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.
4.1 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
