Dydrogesterone
A white lo pale yellow crystalline powder; odourless or al-
most odourless. Practically insoluble in water: soluble I in 40
of alcohol. I in 2 of chloroform, and I in 200 of ether; soluble
in acetone: sparingly soluble in ethyl alcohol; slightly solu-
ble in fixed oils. Protect from light.
Adverse Effects, Precautions and Interactions as for progestogens in general which are shown below :
PROGESTERONE
WARNINGS
The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal thrombosis). Should any of these occur or be suspected, the drug should be discontinued immediately.
Discontinue medication pending examination if there is sudden partial or complete loss of vision, or if there is a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, medication should be withdrawn.
The administration of any drug to nursing mothers should be done only when clearly necessary since many drugs are excreted in human milk. Detectable amounts of progestin have been identified in the milk of mothers receiving progestins. The effect of this on the nursing infant has not been determined.
Retrospective studies of morbidity and mortality in Great Britain and studies of morbidity in the United States have shown a statistically significant association between thrombophlebitis, pulmonary embolism, cerebral thrombosis and embolism, and the use of oral contraceptives. The estimate of the relative risk of thromboembolism in the study by Vessey and Doll was about seven fold, while Sartwell and associates in the United States found a relative risk of 4.4, meaning that the users are several times as likely to undergo thromboembolic disease without evident cause as nonusers. The American study also indicated that the risk did not persist after discontinuation of administration, and that it was not enhanced by long-continued administration. The American study was not designed to evaluate a difference between products.
PRECAUTIONS
General
The pretreatment physical examination should include special reference to breast and pelvic organs, as well as Papanicolaou smear.
Because progesterone may cause some degree of fluid retention, conditions which might be influenced by this factor, such as epilepsy, migraine, asthma, cardiac or renal dysfunction, require careful observation.
In cases of breakthrough bleeding, as in any cases of irregular bleeding per vaginum, nonfunctional causes should be borne in mind. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures are indicated.
Patients who have a history of psychic depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.
Any possible influence of prolonged progestin therapy on pituitary, ovarian, adrenal, hepatic or uterine functions awaits further study.
Although concomitant use of conjugated estrogens and ORGAGEST Capsules did not result in a decrease in glucose tolerance, diabetic patients should be carefully observed while receiving estrogen-progestin therapy.
The pathologist should be advised of progestin therapy when relevant specimens are submitted.
Because of the occurrence of thrombotic disorders (thrombophlebitis, pulmonary embolism, retinal thrombosis, and cerebrovascular disorders) in patients taking estrogen-progestin combinations, the physician should be alert to the earliest manifestation of these disorders.
Transient dizziness may occur in some patients. Use caution when driving a motor vehicle or operating machinery. A small percentage of women may experience extreme dizziness and/or drowsiness during initial therapy. For these women, bedtime dosing is advised.
Information for the Patient
See accompanying Patient Insert.
General: This product contains peanut oil and should not be used if you are allergic to peanuts.
Drug Lab Test Interactions
The following laboratory results may be altered by the use of estrogen-progestin combination drugs:
Increased sulfobromophthalein retention and other hepatic function tests.
Coagulation tests: increase in prothrombin factors VII, VIII, IX and X.
Metyrapone test.
Pregnanediol determination.
Thyroid function: increase in PBI, and butanol extractable protein bound iodine and decrease in T3 uptake values.
Fasting and 2-hour plasma insulin and glucose levels following an oral glucose tolerance test (OGTT) and fibrinogen levels were measured in patients receiving ORGAGEST Capsules at a dose of 200 mg/day for 12 days per 28 day cycle in combination with conjugated estrogens 0.625 mg/day (n=120). Table 6 summarizes this data. Plasma insulin levels 2 hours post-OGTT were decreased from baseline. The fasting plasma glucose and fasting plasma insulin levels were also decreased from baseline. Glucose levels 2 hours post-OGTT were increased slightly. There was no effect on fibrinogen levels.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Progesterone has not been tested for carcinogenicity in animals by the oral route of administration. When implanted into female mice, progesterone produced mammary carcinomas, ovarian granulosa cell tumors and endometrial stromal sarcomas (1). In dogs, long-term intramuscular injections produced nodular hyperplasia and benign and malignant mammary tumors (2). Subcutaneous or intramuscular injections of progesterone decreased the latency period and increased the incidence of mammary tumors in rats previously treated with a chemical carcinogen (3).
Progesterone did not show evidence of genotoxicity in in vitro studies for point mutations or for chromosomal damage. In vivo studies for chromosome damage have yielded positive results in mice at oral doses of 1000 mg/kg and 2000 mg/kg (4). Exogenously administered progesterone has been shown to inhibit ovulation in a number of species and it is expected that high doses given for an extended duration would impair fertility until the cessation of treatment.
Pregnancy Category B
Reproductive studies have been performed in mice at doses up to 9 times the human oral dose (5, 6), in rats at doses up to 44 times the human oral dose (7, 8), in rabbits at a dose of 10 Β΅g/day delivered locally within the uterus by an implanted device (9), in guinea pigs at doses of approximately one-half the human oral dose (10) and in rhesus monkeys (11) at doses approximately the human dose, all based on body surface area, and have revealed little or no evidence of impaired fertility or harm to the fetus due to progesterone.
Several studies in women exposed to progesterone have not demonstrated any significant increase in fetal malformations (12). A single case of cleft palate was observed in the child of a woman using ORGAGEST Capsules in early pregnancy, although definitive causality has not been established. Rare instances of fetal death have been reported in pregnant women prescribed ORGAGEST Capsules for unapproved indications. Because the studies in humans cannot rule out the possibility of harm, ORGAGEST Capsules should be used during pregnancy only if indicated (see CONTRAINDICATIONS ).
Nursing Mothers
The administration of any drug to nursing mothers should be done only when clearly necessary since many drugs are excreted in human milk. Detectable amounts of progestin have been identified in the milk of nursing mothers receiving progestins. The effect of this on the nursing infant has not been determined.
Pediatric Use
The safety and effectiveness of ORGAGEST Capsules in pediatric patients have not been established.
ADVERSE REACTIONS
Endometrial Protection
Table 7 lists adverse experiences which were reported in >/=2% of patients (regardless of relationship to treatment) who received cyclic ORGAGEST Capsules, 200 mg daily (12 days per calendar month cycle) with daily 0.625 mg conjugated estrogen, in a multicenter, randomized, double-blind, placebo-controlled clinical trial in 875 postmenopausal women.
Table 7 Adverse Experiences (>/=2%) Reported in an 875 Patient Placebo-Controlled Trial in
Postmenopausal Women over a 3-Year Period (Percentage (%) of Patients Reporting)
ORGAGEST Capsules Conjugated Estrogens Placebo
200 mg with 0.625 mg (only)
Conjugated Estrogens
0.625 mg
(N=178) (N=175) (N=174)
Headache 31 30 27
Breast Tenderness 27 16 6
Joint Pain 20 22 29
Depression 19 18 12
Dizziness 15 5 9
Abdominal Bloating 12 10 5
Hot Flashes 11 14 35
Urinary Problems 11 10 9
Abdominal Pain 10 13 10
Vaginal Discharge 10 10 3
Nausea/Vomiting 8 6 7
Worry 8 5 4
Chest Pain 7 4 5
Diarrhea 7 7 4
Night Sweats 7 5 17
Breast Pain 6 6 2
Swelling of Hands and Feet 6 9 9
Vaginal Dryness 6 8 10
Constipation 3 3 2
Breast Carcinoma 2 <1 <1
Breast Excisional Biopsy 2 1 <1
Cholecystectomy 2 <1 <1
Secondary Amenorrhea
Table 8 lists adverse experiences which were reported in >/=5% of patients receiving ORGAGEST Capsules, 400 mg/day, in a multicenter, randomized, double-blind, placebo-controlled clinical trial in estrogen-primed (6 weeks) postmenopausal women receiving conjugated estrogens 0.625 mg/day and cyclic (10 days per calendar month cycle) ORGAGEST Capsules at a dose of 400 mg/day, for three cycles.
Table 8 Adverse Experiences (>/=5%) Reported in Patients Using 400 mg/day in a
Placebo-Controlled Trial in Estrogen-Primed Postmenopausal Women
Adverse Experience
ORGAGEST Capsules 400 mg Placebo
N=25 N=24
Percentage (%) of Patients
Fatigue 8 4
Headache 16 8
Dizziness 24 4
Abdominal Distention (Bloating) 8 8
Abdominal Pain (Cramping) 20 13
Diarrhea 8 4
Nausea 8 0
Back Pain 8 8
Musculoskeletal Pain 12 4
Irritability 8 4
Breast Pain 16 8
Infection Viral 12 0
Coughing 8 0
The most common adverse experiences reported in >/=5% of patients in all ORGAGEST Capsules dosage groups studied in this trial (100 mg/day to 400 mg/day) were: dizziness (16%), breast pain (11%), headache (10%), abdominal pain (10%), fatigue (9%), viral infection (7%), abdominal distention (6%), musculoskeletal pain (6%), emotional lability (6%), irritability (5%), and upper respiratory tract infection (5%).
Other adverse events reported in <5% of patients taking ORGAGEST Capsules include:
Autonomic Nervous System Disorders: dry mouth
Body As A Whole: accidental injury, chest pain, fever
Cardiovascular System Disorders: hypertension
Central and Peripheral Nervous System Disorders: confusion, somnolence, speech disorder
Gastrointestinal System Disorders: constipation, dyspepsia, gastroenteritis, hemorrhagic rectum, hiatus hernia, vomiting
Hearing and Vestibular Disorders: earache
Heart Rate and Rhythm Disorders: palpitation
Metabolic and Nutritional Disorders: edema, edema peripheral
Musculoskeletal System Disorders: arthritis, leg cramps, hypertonia, muscle disorder, myalgia
Myo/Endo/Pericardial and Valve Disorders: angina pectoris
Psychiatric Disorders: anxiety, impaired concentration, insomnia, personality disorder
Reproductive System Disorders: leukorrhea, uterine fibroid, vaginal dryness, fungal vaginitis, vaginitis
Resistance Mechanism Disorders: abscess, herpes simplex
Respiratory System Disorders: bronchitis, nasal congestion, pharyngitis, pneumonitis, sinusitis
Skin and Appendages Disorders: acne, verruca, wound debridement
Urinary System Disorders: urinary tract infection
Vision Disorders: abnormal vision
White Cell and Resistance Disorders: lymphadenopathy
The following adverse experiences have been reported with ORGAGEST Capsules in other U.S. clinical trials: increased sweating, asthenia, tooth disorder, anorexia, increased appetite, nervousness, and breast enlargement.
The following spontaneous adverse events have been reported during the foreign marketing of ORGAGEST Capsules: reversible cases of hepatitis and elevated transaminases. These events occurred mainly in patients receiving high doses of up to 1200 mg.
The following additional adverse experiences have been observed in women taking progestins in general: breakthrough bleeding, spotting, change in menstrual flow, amenorrhea, changes in weight (increase or decrease), changes in the cervical squamo-columnar junction and cervical secretions, cholestatic jaundice, anaphylactoid reactions and anaphylaxis, rash (allergic) with and without pruritus, melasma or chloasma, pyrexia, and insomnia.
Pregnancy. Anomalies (non-virilizing) of the genito-urinary
tract were found in a 4-month-old baby whose mother had
taken dydrogesterone 20 mg daily from the 8th to 20th week
of pregnancy and 10 mg daily from then until term. She had
also been given hydroxyprogesterone hexanoate 250 mg by
intramuscular injection weekly from the 8th to the 20th week.
Uses and Administration
Dydrogesterone is a progestogen structurally related to pro-
gesterone . It does not have estrogenic or androgen-
ic properties.
Dydrogesterone is given by mouth in the treatment of men-
strual disorders such as menorrhagia , usually in a
dose of 10 mg twice daily in a cyclical regimen, and for the
treatment of endometriosis at a dose of 10 mg two or
three times daily. It is also given cyclically in doses of 10 mg
once or twice daily for endometrial protection during meno-
pausal hormone replacement therapy .
In threatened abortion suggested doses have been 40 mg ini-
tially followed by 10 mg or more every 8 hours, continued for
a week after symptoms cease. In habitual abortion suggested
doses have been 10 mg twice daily. However, such use is not
recommended unless there is proven progesterone deficiency.
Cyclical dydrogesterone has also been used in infertility
in doses of 10 mg twice daily.