Dienogest

Dienogest is an orally-active semisynthetic, steroidal progestogen (or progestin). It is available for use as an oral contraceptive in combination with ethinylestradiol. It has antiandrogenic activity and as a result can improve androgenic symptoms. It is a non-ethinylated progestin which is structurally related to testosterone. Dienogest given in isolation is available for the treatment of endometriosis under the trade name Dienogest.

Herbal preparations containing St John’s wort are used, frequently for self-medication, in the treatment of depression. Such preparations are also promoted for the treatment of other nervous disorders such as insomnia and anxiety, particularly if associated with the menopause.

Hypericin, a major constituent of St John’s wort, has been investigated as an antiviral in the treatment of HIV infection and AIDS.

St John’s wort has been used in homoeopathic preparations.

1 tab 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.

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

There is no experience with Dienogest treatment >15 months in patients with endometriosis.

The efficacy of Dienogest may be reduced in the event of missed tablets, vomiting and/or diarrhea (if occurring within 3-4 hrs after tab taking). In the event of missed tablet(s), the woman should take 1 tab only, as soon as she remembers, and should then continue the next day to take the tab at her usual time. A tablet not absorbed due to vomiting or diarrhea should likewise be replaced by 1 tablet.

Renal Impairment: There are no data suggesting the need for a dosage adjustment in patients with renal impairment.

Hepatic Impairment: Dienogest is contraindicated in patients with present or past severe hepatic disease.

Administration: For oral use.

Hypersensitivity to Dienogest or to any of the excipients of Dienogest.

Dienogest should not be used in the presence of any of the conditions listed as follows, 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: Active venous thromboembolic disorder, arterial and cardiovascular disease, present or in history (eg, 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, liver tumors (benign or malignant); known or suspected sex hormone-dependent malignancies; undiagnosed vaginal bleeding.

Use in pregnancy: There are limited data from the use of Dienogest in pregnant women. Animal studies and data from women exposed to Dienogest during pregnancy reveal no special risks on pregnancy, embryonic/fetal development, birth or development after birth for humans. However, Dienogest should not be administered to pregnant women because there is no need to treat endometriosis during pregnancy.

Effects of Other Medicaments on Dienogest: Individual Enzyme Inducers or Inhibitors (CYP3A4): Progestogens including Dienogest are metabolized mainly by the cytochrome P450 (CYP450) 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 adverse effects eg, 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 adverse effects.

Substances with Enzyme-Inducing Properties: Interactions can occur with drugs (eg, phenytoin, barbiturates, primidone, carbamazepine, rifampicin and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, nevirapine and products containing St. John's wort) that induce microsomal enzymes (eg, CYP450 enzymes) which can result in increased clearance of sex hormones.

Maximum enzyme induction is generally not seen for 2-3 weeks but may then be sustained for at least 4 weeks after the cessation of therapy.

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_{0-24 hrs}, was decreased by 83%.

Substances with Enzyme-Inhibiting Properties: Known CYP3A4 inhibitors eg, azole antifungals (eg, ketoconazole, itraconazole, fluconazole), cimetidine, verapamil, macrolides (eg, erythromycin, clarithromycin and roxithromycin), diltiazem, protease inhibitors (eg, ritonavir, saquinavir, indinavir, nelfinavir), antidepressants (eg, nefazodone, fluvoxamine, fluoxetine) and grapefruit juice may increase plasma levels of progestogens and result in adverse effects.

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_{0-24 hrs} at steady state for Dienogest. When co-administered with the moderate inhibitor erythromycin, the AUC_{0-24 hrs} of Dienogest at steady state was increased by 62%. The clinical relevance of these interactions is unknown.

Effects of Dienogest on Other Medicaments: Based on in vitro inhibition studies, a clinically relevant interaction of Dienogest with the CYP450 enzyme-mediated metabolism of other medicaments is unlikely.

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

Drug-Food Interactions: A standardized high fat meal did not affect the bioavailability of Dienogest.

Other Forms of Interactions: 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 eg, lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.

Summary of the Safety Profile: Adverse effects are more common during the first months after start of intake of Dienogest and subside with duration of treatment. The following adverse effects have been reported in users of Dienogest.

The most frequently reported adverse effects during treatment that were considered at least possibly related to Dienogest were headache (9%), 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 summarized in the table as follows. Within each frequency grouping, adverse 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 4 clinical trials including 332 patients (100%).

*The most appropriate MedDRA term (version 11.0) to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well.

Description of Selected Adverse Reactions: Uterine Bleeding Irregularities: Menstrual bleeding patterns were assessed systematically using patient diaries and were analyzed using the WHO 90 days reference period method. During the first reference period (ie, first 90 days of treatment with Dienogest): The following bleeding patterns were observed (n=290; 100%): Amenorrhea (1.7%), infrequent bleeding (27.2%), frequent bleeding (13.4%), irregular bleeding (35.2%), prolonged bleeding (38.3%), normal bleeding ie, none of the previous categories (19.7%).

During the 4th reference period, the following bleeding patterns were observed (n=149; 100%): Amenorrhea (28.2%), infrequent bleeding (24.2%), frequent bleeding (27.2%), irregular bleeding (21.5%), prolonged bleeding (4%), normal bleeding ie, none of the previous categories (22.8%), changes in menstrual bleeding were only occasionally reported as adverse event by the patients.