Dienogest 2 Mg Tablets

Treatment of endometriosis. Safety and efficacy beyond 24 months have not been established.

Posology Tablet - taking from the very first pack should start on day 1 of the womanu2019s natural cycle (i.e., the first day of her menstrual bleeding). The dosage of DIENOGEST 2 mg PHARMC is one tablet daily without any break, taken preferably at the same time each day with some liquid as needed. Tablets must be taken throughout 28 days without regard for bleeding. When a pack is finished the next one should be started without interruption. The efficacy of DIENOGEST 2 mg PHARMC may be reduced in the event of missed tablets, vomiting, and/or diarrhoea (if occurring within 3 to 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 next day to take tablet at her usual time. A tablet not absorbed due to vomiting or diarrhoea should likewise be replaced by one tablet. Method of administration: For oral use.

DIENOGEST 2 mg PHARMC should not be used in the presence of any condition listed below. Should any of the conditions appear during the use of DIENOGEST 2 mg PHARMC, the use of DIENOGEST 2 mg PHARMC must be discontinued immediately:

• Hypersensitivity to dienogest or to any of the excipients (see section 6.1).
• Known or suspected pregnancy.
• Lactation.
• History of or active venous thromboembolic disorder.
• Arterial and cardiovascular diseases, past or present (e.g., myocardial infarction, cerebrovascular events, ischaemic heart disease).
• Diabetes mellitus with vascular involvement.
• Presence or history of severe hepatic disease as long as liver function values have not returned to normal.
• Presence or history of liver tumours (benign or malignant).
• Known or suspected sex hormone-dependent malignancies.
• Undiagnosed vaginal bleeding.

As DIENOGEST 2 mg PHARMC is a progestogen-only preparation it can be assumed that the special warnings and precautions for use of progestogen-only preparations are also valid for the use of DIENOGEST 2 mg PHARMC 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 treatment with DIENOGEST 2 mg PHARMC can be started or continued.

Serious uterine bleeding
Uterine bleeding, for example in women with adenomyosis uteri or uterine leiomyomata, may be aggravated with the use of DIENOGEST 2 mg PHARMC. If bleeding is heavy and continuous over time, this may lead to anemia (severe in some cases). In the event of anemia, discontinuation of DIENOGEST 2 mg PHARMC should be considered.

Changes in bleeding pattern
The majority of patients treated with dienogest experience changes in their menstrual bleeding pattern (see section 4.8).

Circulatory disorders
From epidemiological studies there is little evidence for an association between progestogen-only preparations and an increased risk of myocardial infarction or cerebral thromboembolism. Rather, 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. Although not statistically significant, some studies indicate that there may be a slightly increased risk of venous thromboembolism (deep venous thrombosis, pulmonary embolism) associated with the use of progestogen-only preparations. Generally recognized 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 immobilization, major surgery or major trauma. In case of long-term immobilization, it is advisable to discontinue the use of DIENOGEST 2 mg PHARMC (in the case of elective surgery at least four weeks in advance) and not to resume treatment until two weeks after complete remobilization. The increased risk of thromboembolism in the puerperium must be considered. Treatment should be stopped at once if there are symptoms of an arterial or venous thrombotic event or suspicion thereof.

Tumours
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 using oestrogen-progestogen preparations. The excess risk gradually disappears during the course of the 10 years after cessation of combined OC (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 users of progestogen-only preparations is possibly of similar magnitude to that associated with COC. However, for progestogen-only preparations, the evidence is based on much smaller populations of users and so is less conclusive than that 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 users of OCs tend to be less advanced clinically than the cancers diagnosed in those who have never used OCs. 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 2 mg PHARMC. 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 2 mg PHARMC.

Osteoporosis
Changes in bone mineral density (BMD). The use of dienogest in adolescents (12 to <18 years) over a treatment period of 12 months was associated with a decrease in bone mineral density (BMD) in the lumbar spine (L2 - L4). The mean relative change in BMD from baseline to the end of treatment (EOT) was u2013 1, 2 % with a range between - 6 % and 5 % (IC 95 %: - 1, 70 % and - 0, 78 %, n=103. Repeated measurement at 6 months after the EOT in a subgroup with decreased BMD values showed a trend towards recovery. (Mean relative change from baseline: u2013 2, 3 % at EOT and u2013 0, 6 % at 6 months after EOT with a range between - 9 % and 6 % (IC 95 %: - 1, 20 % and 0, 06 % (n=60). 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. In patients who are at an increased risk of osteoporosis a careful risk-benefit assessment should be performed before starting DIENOGEST 2 mg PHARMC because endogenous oestrogen levels are moderately decreased during treatment with DIENOGEST 2 mg PHARMC. Adequate intake of calcium and Vitamin D, whether from the diet or from supplements, is important for bone health in women of all ages.

Other conditions
Patients who have a history of depression should be carefully observed and the DIENOGEST 2 mg PHARMC should be 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 2 mg PHARMC, it is advisable to withdraw DIENOGEST 2 mg PHARMC 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 2 mg PHARMC.

DIENOGEST 2 mg PHARMC may have a slight effect on peripheral insulin resistance and glucose tolerance. Diabetic women, especially those with a history of gestational diabetes mellitus, should be carefully observed while taking DIENOGEST 2 mg PHARMC. 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 2 mg PHARMC. Pregnancies that occur among users of progestogen-only preparations used for contraception 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 2 mg PHARMC should be decided on only after carefully weighing the benefits against the risks. Patients are advised to use non-hormonal methods of contraception (barrier contraception, e.g., condom) to prevent unwanted pregnancies. Persistent ovarian follicles (often referred to as functional ovarian cysts) may occur during the use of DIENOGEST 2 mg PHARMC. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain.

Excipient warning
DIENOGEST 2 mg PHARMC contains lactose monohydrate which may have an effect on the glycaemic control of patients with diabetes mellitus. Patients with rare hereditary conditions of galactose intolerance e.g., galactosaemia, Lapp lactase deficiency, glucose-galactose malabsorption or fructose intolerance should not take DIENOGEST 2 mg PHARMC.

Note: The prescribing information of concomitant medication should be consulted to identify potential interactions.

Effects of other medicines on DIENOGEST 2 mg PHARMC
Individual enzyme-inducers or inhibitors (CYP3A4): 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 metabolism. An increased clearance of sex hormones due to enzyme induction may reduce the therapeutic effect of DIENOGEST 2 mg PHARMC 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.

Medicines with enzyme-inducing properties:
Interactions can occur with medicines 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 medicines containing St. Johnu2019s wort (Hypericum perforatum). Enzyme induction can already be observed after a few days of treatment. Maximum enzyme induction is generally seen within a few weeks. After 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 and oestradiol. The systemic exposure of dienogest and oestradiol at steady state, measured by AUC(0 - 24h), were decreased by 83 % and 44 %, respectively.

Medicines with variable effects on the clearance of sex hormones:
When co-administered with sex hormones, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with HCV inhibitors can increase or decrease plasma concentrations of the progestin. The net effect of these changes may be clinically relevant in some cases.

Medicines decreasing the clearance of sex hormones (enzyme inhibitors):
Known CYP3A4 inhibitors like azole antifungals (e.g., ketoconazole, itraconazole, fluconazole), cimetidine, verapamil, macrolides (e.g., erythromycin, clarithromycin and roxithromycin), diltiazem, protease inhibitors (e.g., ritonavir, saquinavir, indinavir, nelfinavir), antidepressants (e.g., nefazodone, fluvoxamine, fluoxetine) may increase plasma levels of progestogens and result in undesirable effects. Dienogest is a substrate of cytochrome P450 (CYP) 3A4. The clinical relevance of potential interactions with enzyme inhibitors remains unknown. Concomitant administration of strong CYP3A4 inhibitors can increase plasma concentrations of dienogest. Coadministration with the strong CYP3A4 enzyme inhibitor ketoconazole resulted in a 2, 9-fold increase of AUC (0 - 24h) at steady state for dienogest. Concomitant administration of the moderate inhibitor erythromycin increased the AUC (0 - 24h) of dienogest at steady state by 1, 6-fold.

Effects of DIENOGEST 2 mg PHARMC on other medicines
Based on in vitro inhibition studies, a clinically relevant interaction of dienogest with the cytochrome P450 enzyme mediated metabolism of other medication is unlikely.

Interaction with food
A standardized high fat meal did not affect the bioavailability of dienogest 2 mg. Due to the metabolism of dienogest, which is mainly by the cytochrome P450 3A4 system (CYP3A4), patients should avoid grapefruit juice while being treated with DIENOGEST 2 mg PHARMC, as grapefruit juice is an inhibitor of CYP3A4.

Laboratory tests
The use of progestogens may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins (e.g., corticosteroid binding globulin and lipid/lipoprotein fractions), parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.

Pregnancy
There is limited data from the use of dienogest in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. DIENOGEST 2 mg PHARMC must not be administered to pregnant women because there is no need to treat endometriosis during pregnancy.

Breast feeding
Treatment with DIENOGEST 2 mg PHARMC during lactation is not recommended. It is unknown whether dienogest is excreted in human milk. Data in animals have shown excretion of dienogest in rat milk.

Fertility
Based on the available data, ovulation is inhibited in the majority of patients during treatment with dienogest. However, DIENOGEST 2 mg PHARMC is not a contraceptive. If contraception is required a non-hormonal method should be used (see section 4.2). Based on available data, the menstrual cycle returns to normal within 2 months after cessation of treatment with DIENOGEST 2 mg PHARMC.

No effects on the ability to drive and use machines have been observed in users of medicines containing dienogest.

a. Summary of the safety profile
Undesirable effects are more frequent during the first months after the start of treatment with DIENOGEST 2 mg PHARMC and subside with continued treatment. There may be changes in bleeding pattern, such as spotting, irregular bleeding or amenorrhea. The following undesirable effects have been reported in users of dienogest 2 mg tablets. The most frequently reported undesirable effects under treatment with dienogest 2 mg are 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 2 mg are summarized in the table below. Within each frequency grouping, undesirable effects are presented in order of decreasing frequency.

MedDRA system organ class Frequency Adverse reactions Blood and lymphatic system disorders Less frequent Anaemia Metabolism and nutrition disorders Frequent Increased weight Less frequent Decreased weight, increased appetite Psychiatric disorders Frequent Depressed mood, sleep disorder, nervousness, loss of libido, altered mood Less frequent Anxiety, depression, mood swings Nervous system Frequent Headache, migraine Less frequent Autonomic nervous system imbalance, disturbance in attention Eye disorders Less frequent Dry eyes Ear and labyrinth disorders Less frequent Tinnitus Cardiac disorders Less frequent Unspecific circulatory system disorder, palpitations Vascular disorders Less frequent Hypotension Respiratory, thoracic and mediastinal disorders Less frequent Dyspnoea Gastrointestinal disorders Frequent Nausea, abdominal pain, flatulence, abdominal distension, vomiting Less frequent Diarrhoea, constipation, abdominal discomfort, gastrointestinal inflammation, gingivitis Skin and subcutaneous tissue disorders Frequent Acne, alopecia Less frequent Dry skin, hyperhidrosis, pruritus, hirsutism, onychoclasis, dandruff, dermatitis, abnormal hair growth, photosensitivity reaction, pigmentation disorder Musculoskeletal and connective tissue disorders Frequent Back pain Less frequent Bone pain, muscle spasms, pain in extremity, heaviness in extremities Renal and urinary disorders Less frequent Urinary tract infection Reproductive system and breast disorders Frequent Breast discomfort, ovarian cyst, hot flushes, uterine/vaginal bleeding including spotting Less frequent Vaginal candidiasis, vulvovaginal dryness, genital discharge, pelvic pain, atrophic vulvovaginitis, breast mass, fibrocystic breast disease, breast induration General disorders and administrative site conditions Frequent Asthenic conditions, irritability Less frequent Oedema

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions & Quality Problem Reporting Formu201d, found online under SAHPRAu2019s publications:

Acute toxicity studies performed with dienogest did not indicate a risk of acute adverse effects in case of inadvertent intake of a multiple of the daily therapeutic dose. There is no specific antidote. A daily intake of 20 - 30 mg dienogest (10 to 15 times higher dose than in DIENOGEST 2 mg PHARMC) over 24 weeks of use was very well tolerated. Treatment is symptomatic and supportive.