Oligest

Double convex, round and white colored tablet imprinted with "T60" on one side.
Each tablet contains 2 mg of dienogest.
Excipients/Inactive Ingredients: Lactose monohydrate, Microcrystalline cellulose, Crospovidone, Povidone K-30, Pregelatinized starch, Talc, Magnesium stearate.

Pharmacotherapeutic group: Progestogens. ATC code: G03DB08.
Pharmacology: Pharmacodynamics: Dienogest is a nortestosterone derivative with no androgenic but rather an 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 estradiol and thereby suppresses the trophic effects of estradiol on both the eutopic and ectopic endometrium. When given continuously, dienogest leads to a hypoestrogenic, hypergestagenic endocrine environment causing initial decidualization of endometrial tissue followed by atrophy of endometriotic lesions.
Data on efficacy: Superiority of dienogest over placebo was demonstrated in a 3-months study including 102 patients with dienogest for the reduction of endometriosis-associated pelvic pain (EAPP). Endometriosis-associated pelvic pain 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, a reduction of endometriosis-associated pelvic pain 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 endometriosis-associated pelvic pain 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 suggested a continued improvement of endometriosis-associated pelvic pain for a treatment duration of up to 15 months.
The placebo-controlled results were also supported by the results obtained in a 6 months active-controlled study versus a GnRH agonist including 252 patients with endometriosis. The studies have shown that patients who received a daily dose of 2 mg dienogest demonstrated a reduction of endometriotic lesions after 6 months of treatment.
Pharmacokinetics: Absorption: Orally administered dienogest is rapidly and almost completely absorbed. Peak serum concentrations of 47 ng/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 concentration is present as free steroid, 90% is non-specifically bound to albumin.
The apparent volume of distribution (V_d/F) of dienogest is 40 L.
Metabolism/Biotransformation: Dienogest is completely metabolized by the known pathways of steroid metabolism, with the formation of metabolites which are mostly inactive endocrinologically. 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; therefore in plasma, unchanged dienogest is the dominating fraction.
The metabolic clearance rate from serum (Cl/F) is 64 ml/min.
Elimination/Excretion: Dienogest serum levels decrease in 2 phases. The terminal disposition phase is characterized by a half-life of approximately 9 to 10 hours. Dienogest is excreted in the form of inactive metabolites which are excreted at a urinary to fecal 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 administered dose is eliminated within 6 days. Most of the drug is excreted in the urine within the first 24 hours.
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 OLIGEST can be predicted from single dose pharmacokinetics.
Pharmacokinetics in Special Population: Dienogest has not been studied specifically in renally impaired subjects. Dienogest has not been studied in subjects with hepatic impairment.
Toxicology: Preclinical safety data: Preclinical data reveal no special risks for humans based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. However, it should be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.

Endometriosis: OLIGEST is indicated for the management of endometriosis.

The dosage of OLIGEST is one tablet daily without any break, taken preferably at the same time each day with some liquid as needed. The tablet can be taken with or without food. Tablets must be taken continuously without regard to vaginal bleeding.
When a pack is finished the next one should be started without interruption. Treatment can be started on any day of the menstrual cycle. 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).
Management of missed tablets: The efficacy of OLIGEST may be reduced in the event of missed tablets, vomiting and/or diarrhea (if occurring within 3-4 hours after tablet taking). In the event of one or more missed tablets, the woman should take one tablet only, as soon as she remembers, and should then continue the next day at her usual time. A tablet not absorbed due to vomiting or diarrhea should likewise be replaced by one tablet.
Additional Information on Special Populations: Paediatric Population: Dienogest is not indicated in children prior to menarche.
Adolescent Population: The safety and efficacy of dienogest was investigated in clinical trial over 12 months in 111 adolescent women (12-18 years) with clinically suspected or confirmed endometriosis. The use of dienogest in adolescents over a treatment period of 12 months was associated with a mean decrease in BMD in the lumbar spine of 1.2%. After cessation of treatment, BMD increased towards pre-treatment levels in majority of these patients.
Therefore, the treating physician should weigh the benefits of dienogest against the possible risks of use in each individual adolescent patient and re-evaluate on a regular basis. (See Precautions and Pharmacology: Pharmacodynamics under Actions).
Geriatric Population: There is no relevant indication for use of dienogest in the post menopause.
Patients with Hepatic Impairment: Dienogest is contraindicated in patients with present or past severe hepatic disease (see Contraindications).
Patients with Renal Impairment: There are no data suggesting the need for a dosage adjustment in patients with renal impairment.

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) over 24 weeks of use was very well tolerated.

Dienogest should not be used in the presence of any of the conditions listed as follows, which are partially derived from information on other progesterone-only preparations. Should any of the conditions appear during the use of dienogest, treatment must be discontinued immediately.
Active venous thromboembolic disorder.
Arterial and cardiovascular disease, past or present (e.g. myocardial infarction, cerebrovascular accident, ischemic 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 tumors (benign or malignant).
Known or suspected sex hormone-dependent malignancies.
Undiagnosed vaginal bleeding.
Hypersensitivity to the active substance or to any of the excipient.
Ocular lesions due to ophthalmic vascular disease, such as partial or complete vision loss or defect in visual.
Presence or history of migraine with focal aura.
Breastfeeding or pregnancy.

As dienogest 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 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 as follows is present or deteriorates, an individual risk-benefit analysis should be done before treatment with dienogest can be started or continued.
Changes in Bleeding Pattern: The majority of patients treated with dienogest experience with irregular menstrual bleeding pattern e.g. amenorrhea, infrequent or frequent bleeding, prolonged bleeding. And may be aggravated in some patients. Bleeding patterns generally show a reduced intensity over time. If bleeding irregularities continue with prolonged use, appropriate diagnostic measures should be taken to rule out endometrial pathology e.g. endometrial sampling, pelvic ultrasound. Consider discontinuation of therapy with prolonged heavy bleeding. Pretreatment menstrual bleeding patterns return within 2 months of therapy discontinuation.
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. The risk of stroke may be increased in patients with hypertension. Discontinue if clinically significant hypertension develops during therapy.
Use with caution in patients with risk factors for venous thromboembolism (VTE) including, personal or family history (VTE in a sibling or a parent at a relatively early age), obesity, prolonged immobilization, major surgery, or major trauma.
Treatment should be stopped at once if there are symptoms of an arterial or venous thrombotic event or suspicion thereof.
Tumors: 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 estrogen-progestogen preparations. The excess risk gradually disappears during the course of the 10 years after cessation of combined OC (COC) use. There are insufficient data specific to progestin-only preparations. However, breast cancer is a hormonal-sensitive tumor and prognosis for patients with a current or recent history of breast cancer may be worse with contraceptive use.
In rare cases, benign liver tumors, and even more rarely, malignant liver tumors have been reported in users of hormonal substances.
Osteoporosis: Bone Mineral Density (BMD) in Adult Women: Endogenous estrogen levels are moderately decreased during treatment with dienogest.
Currently, long-term data on bone mineral density (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.
Bone Mineral Density in Adolescent Females: The use of dienogest in adolescents (12 to 18 years) over a treatment period of 12 months was associated with a mean decrease in BMD in the lumbar spine of 1.2%. Follow-up measurement at 6 months after the treatment in a subgroup with decreased BMD values showed that the mean BMD was increased to -0.6%. After cessation of treatment, BMD increased towards pre-treatment levels in majority of these patients.
In adolescent patients, the use of dienogest has been associated with plateauing and loss of BMD which may not be completely reversible. Loss of BMD is of particular concern during adolescence and early adulthood, as this is a critical period of bone accretion. BMD loss may be greater with increasing duration of use. It is unknown if BMD decrease in this population will reduce peak bone mass and increase the risk for fracture in later life.
Risk/benefits of therapy in adolescents should be evaluated prior to initialing therapy and regularly during therapy. (See Additional Information on Special Populations: Pediatric Population under Dosage & Administration and Pharmacology: Pharmacodynamics under Actions.)
In patients who are at an increased risk of osteoporosis a careful risk-benefit assessment should be performed before starting dienogest because endogenous estrogen levels are moderately decreased during treatment with dienogest. (See Pharmacology: Pharmacodynamics under Actions.)
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 drug 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, it is advisable to withdraw dienogest and treat the hypertension.
Patients with a prior history of cholestatic jaundice and/or pruritus during pregnancy or due to the use of sex steroids should discontinue use of dienogest if cholestatic jaundice and/or pruritus reoccurs during therapy.
Dienogest may impair glucose tolerance. Diabetic women, especially those with a history of gestational diabetes mellitus, should be carefully observed while taking dienogest. Chloasma may occasionally occur, especially in women with a history of chloasma. Patients should avoid exposure to the sun or ultraviolet radiation whilst taking dienogest.
Persistent ovarian follicles (often referred to as functional ovarian cysts) which are often asymptomatic may occur during therapy.
Lactose: Each OLIGEST tablet contains 102.9 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 OLIGEST.
Effects on Ability to Drive and Use Machines: No effects on the ability to drive and use machines have been observed in users of products containing dienogest.

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 (see Pharmacology: Toxicology: Preclinical safety data under Actions). Dienogest must not be administered to pregnant women because there is no need to treat endometriosis during pregnancy.
Lactation: Treatment with dienogest 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. 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.
Fertility: Based on the 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 (see Precautions).
Based on available data, the menstrual cycle returns to normal within 2 months after cessation of treatment with dienogest.

Undesirable effects are more common during the first months after the start of treatment with dienogest, and subside with continued treatment. The following undesirable effects have been reported in users of dienogest.
The most frequently reported undesirable effects under treatment with dienogest (considered at least possibly dienogest-related) are headache (9.0%), breast discomfort (5.4%), depressed mood (5.1%) and acne (5.1%).
Adverse event summary table: The frequencies of adverse drug reactions (ADRs) by MedDRA system organ classes (MedDRA SOCs) reported with dienogest are summarized in the table as follows. 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 (≥1/1,000 to <1/100). The frequencies are based on pooled data of four clinical trials, including 332 patients (100.0%). (See table.)

Click on icon to see table/diagram/image

No significant changes of the mean values of standard laboratory parameters (including haematology, blood chemistry, liver enzymes, lipids and HbA1C) were observed during treatment with dienogest for up to 15 months (n=168).
Decrease of bone mineral density: In an uncontrolled clinical trial with 111 adolescent women (12 to <18 years) who were treated with dienogest, 103 had BMD measurements. Approximately 72% of these study participants experienced a decrease in BMD of the lumbar spine (L2-L4) after 12 months of use (see Precautions).

Effects of Other Medicinal Products on Dienogest: Progestogens including dienogest are metabolized mainly by the cytochrome P450 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 cessation of drug therapy, enzyme induction may be sustained for about 4 weeks.
The effect of the CYP3A4 inducer rifampicin was studied in healthy postmenopausal women. Coadministration of rifampicin with estradiol valerate/dienogest tablets led to significant decreases in steady state concentrations and systemic exposures of dienogest.
Substances with variable effects on the clearance of sex hormones, e.g.: When co-administered with sex hormones, many combinations of HIV/HCV protease inhibitors and nonnucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of the progestin. The net effect of 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.
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 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 medication is unlikely.
Interaction with Food: A standardized high fat meal did not affect the bioavailability of dienogest.
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.

Incompatibilities: Not applicable.

Store below 30°C and keep in the original package, protect from light.

Oestrogens, Progesterones & Related Synthetic Drugs

G03DB08 - dienogest ; Belongs to the class of pregnadien derivative progestogens used in progestogenic hormone preparations.

D