Consumer medicine information

Visanne

Dienogest

BRAND INFORMATION

Brand name

Visanne

Active ingredient

Dienogest

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Visanne.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Visanne. 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 Visanne against the benefits they expect it will have for you.

If you have any concerns, or are unsure 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 IS VISANNE USED FOR

Visanne is used for the treatment of the painful symptoms of endometrial lesions (displaced tissue of the lining of the womb).

Visanne contains a progestogen hormone, dienogest.

Taking one Visanne tablet every day leads to the shrinking of the endometrial tissue and reduces associated complaints such as pelvic pain and painful monthly bleedings.

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 VISANNE

When you must not take it

Do not take Visanne if you have an allergy to:

  • dienogest (the active ingredient in Visanne)
  • 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 in breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take Visanne if you have or have had a blood clot in:

  • the blood vessels of the legs (deep vein thrombosis - DVT)
  • the lungs (pulmonary embolism - PE)
  • the heart (heart attack)
  • the brain (stroke)
  • other parts of the body.

Do not take Visanne if you are concerned about an increased risk of blood clots. Blood clots are rare. Very occasionally blood clots may cause serious permanent disability, or may even be fatal.

Do not take Visanne if you have or have had:

  • diabetes mellitus with blood vessel damage
  • severe liver disease and your liver function has not returned to normal
  • cancer that may grow under the influence of sex hormones (e.g. of the breast or the genital organs)
  • benign or malignant liver tumour
  • unexplained vaginal bleeding.

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

Do not take Visanne if you are pregnant or think you might be pregnant. The possibility of pregnancy should be ruled out before starting Visanne.

Do not take Visanne if you are breastfeeding.

Do not give Visanne to a child. Visanne is not for use in female children before menarche (first menstrual bleed).

Do not take Visanne 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.

Do not take Visanne if the packaging is torn or shows signs of tampering. If the packaging is damaged, 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.

If Visanne is used in the presence of any of the conditions listed below you may need to be kept under close supervision. Your doctor can explain this to you. Therefore, if any of these apply to you, tell your doctor before starting to use Visanne:

  • you smoke
  • you are overweight
  • you have diabetes or had diabetes temporarily during previous pregnancy
  • you have high blood pressure or develop high blood pressure while taking Visanne
  • you have suffered from depression
  • if you have had an ectopic pregnancy
  • you develop a liver disease while taking Visanne.
    Symptoms may include yellowing of the skin or eyes or itching all over the body. Inform your doctor also if such symptoms occurred during a previous pregnancy
  • you have chloasma (yellowish-brown pigmentation patches on the skin, particularly of the face)
    – if so, avoid exposure to the sun or ultraviolet radiation
  • you or anyone in your immediate family has had blood clots in the legs or lungs, a heart attack, a stroke, breast cancer or high cholesterol.

Visanne contains lactose monohydrate. If you have intolerance to some sugars, contact your doctor before you start taking Visanne.

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/foods and Visanne may interfere with each other. These include:

  • medicines used to treat epilepsy such as phenytoin, primidone, barbiturates (e.g. phenobarbitone), carbamazepine, oxcarbamazepine, topiramate, felbamate
  • medicines used to treat depression such as fluoxetine, fluvoxamine
  • diltiazem, verapamil which are medicines used to treat high blood pressure, chest pain or irregular heartbeats
  • medicines used to treat tuberculosis such as rifampicin, rifabutin
  • medicines used to treat HIV or hepatitis C virus (HCV)
  • medicines used to treat fungal infections such as ketoconazole, itraconazole, fluconazole, voriconazole)
  • some antibiotics (e.g. erythromycin, clarithromycin)
  • cimetidine, an antacid
  • herbal medicines containing St. John’s Wort
  • grapefruit.

These medicines/foods may be affected by Visanne, or may affect how well it works. Your doctor may need to alter the dose of your medicine, or prescribe a different medicine.

Ask your doctor or pharmacist for advice before taking any other medicine.

HOW TO TAKE VISANNE

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, printed on the pharmacist label or in this leaflet, ask your doctor or pharmacist for help.

How to take it

Take one tablet daily at about the same time each day, without any break.

Follow the direction of the arrows on the blister pack until all the tablets have been taken.

Tablet-taking can be started on any day of your menstrual cycle.

Tablets must be taken continuously without regard to vaginal bleeding. This means that after the first pack has been finished the next should be started without interruption.

Swallow the tablet whole with water. It does not matter if you take it before or after food.

How long to take Visanne

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take Visanne

If you forget to take a tablet or if you suffer from vomiting and/or diarrhoea:
The efficacy of Visanne may be reduced in the event of missed tablets or vomiting and/or diarrhoea (if occurring within 3-4 hours after tablet taking). In the event of missed tablet(s), you should take one tablet only, as soon as you remember, and should then continue to take the tablet at your usual time the next day. A tablet not absorbed due to vomiting or diarrhoea should likewise be replaced by one tablet.

If you take too much (overdose)

Immediately contact 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 Visanne.

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

WHILE YOU ARE TAKING VISANNE

Things you must do

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

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 are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

Keep all of your doctor’s appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

If you become pregnant while taking this medicine, tell your doctor immediately.

Things you must not do

Do not take Visanne 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.

Things to be careful of

To avoid becoming pregnant, you should use non-hormonal contraceptive precautions, such as a condom or another barrier method.

You must not use sex-hormone containing contraceptives of any form (tablet, patch, intrauterine system) while taking Visanne.

Do not use rhythm or temperature methods. These methods can be unreliable.

If in an exceptional case you should become pregnant during the use of Visanne, there is a higher likelihood in users of progestogen containing preparations like Visanne to have an ectopic pregnancy (the embryo develops outside the womb).

Tell your doctor before you start taking Visanne, if you had an ectopic pregnancy in the past, or have an impaired function of the fallopian tubes.

If you experience unexplained abdominal complaints that are different to the symptoms you commonly experience from your endometriosis, you should contact your doctor immediately because an ectopic pregnancy must be considered.

SIDE EFFECTS

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

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

Do not be alarmed by this list of possible side effects, you may not experience any of them.

The following list includes the more common side effects of Visanne. These are usually mild and lessen with time.

If you notice any of the following side effects and they worry you, tell your doctor or pharmacist:

  • headache or migraine
  • breast discomfort,
  • hot flushes
  • mood changes, including depression, irritability, nervousness, problems sleeping, loss of interest in sex
  • acne, hair loss
  • nausea, abdominal pain, wind, swollen tummy or vomiting
  • weight gain
  • back pain
  • uterine/vaginal bleeding including spotting
  • unusual weakness

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed may also occur in some people.

Thrombosis

Thrombosis is the formation of a blood clot which may block a blood vessel.

Thrombosis sometimes occurs in the deep veins of the legs (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 pulmonary embolism (PE).

Deep venous thrombosis is a rare occurrence. It can develop whether or not you are taking Visanne. It can also happen if you become pregnant.

The risk of venous thromboembolism (DVT or PE) appears to be slightly higher in users of hormonal (progestogen containing) preparations like Visanne, than in non-users, but is not as high as during pregnancy or during use of combined oral contraceptives (the Pill).

The risk for venous thromboembolism increases for example:

  • with increasing age
  • if you are overweight
  • shortly after childbirth
  • if you have had a blood clot in the past
  • if anyone in your immediate family has had a blood clot at a relatively early age
  • during long periods of immobilisations, e.g. after surgery or having your leg(s) in plaster/splints etc.

Tell your doctor you are using Visanne well in advance of any expected hospitalisation or surgery.

Your doctor may tell you to stop taking Visanne several weeks before surgery, or at the time of immobilisation and when you can start taking Visanne again.

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

From studies there is little or no evidence for a link between progestogen containing preparations similar to Visanne and an increased risk of heart attack or stroke.

The risk of such events is rather related to increasing age, hypertension (high blood pressure), and smoking.

In women with hypertension the risk of stroke may be slightly increased by progestogen containing preparations like Visanne.

If you develop high blood pressure while using Visanne, you may be told to stop using it.

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

Possible signs of a blood clot include:

  • an unusual cough
  • pain in the chest, arm or below the breastbone
  • discomfort radiating to the back
  • breathlessness and/or difficulty breathing
  • swelling, pain or tenderness of one leg
  • sudden weakness, numbness or bad ‘pins and needles’ of the face, arm or leg, especially on one side of the body
  • sudden trouble walking, dizziness, loss of balance or coordination
  • severe, sudden stomach pains
  • a fainting attack, or you collapse
  • unusual headaches or migraines that are worse than usual
  • sudden problems with your speech, understanding or eyesight

Cancer

Breast cancer has been diagnosed slightly more often in women who use combined oral contraceptives (the Pill) than in women of the same age who do not use the Pill. It is not known whether the difference is caused by the Pill or whether cancers were detected earlier in Pill users.

The evidence is inconclusive for progesterone only preparations like Visanne.

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

In rare cases benign liver tumours and even more rarely, malignant liver tumours have been reported in users of the Pill. These tumours may lead to internal bleeding.

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

Bleeding Patterns

Visanne treatment affects the menstrual bleeding pattern in the majority of women.

Uterine bleeding in women with e.g. adenomyosis uteri or uterine leiomyomata, may be worse with Visanne.

If bleeding is heavy and continuous over time, this may lead to anaemia (severe in some cases). In such cases, your doctor may advise you to stop taking Visanne.

Bone Mineral Density (BMD)

The long term use of Visanne may affect the bone mineral density (BMD) of adolescents (12 to < 18 years) and therefore your doctor will carefully weigh the benefits of using Visanne against other potential risks for bone loss (osteoporosis) e.g.

  • metabolic bone disease
  • if anyone in your immediate family has ever suffered from bone loss (osteoporosis)
  • if you have ever broken a bone that was not caused by a fall or accident
  • use of medications that can reduce bone mass e.g. epilepsy medication or steroids
  • low body mass index or eating disorders e.g. anorexia nervosa or bulimia
  • alcohol use
  • smoking

When using Visanne, your doctor may also recommend dietary and lifestyle modifications such as weight bearing exercise and a healthy diet including adequate calcium and vitamin D, to reduce your risk of osteoporosis. Ask your doctor for their advice to improve your bone health.

AFTER TAKING VISANNE

Storage

Keep your tablets in the blister 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 Visanne or any other medicine in the bathroom, near a sink, or on a window-sill. Do not leave medication in the car. Heat and damp can destroy some medicines.

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

Visanne is a round, white to off-white tablet marked with “B” on one side. The blister pack is marked with the days of the week and contains 14 tablets.

Visanne comes in packs of 1 month, 3 months and 6 months. Not all pack sizes may be marketed.

Ingredients

Active ingredients:

  • dienogest 2mg

Inactive ingredients:

  • lactose monohydrate
  • starch potato
  • cellulose-microcrystalline
  • povidone
  • purified talc
  • crospovidone
  • magnesium stearate

Visanne tablets do not contain gluten, tartrazine or azo dyes.

Supplier

Made in Germany for:

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

Australian registration number:

Visanne - AUST R 160465

Date of Preparation

26 February 2020

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 May 2020

BRAND INFORMATION

Brand name

Visanne

Active ingredient

Dienogest

Schedule

S4

 

1 Name of Medicine

Dienogest.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

65928-58-7.
INN: Dienogest.
IUPAC/ WHO: 17α-Hydroxy-3-oxo-19-norpregna-4,9-diene-21-nitrile (IUPAC).
Molecular formula: C20H25NO2.
Molecular weight: 311.43.
Appearance: White to off-white crystalline powder.

2 Qualitative and Quantitative Composition

Each Visanne tablet contains 2 mg of dienogest.
Visanne tablet contains lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

The tablets are white to off-white, round, flat-faced, bevelled edge marked with the letter "B" on one side and have a diameter of 7 mm.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pharmacotherapeutic group: progestogens.
ATC code: G03D.
Dienogest is a nortestosterone derivative with antiandrogenic activity of approximately one-third of that of cyproterone acetate. Dienogest binds to the progesterone receptor of the human uterus with only 10% of the relative affinity of progesterone. Despite its low affinity to the progesterone receptor, dienogest has a strong progestogenic effect in vivo. Dienogest has no significant androgenic, mineralocorticoid or glucocorticoid activity in vivo.
Dienogest acts on endometriosis by reducing the endogenous production of oestradiol and thereby suppressing the trophic effects of oestradiol on both the eutopic and ectopic endometrium. When given continuously, dienogest leads to a hypoestrogenic, hypergestagenic endocrine environment causing initial decidualisation of endometrial tissue followed by atrophy of endometriotic lesions. Additional properties, like immunologic and antiangiogenic effects, seem to contribute to the inhibitory action of dienogest on cell proliferation.

Clinical trials.

Efficacy.

Superiority of Visanne over placebo with regard to reduction of endometriosis-associated pelvic pain (EAPP) and clinically meaningful reduction of pain compared to baseline were demonstrated in a 3-month study including 102 patients on Visanne. EAPP was measured on a Visual Analog Scale (VAS) (0-100 mm). After 3 months of treatment with Visanne, a statistically significant difference compared to placebo (Δ = 12.3 mm; 95% CI: 6.4-18.1; p < 0.0001) and a clinically meaningful reduction of pain compared to baseline (mean reduction = 27.4 mm ± 22.9) were demonstrated.
After 3 months of treatment, reduction of EAPP by 50% or more without relevant increase of concomitant pain medication was achieved in 37.3% of patients on Visanne (placebo: 19.8%); a reduction of EAPP by 75% or more without relevant increase of concomitant pain medication was achieved in 18.6% of patients on Visanne (placebo: 7.3%).
The open-label extension to this placebo controlled study showed a continued improvement of endometriosis associated pelvic pain for a treatment duration of up to 15 months (mean reduction at end of treatment = 43.2 ± 21.7 mm).
In addition, efficacy on EAPP was shown in a 6-months comparative trial of Visanne versus the GnRH analogue leuprorelin acetate (LA) including 120 patients on Visanne. EAPP was measured on a VAS (0-100 mm). A clinically meaningful reduction of pain compared to baseline and statistical non-inferiority versus LA were demonstrated (Visanne 47.5 ± 28.8 mm, LA 46.0 ± 24.8 mm). Non-inferiority versus LA based on a pre-defined non-inferiority margin of 15 mm was demonstrated (p < 0.0001).
Three studies including a total of 252 patients who received a daily dose of 2 mg dienogest demonstrated a substantial reduction of endometriotic lesions after 6 months of treatment.
A randomised, double-blind, parallel-group study (n = 20 to 23 per dose group) investigated pharmacodynamic effects of four dienogest doses (0.5, 1.0, 2.0 or 3.0 mg/day) for a maximum of 72 days. Ovulations were observed in 14% and 4% of women of the 0.5 mg and 1 mg groups, respectively. No ovulations occurred in the 2 mg and 3 mg groups. Visanne has not been tested for contraceptive efficacy in larger studies.
The efficacy of Visanne was demonstrated in the treatment of endometriosis related symptoms (pelvic pain, dysmenorrhea and dyspareunia) in a 12 month study with 111 female adolescents (after menarche between 12 and < 18 years of age).

Safety.

Endogenous oestrogen levels are only moderately suppressed during treatment with Visanne.
Bone mineral density (BMD) was assessed in 21 adult patients before and after 6 months of treatment and there was no reduction in the mean BMD. In a 12 month study involving 103 adolescents the mean relative change in BMD of the lumbar spine (L2-L4) from baseline to the end of treatment (EOT) was -1.2% (95% CI: -1.70% and -0.78%). In a subset of patients with decreased BMD at the EOT (n = 60), a follow up measurement performed 6 months after cessation of treatment showed an increase in BMD towards baseline levels (mean relative change from baseline: -2.3% at EOT and -0.6% at 6 months after EOT [95% CI: -1.20% and 0.06%]).
No significant impact on standard laboratory parameters, including haematology, blood chemistry, liver enzymes, lipids, and HbA1c was observed during treatment with Visanne for up to 15 months (n = 168).

5.2 Pharmacokinetic Properties

Absorption.

Orally administered dienogest is rapidly and almost completely absorbed. Peak serum concentrations of approximately 47 nanogram per mL are reached at about 1.5 hours after single ingestion. Bioavailability is about 91%. The pharmacokinetics of dienogest are dose-proportional within the dose range of 1-8 mg.

Distribution.

Dienogest is bound to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). 10% of the total serum drug concentrations are present as free steroid, 90% are non-specifically bound to albumin.
The apparent volume of distribution (Vd/F) of dienogest is 40 L.

Metabolism.

Dienogest is completely metabolised by the known pathways of steroid metabolism, with the formation of endocrinologically mostly inactive metabolites. Based on in vitro and in vivo studies, CYP3A4 is the major enzyme involved in the metabolism of dienogest. The metabolites are excreted very quickly so that in plasma unchanged dienogest is the dominating fraction.
The metabolic clearance rate from serum Cl/F is 64 mL/min.

Excretion.

Dienogest serum levels decrease in two phases. The terminal disposition phase is characterised by a half-life of approximately 9-10 hours. Dienogest is excreted in the form of metabolites which are excreted at a urinary to faecal ratio of about 3:1 after oral administration of 0.1 mg/kg. The half-life of urinary metabolites excretion is 14 hours. Following oral administration approximately 86% of the dose administered is eliminated within 6 days, the bulk of this amount is excreted within the first 24 h, mostly with the urine.

Steady-state conditions.

Pharmacokinetics of dienogest are not influenced by SHBG levels. Following daily ingestion, drug serum levels increase about 1.24-fold reaching steady-state conditions after 4 days of treatment. The pharmacokinetics of dienogest after repeated administration of Visanne can be predicted from single dose pharmacokinetics.

5.3 Preclinical Safety Data

Genotoxicity.

Dienogest did not exhibit any evidence of genotoxic potential in assays for gene mutations in bacterial or mammalian cells, in vitro and in vivo.

Carcinogenicity.

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 oral contraceptives (OCs), mainly oestrogen-progestogen preparations. The excess risk gradually disappears during the course of the 10 years after cessation of combined oral contraceptives (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. The risk of having breast cancer diagnosed in progestogen-only pill users is possibly of similar magnitude to that associated with COC, i.e. the pill. However, for progestogen-only preparations, the evidence is based on much smaller patient numbers and so is less conclusive than for COCs. 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 OC users, the biological effects of OCs 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.
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 Visanne. 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 Visanne.
Long-term studies in rats and mice with dienogest showed increased incidences of pituitary adenomas, fibroepithelial mammary tumours, stromal polyps of the uterus and malignant lymphoma, at doses corresponding to exposure levels about 10 times that anticipated at the maximum recommended clinical dose, based on area under the plasma concentration time curve (AUC). Similar tumours have been shown to develop with other oestrogenic/ progestogenic compounds. The tumours are thought to result from marked species differences in the optimal oestrogen:progestogen ratio for reproductive function. Dienogest showed no tumour promotion activity in the rat liver foci assay at exposure levels corresponding to > 100 times the estimated human exposure at the clinical dose, based on AUC.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of endometriosis.

4.3 Contraindications

Visanne should not be used in the presence of any of the conditions listed below, which are partially derived from information on other progestogen only preparations. Should any of the conditions appear during the use of Visanne, treatment must be discontinued immediately.
Known or suspected pregnancy.
Lactation.
Active venous thromboembolic disorder.
Arterial and cardiovascular disease, present or in history (e.g. myocardial infarction, cerebrovascular accident, ischaemic heart disease).
Diabetes mellitus with vascular involvement.
Present or history of severe hepatic disease as long as liver function values have not returned to normal.
Present or history of liver tumours (benign or malignant).
Known or suspected sex hormone dependent malignancies.
Undiagnosed vaginal bleeding.
Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings and Precautions for Use

General.

Before starting Visanne treatment, pregnancy must be excluded. During treatment, patients are advised to use nonhormonal methods of contraception (e.g. barrier contraception such as condom) to prevent unwanted pregnancies.
Pregnancies that occur among users of progestogen-only preparations used for contraception (e.g. minipill) are more likely to be ectopic than are pregnancies among users of combined oral contraceptives. Therefore, in women with a history of extrauterine pregnancy or an impairment of tube function, the use of Visanne should be decided on only after carefully weighing the benefits against the risks.
As Visanne is a progestogen-only preparation it can be assumed that special warnings and special precautions for use of other progestogen only preparations are also valid for the use of Visanne although not all of the warnings and precautions are based on respective findings in the clinical studies with Visanne.
If any of the conditions/risk factors mentioned below is present or deteriorates, an individual risk-benefit analysis should be done before Visanne is started or continued.

Circulatory disorders.

From epidemiological studies there is little evidence of an association between progestogen-only preparations and an increased risk of myocardial infarction or cerebral thromboembolism. The risk of cardiovascular and cerebral events is related to increasing age, hypertension, and smoking. In women with hypertension the risk of stroke may be slightly enhanced by progestogen-only preparations.
Some studies indicate that there may be a slightly, but not statistically significant increased risk of venous thromboembolism (deep venous thrombosis, pulmonary embolism) associated with the use of progestogen-only preparations. 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. In case of long-term immobilisation it is advisable to discontinue the use of Visanne (in the case of elective surgery at least four weeks in advance) and not to resume treatment until two weeks after complete remobilisation.
The increased risk of thromboembolism in the puerperium must be considered.
Treatment should be stopped at once if there are symptoms or suspicion of an arterial or venous thrombotic event.

Changes in bleeding pattern.

Visanne treatment affects the menstrual bleeding pattern in the majority of women (see Section 4.8 Adverse Effects (Undesirable Effects)). Uterine bleeding, for example in women with adenomyosis uteri or uterine leiomyomata, may be aggravated with the use of Visanne. If bleeding is heavy and continuous over time this may lead to anaemia (severe in some cases). In the event of anaemia, discontinuation of Visanne should be considered.

Chloasma.

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 whilst taking Visanne.

Osteoporosis and changes in bone mineral density (BMD).

Currently, long-term data on BMD and risk of fractures in users of Visanne are not available. BMD was assessed in 21 adult patients before and after 6 months of treatment with Visanne and there was no reduction of mean BMD. In 29 patients treated with leuprorelin acetate (LA), a mean reduction of 4.04% ± 4.84 was noted after the same period (Δ between groups = 4.29%; 95% CI: 1.93-6.66; p < 0.0003). In patients who are at an increased risk of osteoporosis a careful risk-benefit assessment should be performed before starting Visanne because endogenous oestrogen levels are moderately decreased during treatment with Visanne (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Safety).
The use of Visanne in adolescents (12 to < 18 years) over a treatment period of 12 months was associated with a mean decrease in bone mineral density (BMD) in the lumbar spine of 1.2%. After cessation of treatment, BMD increased towards pre-treatment levels over a period of 6 months in a subset of patients with decreased BMD (mean change from baseline -0.6%) see Section 5.1 Pharmacodynamic Properties, Clinical trials.
Loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. It is unknown if BMD decrease in this population will reduce peak bone mass and increase the risk for fracture in later life (see Section 5.1 Pharmacodynamic Properties, Paediatric use, Clinical trials).
Therefore the treating physician should weigh the benefits of Visanne against the possible risks of use in each individual adolescent patient also taking into account the presence of significant risk factors for osteoporosis (e.g. metabolic bone disease, family history of osteoporosis, low body mass index or eating disorders such as anorexia nervosa or bulimia, chronic use of medicines that can reduce bone mass e.g. anticonvulsants or corticosteroids, previous low trauma fracture, alcohol abuse and/or smoking).
Adequate intake of calcium and Vitamin D, whether from the diet or from supplements, is important for bone health in women of all ages.
If clinically warranted, BMD may be monitored and the results used in the risk benefit assessment of use of Visanne.

Other.

Patients who have a history of depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.
Visanne generally does not appear to affect blood pressure in normotensive women. However, if a sustained clinically significant hypertension develops during the use of Visanne, it is advisable to withdraw Visanne and treat the hypertension.
Recurrence of cholestatic jaundice and/or pruritus which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of Visanne.
Persistent ovarian follicles (often referred to as functional ovarian cysts) may occur during the use of Visanne. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain.
Each Visanne tablet contains 63 mg of lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption who are on a lactose free diet should consider the amount contained in Visanne.

Diabetes.

Visanne may have a slight effect on peripheral insulin resistance and glucose tolerance. Women with diabetes, especially those with a history of gestational diabetes mellitus, should be carefully observed while taking Visanne.

Medical examination.

A complete medical history and physical and gynaecological examination should be taken prior to the initiation or reinstitution of Visanne, see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, and should be repeated at least annually during the use of Visanne. 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.

Use in hepatic impairment.

Visanne is contraindicated in patients with present or past severe hepatic disease.

Use in renal impairment.

There is no data suggesting the need for a dosage adjustment in patients with renal impairment.

Use in the elderly.

There is no relevant indication for the use of Visanne in the geriatric population.

Paediatric use.

Visanne is not indicated in children prior to menarche.
The efficacy of Visanne has been demonstrated in the treatment of endometriosis associated pelvic pain in adolescent patients (12 - < 18 years).
The use of Visanne in adolescent patients over a treatment period of 12 months was associated with a mean decrease in Bone Mineral Density (BMD) in the lumbar spine of 1.2%. After cessation of treatment, BMD increased towards pre-treatment levels over a period of 6 months in a subset of patients with decreased BMD (mean change from baseline -0.6%) see Section 5.1 Pharmacodynamic Properties, Clinical trials.
Loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. It is unknown if BMD decrease in this population will reduce peak bone mass and increase the risk for fracture in later life.
Therefore the treating physician should weigh the benefits of Visanne against the possible risks of use in each individual adolescent patient (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.4 Special Warnings and Precautions for Use, Osteoporosis and changes in bone mineral density (BMD)).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Progestogens, including dienogest are metabolised mainly by the cytochrome P450 3A4 system (CYP3A4) located both in the intestinal mucosa and in the liver. Therefore, inducers or inhibitors of CYP3A4 may affect the progestogen drug metabolism.
An increased clearance of sex hormones due to enzyme induction may reduce the therapeutic effect of Visanne and may result in undesirable effects e.g. changes in the uterine bleeding profile.
A reduced clearance of sex hormones due to enzyme inhibition may increase the exposure to dienogest and may result in undesirable effects.

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.
Enzyme induction can already be observed after a few days of treatment. Maximum enzyme induction is generally seen within a few weeks. After the cessation of therapy enzyme induction may be sustained for about 4 weeks.
The effect of the CYP3A4 inducer rifampicin was studied in healthy postmenopausal women. Co-administration of rifampicin with oestradiol valerate/ dienogest tablets led to significant decreases in steady-state concentrations and systemic exposures of dienogest. The systemic exposure of dienogest at steady state, measured by AUC(0-24h), was decreased by 83%.

Substances with variable effects on the clearance of sex hormones, (e.g. nevirapine).

When co-administered with sex hormones, many HIV/HCV protease inhibitors (e.g. ritonavir, saquinavir, indinavir, nelfinavir) and non-nucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of the progestogen. These changes may be clinically relevant in some cases.

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

Dienogest is a substrate of cytochrome P450 (CYP) 3A4.
Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. ketoconazole, itraconazole, fluconazole, voriconazole), verapamil, macrolides (e.g. erythromycin, clarithromycin), diltiazem, antidepressants (e.g. fluvoxamine, fluoxetine) and grapefruit juice can increase plasma concentrations of the progestogens.
In a study investigating the effect of CYP3A4 inhibitors (ketoconazole, erythromycin) on the combination of oestradiol valerate/ dienogest, steady state dienogest plasma levels were increased. Co-administration with the strong inhibitor ketoconazole resulted in a 186% increase of AUC(0-24h) at steady state for dienogest. When co-administered with the moderate inhibitor erythromycin, the AUC(0-24h) of dienogest at steady state was increased by 62%. The clinical relevance of these interactions is unknown.

Effects of Visanne on other medicinal products.

Based on in vitro inhibition studies, a clinically relevant interaction of Visanne with the cytochrome P450 enzyme mediated metabolism of other medicaments is unlikely.

Drug food interactions.

A standardised high fat meal did not affect the bioavailability of Visanne.

Effects 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. lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Based on available data, ovulation is inhibited in the majority of patients during treatment with Visanne. However, Visanne is not a contraceptive.
If contraception is required a non-hormonal method should be used (e.g. condom). Based on available data, the menstrual cycle returns to normal within 2 months after cessation of treatment with Visanne.
(Category B3)
The administration of Visanne during pregnancy is contraindicated. If pregnancy occurs during use of Visanne, use of the product must be discontinued.
There are limited data from the use of dienogest in pregnant women. To date, no significant epidemiological data has been obtained. Animal studies and data from women exposed to dienogest during pregnancy reveal no special risks on pregnancy, embryonic/ foetal development, birth or development after birth for humans. However, Visanne must not be administered to pregnant women because there is no need to treat endometriosis during pregnancy.
Oral treatment of rats and rabbits with dienogest during organogenesis caused an increase in post-implantation loss at systemic exposure levels (based on AUC) similar to that anticipated clinically. No teratogenicity was evident in either species at systemic exposure levels up to ten-fold higher than that expected at the clinical dose, based on AUC. Oral treatment of rats with dienogest during late pregnancy and lactation was shown to impair fertility in the offspring at maternal systemic exposure levels (based on AUC) approximately one-third of that anticipated clinically.
Treatment with Visanne during lactation is not recommended. Physiochemical properties and animal data indicate excretion of dienogest in breast milk.
A decision must be made whether to discontinue breastfeeding or to abstain from Visanne therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

4.8 Adverse Effects (Undesirable Effects)

Undesirable effects are more common during the first months after start of intake of Visanne, and subside with duration of treatment (see Section 4.4 Special Warnings and Precautions for Use). The following undesirable effects have been reported in users of Visanne.
The most frequently reported undesirable effects during treatment that were considered at least possibly related to Visanne were headache (9.0%), breast discomfort (5.4%), depressed mood (5.1%), and acne (5.1%).
The frequencies of adverse drug reactions (ADRs) by MedDRA system organ classes (MedDRA SOCs) reported with Visanne are summarised in Table 1. Within each frequency grouping, undesirable effects are presented in order of decreasing frequency. Frequencies are defined as common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1000 to < 1/100). The frequencies are based on pooled data of four clinical trials including 332 patients (100.0%).

Uterine bleeding irregularities.

Menstrual bleeding patterns were assessed systematically using patient diaries and were analysed using the WHO 90 day reference period method.
During the first reference period (i.e. first 90 days of treatment with Visanne): The following bleeding patterns were observed (n = 290; 100%): amenorrhoea (1.7%), infrequent bleeding (27.2%), frequent bleeding (13.4%), irregular bleeding (35.2%), prolonged bleeding (38.3%), normal bleeding, i.e. none of the previous categories (19.7%)1.
During the fourth reference period the following bleeding patterns were observed (n = 149; 100%): amenorrhoea (28.2%), infrequent bleeding (24.2%), frequent bleeding (2.7%), irregular bleeding (21.5%), prolonged bleeding (4.0 %), normal bleeding, i.e. none of the previous categories (22.8%)1.
Changes in menstrual bleeding patterns were only occasionally reported as adverse event by the patients (see Table 1).
1 Sums up to more than 100% because one patient may fall into more than one category at the same time, e.g. 'frequent bleeding' and 'irregular bleeding'.

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

Tablet taking can start on any day of the menstrual cycle. The dosage of Visanne is one tablet daily without any break, taken preferably at the same time each day with some liquid as needed. Tablets must be taken continuously without regard to vaginal bleeding. When a pack is finished the next one should be started without interruption.
The efficacy of Visanne may be reduced in the event of missed tablets, vomiting and/or diarrhoea (if occurring within 3-4 hours after tablet taking). In the event of missed tablet(s), the woman should take one tablet only, as soon as she remembers, and should then continue on the next day to take the tablet at her usual time. A tablet not absorbed due to vomiting or diarrhoea should likewise be replaced by one tablet.
If a short acting, e.g. oral, hormonal treatment was prescribed before starting treatment with dienogest, treatment may be started on the first day of menstrual bleeding after cessation of treatment.
If a long-acting, i.e. injectable, hormonal treatment was administered before starting treatment with dienogest, then dienogest may be started once metabolism/excretion of the previously administered drug is expected to be completed.
There is no experience with Visanne treatment for more than 15 months in patients with endometriosis.

4.7 Effects on Ability to Drive and Use Machines

Not known.

4.9 Overdose

Acute toxicity studies performed with Visanne did not indicate a risk of acute adverse effects in case of inadvertent multiple daily therapeutic dose. There is no specific antidote. 20-30 mg dienogest per day (10 to 15 times higher dose than in Visanne) over 24 weeks of use was well tolerated.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Visanne contains the following inactive ingredients: lactose, potato starch, microcrystalline cellulose, povidone, talc-purified, crospovidone, magnesium stearate, water-purified.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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

Visanne tablets are contained in blister packs. Each blister contains 14 white tablets containing dienogest 2 mg.
Carton containing blister packs of 2 x 14, 6 x 14 or 12 x 14 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 by taking it to your local pharmacy.

Summary Table of Changes