Consumer medicine information

Dinasane

Dienogest

BRAND INFORMATION

Brand name

Dinasane

Active ingredient

Dienogest

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Dinasane.

SUMMARY CMI

Dinasane

Consumer Medicine Information (CMI) summary

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

1. Why am I using Dinasane?

Dinasane contains the active ingredient dienogest. It is used to treat painful symptoms of endometrial lesions (displaced tissue of the lining of the womb).

For more information, see Section 1. Why am I using Dinasane? in the full CMI.

2. What should I know before I use this medicine?

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

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. There are a number of circumstances in which a person should not use this medicine or may need to use caution. It is important to understand if these apply to you before taking this medicine.

For more information, see Section 2. What should I know before I use Dinasane? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with dienogest and affect how it works.

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

4. How do I use this medicine?

Follow all directions given to you by your doctor and other health professionals carefully:

  • 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.
  • You must take the tablets continuously without regard to vaginal bleeding. This means that after the first pack has been finished you should start the next without interruption.
  • Swallow the tablet whole with water.

More instructions can be found in Section 4. How do I use Dinasane? in the full CMI.

5. What should I know while using this medicine?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using this medicine.
  • Tell your doctor you are using this medicine well in advance of any expected hospitalisation or surgery.
  • To avoid becoming pregnant, you should use non-hormonal contraceptive precautions, such as a condom or another barrier method.
  • Call you doctor straight away if you experience unexplained abdominal complaints that are different to the symptoms you commonly experience from your endometriosis.
Things you should not do
  • Do not use sex-hormone containing contraceptives, or use rhythm or temperature contraception methods, while taking this medicine.
Looking after your medicine
  • Keep your tablets below 25°C.
  • Protect from light.

For more information, see Section 5. What should I know while using Dinasane? in the full CMI.

6. Are there any side effects?

There are a number of side effects associated with this medicine. It is important to be aware of them so that you can identify any symptoms if they occur.

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



FULL CMI

Dinasane

Active ingredient(s): dienogest

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

1. Why am I using Dinasane?
2. What should I know before I use this medicine?
3. What if I am taking other medicines?
4. How do I use this medicine?
5. What should I know while using this medicine?
6. Are there any side effects?
7. Product details

1. Why am I using Dinasane?

Dinasane contains the active ingredient dienogest. It is a progesterone hormone.

This medicine name is used to treat painful symptoms of endometrial lesions (displaced tissue of the lining of the womb). Taking this medicine leads to the shrinking of the endometrial tissue and reduces associated complaints such as pelvic pain and painful monthly bleedings.

2. What should I know before I use this medicine?

Warnings

Do not use this medicine if:

  • you are allergic to dienogest, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • you have or have had a blood clot in the blood vessels of the legs, the lungs, the heart, the brain, or other parts of the body, or you are concerned about an increased risk of blood clots
  • you have or have had diabetes mellitus with blood vessel damage
  • you have or have had severe liver disease and your liver function has not returned to normal
  • you have or have had cancer that may grow under the influence of sex hormones (e.g. of the breast or the genital organs)
  • you have or have had liver tumours (benign or malignant)
  • you have or have had unexplained vaginal bleeding
  • you are pregnant or think you might be pregnant
  • you are breastfeeding.

If any of the conditions listed above appear while taking this medicine, stop taking it at once and tell your doctor.

Check with your doctor if you:

  • smoke
  • are overweight
  • have diabetes or had diabetes temporarily during previous pregnancy
  • have high blood pressure or develop high blood pressure while taking this medicine
  • have suffered from depression
  • have had an ectopic pregnancy (the embryo develops outside the womb)
  • have an impaired function of the fallopian tubes
  • develop a liver disease while taking this medicine.
    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.
  • 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
  • take any medicines for any other condition.

If you have any of the conditions listed above you may need to be kept under close supervision. Your doctor can explain this to you.

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

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. The possibility of pregnancy should be ruled out before starting this medicine.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Children

Do not give this medicine to a child.

This medicine is not for use in female children before the first menstrual bleed.

3. What if I am taking other medicines?

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

Some medicines/foods may interfere with dienogest and affect how it works. 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.

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

4. How do I use this medicine?

How much to take

  • Take one tablet daily at about the same time each day, without any break.
  • Follow the instructions provided and use this medicine until your doctor tells you to stop.

When to take this medicine

  • It does not matter if you take the medicine before or after food.

How to take it

  • Follow the direction of the arrows on the blister pack until all the tablets have been taken.
  • You can start taking the tablet on any day of your menstrual cycle.
  • You must take the tablets continuously without regard to vaginal bleeding. This means that after the first pack has been finished you should start the next without interruption.
  • Swallow the tablet whole with water.

If you forget to take this medicine

This medicine should be used regularly at the same time each day. This medicine may not work as well if you miss tablets or have vomiting and/or diarrhoea within 3-4 hours after tablet taking.

If you miss your dose at the usual time, you should take one tablet only, as soon as you remember. Then continue to take the tablet at your usual time the next day.

If you have vomiting and/or diarrhoea after taking the tablet, you should take one tablet, and then continue to take the tablet at your usual time the next day.

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

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

If you use too much dienogest

If you think that you have used too much dienogest, you may need urgent medical attention.

You should immediately:

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

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

5. What should I know while using this medicine?

Things you should do

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.

Tell your doctor you are using this medicine well in advance of any expected hospitalisation or surgery. Your doctor may tell you to stop taking this medicine several weeks before surgery, or at the time of immobilisation and when you can start taking it again.

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.

Call your doctor straight away if you:

  • become pregnant while taking this medicine. If in an exceptional case you should become pregnant during the use of this medicine, there is a higher likelihood in users of progestogen containing preparations like dienogest to have an ectopic pregnancy (the embryo develops outside the womb).
  • you experience unexplained abdominal complaints that are different to the symptoms you commonly experience from your endometriosis. In this case an ectopic pregnancy must be considered.

Remind any doctor, dentist or pharmacist you visit that you are using this medicine.

Things you should not do

  • Do not take this medicine 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.

Contraception methods

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

Driving or using machines

Be careful before you drive or use any machines or tools until you know how this medicine affects you.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • 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 below 25°C. Protect from light.

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

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

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

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effectsWhat to do
Head complaints:
  • headache or migraine
Food related:
  • weight gain
Mood issues:
  • mood changes, including depression, irritability, nervousness, problems sleeping, loss of interest in sex
Stomach complaints:
  • nausea, abdominal pain, wind, swollen tummy or vomiting
Skin problems:
  • acne, hair loss
Muscle issues:
  • back pain
  • unusual weakness
Women's health:
  • breast discomfort
  • hot flushes
  • uterine/vaginal bleeding including spotting
Speak to your doctor if you have any of these less serious side effects and they worry you.
Menstrual bleeding patterns:
  • Dienogest treatment affects the menstrual bleeding pattern in the majority of women. If bleeding is heavy and continuous over time, this may lead to anaemia.
Speak to your doctor if bleeding is heavy and continuous over time. Your doctor may advise you to stop taking this medicine.
Bone mineral density (BMD):
  • The long term use of this medicine may affect the bone mineral density (BMD) of adolescents (12 to < 18 years).
Ask your doctor for their advice to improve your bone health and reduce your risk of bone loss (osteoporosis).

Serious side effects

Serious side effectsWhat to do
Blood clot (thrombosis):

Thrombosis is the formation of a blood clot which may block a blood vessel. It may occur in the deep veins of the legs (causing deep venous thrombosis), arteries of the lungs (causing pulmonary embolism), blood vessels of the heart (causing a heart attack), or the brain (causing a stroke).

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.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
If you notice possible signs of a blood clot, stop taking this medicine and consult your doctor immediately.
Liver tumours:
  • Benign or malignant liver tumours may lead to internal bleeding
Contact your doctor immediately if you have severe pain in your abdomen.
Breast cancer:
  • Lumps in breasts
Contact your doctor if you feel any lump in your breast.

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

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

Reporting side effects

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

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

7. Product details

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

What this medicine contains

Active ingredient
(main ingredient)		Dienogest 2 mg
Other ingredients
(inactive ingredients)		Lactose monohydrate
Potato starch
Microcrystalline cellulose
Povidone
Purified talc
Crospovidone
Magnesium stearate
Potential allergensLactose monohydrate

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

This medicine does not contain gluten, tartrazine or any other azo dyes.

What this medicine looks like

Dinasane 2 mg tablets:

White to off-white, round, flat faced bevelled edge tablets debossed with “NC” on one side and “22” on other side.

Blister packs of 2 x 14, 6 x 14 or 12 x 14 tablets (AUST R 336683).

Not all pack sizes may be available.

Who distributes this medicine

This medicine is supplied in Australia by:

Arrotex Pharmaceuticals
15-17 Chapel St
Cremorne VIC 3121
Australia

This leaflet was prepared in March 2021.

Published by MIMS January 2022

BRAND INFORMATION

Brand name

Dinasane

Active ingredient

Dienogest

Schedule

S4

 

1 Name of Medicine

Dienogest.

2 Qualitative and Quantitative Composition

Each tablet contains 2 mg of dienogest.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

White to off-white, round, flat faced bevelled edge tablets debossed with "NC" on one side and "22" on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of endometriosis.

4.2 Dose and Method of Administration

Tablet taking can start on any day of the menstrual cycle. The dosage of dienogest 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 dienogest 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.

4.3 Contraindications

Dienogest 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 dienogest, 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.

Pregnancy must be excluded and any hormonal contraception needs to be stopped prior to initiation of dienogest. If contraception is required, non-hormonal methods of contraception should be used (e.g. barrier method) 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 dienogest should be decided on only after carefully weighing the benefits against the risks.
As dienogest 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 dienogest although not all of the warnings and precautions are based on respective findings in the clinical studies with dienogest.
If any of the conditions/risk factors mentioned below is present or deteriorates, an individual risk-benefit analysis should be done before dienogest 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 dienogest (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.

Dienogest 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 dienogest. If bleeding is heavy and continuous over time this may lead to anaemia (severe in some cases). In the event of anaemia, discontinuation of dienogest 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 dienogest.

Osteoporosis and changes in bone mineral density (BMD).

Currently, long-term data on BMD and risk of fractures in users of dienogest are not available. BMD was assessed in 21 adult patients before and after 6 months of treatment with dienogest 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 dienogest because endogenous oestrogen levels are moderately decreased during treatment with dienogest (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Safety).
The use of dienogest 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 4.4 Special Warnings and Precautions for Use, Paediatric use; Section 5.1 Pharmacodynamic Properties, Clinical trials).
Therefore the treating physician should weigh the benefits of dienogest 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 dienogest.

Other.

Patients who have a history of depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.
Dienogest generally does not appear to affect blood pressure in normotensive women.
However, if a sustained clinically significant hypertension develops during the use of dienogest, it is advisable to withdraw dienogest 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 dienogest.
Persistent ovarian follicles (often referred to as functional ovarian cysts) may occur during the use of dienogest. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain.
Each dienogest tablet contains 63 mg of lactose monohydrate. 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 dienogest tablets.

Diabetes.

Dienogest tablets 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 dienogest tablets.

Medical examination.

A complete medical history and physical and gynaecological examination should be taken prior to the initiation or reinstitution of dienogest, guided by the Contraindications and Precautions, and should be repeated at least annually during the use of dienogest. 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.

Dienogest 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 dienogest in the geriatric population.

Paediatric use.

Dienogest is not indicated in children prior to menarche.
The efficacy of dienogest has been demonstrated in the treatment of endometriosis-associated pelvic pain in adolescent patients (12 - < 18 years).
The use of dienogest 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 dienogest 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 dienogest 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 estradiol 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 estradiol 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 dienogest on other medicinal products.

Based on in vitro inhibition studies, a clinically relevant interaction of dienogest 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 dienogest.

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 dienogest. However, dienogest 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 dienogest.
(Category B3)
The administration of dienogest during pregnancy is contraindicated. If pregnancy occurs during use of dienogest, 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, dienogest 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 dienogest 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 breast feeding or to abstain from dienogest therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

4.7 Effects on Ability to Drive and Use Machines

Not known.

4.8 Adverse Effects (Undesirable Effects)

Undesirable effects are more common during the first months after start of intake of dienogest, 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 dienogest.
The most frequently reported undesirable effects during treatment that were considered at least possibly related to dienogest 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 dienogest 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 dienogest): 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%)*.
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%)*.
Changes in menstrual bleeding patterns were only occasionally reported as adverse event by the patients (see Table 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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Acute toxicity studies performed with dienogest 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 dienogest tablets) over 24 weeks of use was well tolerated.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

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 dienogest 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 dienogest. EAPP was measured on a Visual Analog Scale (VAS) (0 - 100 mm). After 3 months of treatment with dienogest, 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 dienogest (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 dienogest (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 dienogest versus the GnRH analogue leuprorelin acetate (LA) including 120 patients on dienogest. 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 (dienogest 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. Dienogest has not been tested for contraceptive efficacy in larger studies.
The efficacy of dienogest 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 dienogest.
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 dienogest for up to 15 months (n = 168).

Long-term safety.

A long-term post-approval observational active surveillance study was conducted to investigate the incidence of first-time occurrence or worsening of clinically relevant depression and occurrence of anaemia. A total of 27,840 women with a newly prescribed hormonal therapy for endometriosis were enrolled in the study and followed up for up to 7 years.
A total of 3,023 women started with prescription for dienogest 2 mg and 3,371 patients started with other approved endometriosis drugs. The overall adjusted hazard ratio for new occurrences of anaemia comparing the dienogest patients with the patients on other approved endometriosis drugs was 1.1 (95% CI: 0.4 - 2.6). The adjusted hazard ratio for depression risk comparing dienogest and other approved endometriosis drugs was 1.8 (95% CI: 0.3-9.4). A slightly increased risk of depression in dienogest users compared with users of other approved endometriosis drugs could not be excluded.

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 dienogest 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 dienogest tablets. 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 dienogest.
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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, potato starch, microcrystalline cellulose, povidone, purified talc, crospovidone, magnesium stearate.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

Blister pack (PCV/PVDC/Al) of 2 x 14, 6 x 14 or 12 x 14 tablets (AUST R 336683).
Not all pack sizes may be 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.

6.7 Physicochemical Properties

Dienogest is a white, almost white or slightly yellow, crystalline powder.

Chemical structure.


Chemical Name: 17α-Hydroxy-3-oxo-19-norpregna-4,9-diene-21-nitrile (IUPAC).
Molecular Formula: C20H25NO2.
Molecular Weight: 311.43.

CAS number.

65928-58-7.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes