/ intrauterine ratio has been reported with both combination products and progestogen only oral contraceptives.

Use in the elderly.

Combined oral contraceptives are not indicated for use in postmenopausal women.

Paediatric use.

Safety and efficacy of combined oral contraceptives have been established in women of reproductive age. Use of these products before menarche is not indicated.

Effects on laboratory tests.

Certain endocrine and liver function tests and blood components may be affected by oral contraceptives.
Increased prothrombin and factors VII, VIII, IX, and X.
Decreased antithrombin III.
Increased noradrenaline induced platelet aggregability.
Increased thyroid binding globulin (TGB) leading to increased circulating total thyroid hormone, as measured by protein bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 concentration is unaltered.
Other binding proteins may be elevated in serum.
Sex steroid binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged.
Triglycerides may be increased.
Glucose tolerance may be decreased.
Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interactions between ethinylestradiol and other substances may lead to decreased or increased ethinylestradiol concentrations, respectively.
Concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin may increase the risk of ALT elevations (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Hepatic neoplasia/liver disease/hepatitis C). Therefore, COC users must switch to an alternative method of contraception (e.g. progestogen-only contraception or non-hormonal methods) prior to starting therapy with anti-viral HCV medicinal products such as ombitasvir, paritaprevir, ritonavir, dasabuvir. COCs can be restarted 2 weeks following completion of treatment with an anti-viral HCV medicinal product.
Decreased ethinylestradiol serum concentrations may cause an increased incidence of breakthrough bleeding and menstrual irregularities and may possibly reduce efficacy of the COC.
During concomitant use of ethinylestradiol-containing products and substances that may lead to decreased ethinylestradiol serum concentrations, it is recommended that a non-hormonal back-up method of birth control (such as condoms and spermicide) be used in addition to the regular intake of Brevinor or Brevinor-1. In the case of prolonged use of such substances COCs should not be considered the primary contraceptive.
After discontinuation of substances that may lead to decreased ethinylestradiol serum concentrations, use of a non-hormonal back-up method of contraception is recommended for at least 7 days. Longer use of a back-up method is advisable after discontinuation of substances that have led to induction of hepatic microsomal enzymes, resulting in decreased ethinylestradiol serum concentrations. It may sometimes take several weeks until enzyme induction has completely subsided, depending on dosage, duration of use and rate of elimination of the inducing substance.
Examples of substances that may decrease serum ethinylestradiol concentrations:
any substance that reduces gastrointestinal transit time and, therefore, ethinylestradiol absorption;
substances that induce hepatic microsomal enzymes, such as rifampicin, rifabutin, barbiturates, primidone, phenytoin, dexamethasone, griseofulvin, topiramate, some protease inhibitors, modafinil;
Hypericum perforatum, also known as St. John's wort, and ritonavir (possibly by induction of hepatic microsomal enzymes);
certain antibiotics (e.g. ampicillin and other penicillins, tetracyclines), by a decrease of enterohepatic circulation of estrogens.
Reduced efficacy and increased incidence of breakthrough bleeding and menstrual irregularities have also been associated with concomitant use of carbamazepine, oxacillin and trimethoprim sulfamethoxazole.
Examples of substances that may increase serum ethinylestradiol concentrations:
atorvastatin;
competitive inhibitors for sulfation in the gastrointestinal wall, such as ascorbic acid (vitamin C) and paracetamol;
substances that inhibit cytochrome P450 3A4 isoenzymes such as indinavir and fluconazole.
Ethinylestradiol may interfere with the metabolism of other drugs by inhibiting hepatic microsomal enzymes, or by inducing hepatic drug conjugation, particularly glucuronidation. Accordingly, plasma and tissue concentrations may either be increased (e.g. cyclosporin, theophylline, corticosteroids) or decreased (e.g. lamotrigine).
There have been reports of pregnancy when COCs were co-administered with certain antibiotics (e.g. ampicillin and other penicillins, tetracyclines).
The prescribing information of concomitant medications should be consulted to identify potential interactions.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category B3)
If pregnancy occurs during treatment with COCs, further intake should be discontinued.
Animal studies have shown that high doses of progestogens can cause masculinisation of the female fetus. The results from these experiments in animals do not seem to be relevant to humans, because of the low doses used in contraceptives. There is no conclusive evidence that intake of oral contraceptives during pregnancy represents an increased risk to the fetus.
Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child.

4.8 Adverse Effects (Undesirable Effects)

For the most serious adverse reactions associated with the use of oral contraceptives see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use.
Use of COCs has been associated with increased risk of the following:
arterial and venous thrombotic and thromboembolic events, including myocardial infarction, stroke, transient ischemic attack, venous thrombosis and pulmonary embolism;
cervical intraepithelial neoplasia and cervical cancer;
breast cancer diagnosis;
benign hepatic tumours (e.g. focal nodular hyperplasia, hepatic adenoma.
Adverse reactions are listed in Table 2 per CIOMS frequency.
Very common: ≥ 10%; Common: ≥ 1% and < 10%; Uncommon: ≥ 0.1% and < 1%; Rare: ≥ 0.01% and < 0.1%; Very rare: < 0.01%.

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

Brevinor 28 Day pack.

To achieve maximum contraceptive effectiveness, Brevinor 28 Day must be taken as directed and at daily intervals not exceeding 24 hours. Women should be instructed to take the tablets at the same time every day, preferably at bedtime.

First cycle.

On the first day of the menstrual cycle, i.e. the first day of bleeding, the woman is instructed to take a blue active tablet corresponding to the day of the week from the green area of the Brevinor 28 Day pack. Thereafter one blue active tablet is taken daily, following the arrows on the pack, until all 21 blue tablets have been taken. The woman should then be instructed to take one orange inactive tablet daily for the next seven days. Withdrawal bleeding should usually occur within two to four days after the last blue active tablet has been taken. The woman should be advised that her first cycle after taking all Brevinor 28 Day tablets is likely to be shorter than usual, i.e. approximately 23 to 24 days. Thereafter, her cycles should return to normal, approximately 28 days.
The next and all subsequent courses of Brevinor 28 Day will begin on the day after the last pack was completed, even if withdrawal bleeding is still in progress. Each course of Brevinor 28 Day is begun on the same day of the week as the first course, always beginning with a blue active tablet from the green area.
Brevinor 28 Day is effective from the first day if taken as described above.

Changing from another pill.

If a woman is switching to Brevinor 28 Day from another 28 day oral contraceptive pack, then all tablets in the current 28 day pack should be finished and Brevinor 28 Day started on the next day by taking a blue active tablet which corresponds to the day of the week, from the green area of the pack. During the first Brevinor 28 Day cycle, a nonhormonal contraceptive method (other than the rhythm or temperature method), should be used until seven consecutive blue active tablets have been taken. During this changeover, a period of shortened duration or no period may occur.
If a woman is switching to Brevinor 28 Day from a 21 day oral contraceptive pack, then the woman should wait seven days from when the last active tablet was taken from the old pack and start the new Brevinor 28 Day pack on the eighth day by taking a blue active tablet which corresponds to the day of the week, from the green area of the pack. A nonhormonal contraceptive method (other than the rhythm or temperature method) should be used during the first Brevinor 28 Day cycle, until seven consecutive blue active tablets have been taken.

Brevinor-1 28 Day pack.

To achieve maximum contraceptive effectiveness, Brevinor-1 28 Day must be taken as directed and at daily intervals not exceeding 24 hours. Women should be instructed to take the tablets at the same time every day, preferably at bedtime.

First cycle.

On the first day of the menstrual cycle, i.e. the first day of bleeding, the woman is instructed to take a white active tablet corresponding to the day of the week from the green area of the Brevinor-1 28 Day pack. Thereafter one white active tablet is taken daily, following the arrows on the pack, until all 21 white tablets have been taken. The woman should then be instructed to take one orange inactive tablet daily for the next seven days. Withdrawal bleeding should usually occur within two to four days after the last white tablet has been taken. The woman should be advised that her first cycle after taking all Brevinor-1 28 Day tablets is likely to be shorter than usual, i.e. approximately 23 to 24 days. Thereafter, her cycles should return to normal, approximately 28 days.
The next and all subsequent courses of Brevinor-1 28 Day will begin on the day after the last package was completed, even if withdrawal bleeding is still in progress. Each course of Brevinor-1 28 Day is begun on the same day of the week as the first course, always beginning with a white active tablet from the green area.
Brevinor-1 28 Day is effective from the first day if taken as described above.

Changing from another pill.

If a woman is switching to Brevinor-1 28 Day from another 28 day oral contraceptive pack, then all tablets in the current 28 day pack should be finished and Brevinor-1 28 Day started on the next day by taking a white active tablet which corresponds to the day of the week, from the green area of the pack. During the first Brevinor-1 28 Day cycle, a nonhormonal contraceptive method (other than the rhythm or temperature method), should be used until seven consecutive white active tablets have been taken. During this changeover, a period of shortened duration or no period may occur.
If a woman is switching to Brevinor-1 28 Day from a 21 day oral contraceptive pack, then the woman should wait seven days from when the last active tablet was taken from the old pack and start the new Brevinor-1 28 Day pack on the eighth day by taking a white active tablet which corresponds to the day of the week, from the green area of the pack. A nonhormonal contraceptive method (other than the rhythm or temperature method) should be used during the first Brevinor-1 28 Day cycle, until seven consecutive white active tablets have been taken.
If transient spotting or breakthrough bleeding occurs with either Brevinor 28 Day or Brevinor-1 28 Day, the woman is instructed to continue the regimen since such bleeding is usually without significance. If the bleeding is persistent or prolonged, the woman is advised to consult her physician.
Brevinor 28 Day or Brevinor-1 28 Day can be prescribed postpartum for the nonlactating mother or postabortum as soon as the first normal menstrual period following a normal biphasic cycle occurs. If a further pregnancy is contraindicated for medical reasons, medication with Brevinor 28 Day or Brevinor-1 28 Day must be initiated by the 12th (but not before the 7th) day postpartum, or immediately postabortum or by the 5th day postabortum at the latest. When oral contraceptives are administered in the immediate postpartum/ postabortum period, the increased risk of thromboembolic disease must be considered.

Brevinor and Brevinor-1 28 Day packs.

Missed tablets.

If the woman is less than 12 hours late in taking one of her blue or white active tablets, she should take this tablet at once and then take the next one at her usual time. If the woman is more than 12 hours late in taking one of her blue or white active tablets, she should continue to take her tablets daily as usual, ignoring the missed tablet or tablets, but also take extra contraceptive precautions (other than the rhythm or temperature method) for the next seven days. If these seven days extend into the inactive orange tablet section she should start a new pack on the next day after having taken the last blue or white active tablet from the green section of the current pack (i.e. skip the orange inactive tablets). This will mean that the woman may not have a period until the end of two packs. However, if the woman misses one or more orange inactive tablets, she will be protected against pregnancy provided she begins the active tablets on the appropriate day.
If the woman has not adhered to the prescribed regimen (missed one or more active tablets or started taking them on a day later than recommended), the probability of pregnancy should be considered at the time of the first missed period before Brevinor 28 Day or Brevinor-1 28 Day is resumed. In the case of the continuous intake of active tablets from two packs of Brevinor 28 Day, or Brevinor-1 28 Day (see before), a period should occur at the end of the second pack. If it does not, pregnancy should be ruled out before Brevinor 28 Day or Brevinor-1 28 Day is resumed.

Concurrent medication.

If the woman is taking other drugs that may interact with norethisterone or ethinylestradiol from her 28 day pack, then she should continue to take her tablets as usual but also employ a nonhormonal method of contraception (other than the rhythm or temperature method) during the time she is taking the interacting medication and continue for seven days after the medication is stopped. If these seven days extend into the inactive orange tablet section the woman should start a new pack on the next day after having taken the last blue or white active tablet from the green section of the current pack (i.e. skip the orange inactive tablets). This will mean that the woman may not have a period until the end of two packs. If the woman is taking interacting medications on a chronic basis, another method of contraception should be considered.

Vomiting or diarrhoea.

Mild laxatives do not impair the effectiveness of Brevinor 28 Day, or Brevinor-1 28 Day. If, however, vomiting or diarrhoea occur during or shortly after the intake of Brevinor 28 Day or Brevinor-1 28 Day, contraceptive reliability may be jeopardised. Tablet taking should not be interrupted, to avoid premature withdrawal bleeding. A nonhormonal method of contraception (other than the rhythm or temperature method) should be employed during the period of vomiting or diarrhoea and continued for seven days following the gastrointestinal upset. If these seven days extend into the inactive orange tablet section the woman should start a new pack on the next day after having taken the last active tablet from the green section of the current pack (i.e. skip the orange inactive tablets). This will mean that the woman may not have a period until the end of two packs. If the circumstance reducing the effectiveness of Brevinor 28 Day or Brevinor-1 28 Day is protracted, other methods of contraception should be considered.

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.

4.9 Overdose

Signs and symptoms.

Exact toxic doses have not been determined. When oral contraceptives are the sole medication taken as an acute overdose, the patient may remain clinically well. Overdosage may cause nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may occur in females.

Recommended treatment.

In the case of overdosage or accidental ingestion, the patient should be observed and given supportive treatment, as there is no specific antidote.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Blue active tablet.

Magnesium stearate, povidone, maize starch, lactose monohydrate, indigo carmine.

White active tablet.

Magnesium stearate, povidone, maize starch, lactose monohydrate.

Orange placebo tablet.

Magnesium stearate, lactose, lactose monohydrate, microcrystalline cellulose, sunset yellow FCF.

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 25°C.

6.5 Nature and Contents of Container

Brevinor and Brevinor-1 tablets are presented in PVC/aluminium blister.
One# and four month packs contain 1 and 4 blisters respectively.
# Not currently available.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes