DIMETRUM

Dienogest is an

Oral-active semisynthetic progestogen which also possesses the properties of 17α-hydroxyprogesterone.

It is a derivative of 19-nortestosterone and has antiandrogenic properties.

It is primarily used as a contraceptive in combination with ethinylestradiol, or in other combination form pills approved in United States and Europe however it is not available in the US by itself.

In Europe, Australia, Malaysia, Singapore and Japan, dienogest single therapy is an approved treatment for endometriosis to alleviate painful symptoms of endometriosis and reduce endometriotic lesions 1.

Dienogest is commonly marketed as

Indicated for use as the treatment of endometriosis alone and as a contraceptive in combination with ethinylestradiol.

Dienogest exhibits a very potent progestagenic effect in the endometrium, and causes endometrial atrophy after prolonged use 2.

It also mediates an antiandrogenic effect that is equivalent to approximately one third that of cyproterone acetate 5.

A dose of 2 mg inhibits the growth of ovarian follicles at 10 mm and maintains the concentration of progesterone at a low level, but has a weak inhibitory effect on FSH and LH. 1 mg/kg of dienogest also directly inhibits ovulation 2.

In clinical trials composing of patients with endometriosis, dienogest therapy effectively reduced painful symptoms and endometriotic lesions associated with the disorder 1.

Dienogest displays no antiestrogenic activity as it activate neither estrogen receptor (ER) α nor ERβ 4, and causes hypoestrogenic effects instead as it is shown to decrease the relative expressions of ERβ and ERα 3.

It has no glucocorticoid or mineralocorticoid effects.

In combined oral contraceptive pills (COCP) with ethinyloestradiol, dienogest conjuction therapy effectively reduces the symptoms of acne and hirsutism, as well as improving excessively heavy or prolonged menstrual bleeding 2.

Dienogest is rapidly absorbed following oral administration, with 91% bioavailability.

The peak plasma concentration of 47 ng/mL is reached at about 1.5 hours after single ingestion of 2 mg 5.

The stable concentrations of the drug are reached after two days of initial treatment 2.

The apparent volume of distribution (Vd/F) of dienogest is 40 L 5.

Dienogest undergoes complete metabolism that is mainly mediated by CYP3A4.

The metabolites are pharmacologically inactive and rapidly eliminated from the plasma.

The ratio of renal elimination to fecal elimination of dienogest is 3:1, where dienogest is predominantly excreted in the form of inactive metabolites.

Most of

Oral administered drug is excreted in the urine within the first 24 hours of ingestion 5.

Elimination half-life of dienogest is around 9-10 hours.

The half-life of urinary metabolites excretion is 14 hours 5.

The metabolic clearance rate from serum (Cl/F) is 64 mL/min 5.

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LD50 in mouse is 4 mg/kg MSDS.

In a long-term carcinogenicity study involving rats and mice, exposure of 10 times the dose of maximum recommended clinical dose of dienogest resulted in increased incidences of pituitary adenomas, fibroepithelial mammary tumours, stromal polyps of the uterus and malignant lymphoma 6.

These tumors are thought to arise from marked species differences in the optimal oestrogen:progestogen ratio for reproductive function.

In rat liver foci assay, dienogest did not induce tumor promotion activity 6.

Dienogest does not display genotoxic potential.

• A high risk of arterial or venous thrombotic diseases.

• Smoke, if over age 35.

• Have deep vein thrombosis or pulmonary embolism, now or in the past.

• Have cerebrovascular disease.

• Have coronary artery disease.

• Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation).

• Have inherited or acquired hypercoagulopathies.

• Have uncontrolled hypertension.

• Have diabetes mellitus with vascular disease.

• Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35.

• Undiagnosed abnormal uterine bleeding.

• Current diagnosis of, or history of, breast cancer, which may be hormone sensitive.

• Liver tumors, benign or malignant, or liver disease ).

• Breast cancer.

• Liver tumors or liver disease.

• Take one tablet daily by mouth at the same time every day.

• Tablets must be taken in the order directed on the blister pack.

• Do not skip or delay intake by more than 12 hours. 2.1 How to Take Natazia To achieve maximum contraceptive effectiveness, Natazia must be taken exactly as directed.

Take one tablet by mouth at the same time every day. Tablets must be taken in the order directed on the blister pack.

Tablets should not be skipped or intake delayed by more than 12 hours.

For patient instructions for missed pills, see FDA-Approved Patient Labeling. 2.2 How to Start Natazia Instruct the patient to begin taking Natazia on Day of her menstrual cycle (that is, the first day of her menstrual bleeding).

Instruct the patient to use a non-hormonal contraceptive as back-up during the first 9 days.

For postpartum women who do not breastfeed or after a second trimester abortion, start Natazia no earlier than 4 weeks postpartum due to the increased risk of thromboembolism.

If the patient starts on

Natazia postpartum and has not yet had a period, evaluate for possible pregnancy, and instruct her to use an additional method of contraception until she has taken Natazia for 9 consecutive days.

The possibility of ovulation and conception prior to initiation of medication should also be considered.

• Another pill.

• Vaginal ring.

• Instruct her to take the first dark yellow pill on the first day of her withdrawal bleed.

She should not continue taking the pills from her previous birth control pack.

If she does not have a withdrawal bleed, rule out pregnancy before starting Natazia.

• If she previously used a vaginal ring or transdermal patch, she should start using Natazia on the day the ring or patch is removed.

• Instruct the patient to use a non-hormonal back-up method such as a condom or spermicide for the first 9 days.

• Progestin-only pill.

• Intrauterine system.

• Instruct her to take the first dark yellow pill on the day she would have taken her next progestin-only pill or on the day of removal of her implant or intrauterine system or on the day when she would have had her next injection.

• Instruct the patient to use a non-hormonal back-up method such as a condom or spermicide for the first 9 days. 2.3 Advice in case of Gastrointestinal Disturbances In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken.

If vomiting or diarrhea occurs within 3-4 hours after taking a colored tablet, this can be regarded as a missed tablet.

Natazia (estradiol valerate and estradiol valerate/dienogest) tablets are available in packages of three blister packs (NDC 50419-409-03).

The active and inert film-coated tablets are rounded with biconvex faces, one side is embossed with a regular hexagon shape with the letters DD or DJ or DH or DN or DT.

• 2 round biconvex dark yellow film-coated tablets with embossed “DD” in a regular hexagon on one side each containing 3 mg estradiol valerate.

• 5 round biconvex medium red film-coated tablets with embossed “DJ” in a regular hexagon on one side each containing 2 mg estradiol valerate and 2 mg dienogest.

• 17 round biconvex light yellow film-coated tablets with embossed “DH” in a regular hexagon on one side each containing 2 mg estradiol valerate and 3 mg dienogest.

• 2 round biconvex dark red film-coated tablets with embossed “DN” in a regular hexagon on one side each containing 1 mg estradiol valerate.

• 2 white round biconvex white film-coated tablets with embossed “DT” in a regular hexagon on one side (inert) 16.2 Storage Store at 25º C (77º F); excursions permitted to 15–30 o C (59–86 o F) .

Risk Summary There is no reason to use COCs in pregnancy Discontinue Natazia if pregnancy occurs.

Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to COCs prior to conception or during early pregnancy.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4 percent and to 20 percent, respectively.

Safety and efficacy of

Natazia have been established in women of reproductive age.

Efficacy is expected to be the same for postpubertal adolescents under the age of and for users 18 years and older.

Use of this product before menarche is not indicated.

Natazia has not been studied in postmenopausal women and is not indicated in this population.