ゲストデン

197.9 °C

197.9 °C

Danger

H351 (28.4%): Suspected of causing cancer [Warning Carcinogenicity]

P203, P260, P263, P264, P270, P273, P280, P318, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 88 reports by companies from 9 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

... In a parallel-group study, 15 healthy women using OCs and 15 healthy women without OCs (control subjects) ingested a single dose of 4 mg tizanidine. Plasma and urine concentrations of tizanidine, as well as several of its metabolites (M-3, M-4, M-5, M-9, and M-10), and pharmacodynamic variables were measured until 24 hours after dosing. As a marker of CYP1A2 activity, an oral caffeine test was performed in both groups. The mean area under the plasma concentration-time curve from time 0 to infinity [AUC0-infinity] of tizanidine was 3.9 times greater (P<.001) and the mean peak plasma tizanidine concentration (Cmax) was 3.0 times higher (P<.001) in the OC users than in the control subjects. In 1 OC user the AUC0-infinity of tizanidine exceeded the mean AUC0-infinity of the control subjects by nearly 20 times. There were no significant differences in the elimination half-life or time to peak concentration in plasma of tizanidine between the groups. Tizanidine/metabolite ratios in plasma (M-3 and M-4) and urine (M-3, M-4, M-5, M-9, and M-10) were 2 to 10 times higher in the users of OCs than in the control subjects. In the OC group the excretion of unchanged tizanidine into urine was, on average, 3.8 times greater (P=.008) than in the control subjects. The plasma caffeine/paraxanthine ratio was 2.8 times higher (P<.001) in the OC users than in the control subjects. The caffeine/paraxanthine ratio correlated significantly with the AUC0-infinity and peak concentration of tizanidine in plasma, with its excretion into urine, and with, for example, the tizanidine/M-3 and tizanidine/M-4 area under the plasma concentration-time curve ratios. Both the systolic and diastolic blood pressures were lowered by tizanidine more in the OC users (-29+/- 10 mm Hg and -21+/- 8 mm Hg, respectively) than in the control subjects (-17+/- 9 mm Hg and -13+/- 5 mm Hg, respectively) (P < .01). OCs containing ethinyl estradiol and gestodene increase, to a clinically significant extent, the plasma concentrations and effects of tizanidine, probably mainly by inhibiting its CYP1A2-mediated presystemic metabolism. Care should be exercised when tizanidine is prescribed to OC users.

/HUMAN EXPOSURE STUDIES/ The new low-dose combination oral contraceptive (OC) containing 75 ug of the new progestogen gestodene (GTD) plus 30 ug ethinyl estradiol (EE) was clinically tested and compared with a levonorgestrel (LNG) combined pill (150 ug LNG plus 30 ug EE). In a randomized clinical comparative study (A), 176 women were treated with the GTD-containing pill and 185 with the LNG-containing pill for six cycles. This study was followed by a second multicenter study (B) covering 707 patients taking the GTD-containing pill for up to 24 cycles (total, 9,947 cycles). In a third study (C), metabolic effects were assessed using a randomly organized baseline control trial (pretreatment/treatment cycles); 30 patients received the GTD-containing pill and 30 received the LNG-containing pill. Carbohydrate metabolism, lipid metabolism, and blood clotting were investigated, and an interim analysis was performed after six OC cycles. No pregnancies and no severe side effects occurred in any of the studies. Intermenstrual bleeding decreased as usual during treatment. In the total number of gestodene cycles in studies A and B, there was a 6.9% incidence of spotting, a 0.8% incidence of breakthrough bleeding, and a 0.7% incidence of both spotting and breakthrough bleeding in studies A and B patients taking gestodene. Amenorrhea occurred in 0.6% of cycles. Body weight remained unchanged (+/- 2 kg) after 24 cycles in 80.5% of study B patients taking gestodene. Blood pressure remained normal in about 95% of all study B patients; a normalization was observed in greater than 60% of patients with previously elevated blood pressure. No clinically relevant changes in carbohydrate metabolism, lipid metabolism, or blood clotting were observed in study C. ...

/SIGNS AND SYMPTOMS/ Overdosage may cause nausea, vomiting and, in females, withdrawal bleeding.

/CASE REPORTS/ In hepatic adenomatosis, multiple liver cell adenomas (usually > or = 10) generally affects patients with no prior history of oral contraceptive use, androgenic steroid use, or glycogen storage disease. /The authors/ report a rare case of a 44 year-old female who underwent emergency surgery for hemoperitoneum due to spontaneous rupture of a liver cell adenoma in hepatic adenomatosis, after prolonged use of two different contraceptives (Gestodene and Ethinylestradiol).

/CASE REPORTS/ In Italy, the University of Padua Hospital has treated 45 women for venous and/or arterial thrombosis during oral contraceptive (OC) therapy. Among the 38 who had no other risk factors for thrombosis, 8% had antiphospholipid antibodies. 3 patients featured in the cases were asymptomatic before beginning OC use. All 3 had their first thrombotic event during OC use. They developed thrombosis after 16 cycles of OCs. The first case (age 19) developed thrombotic occlusion on the left side of her body, especially her left leg after about 18 cycles of OC use (0.03 mg ethinyl estradiol and 0.075 mg gestodene). One month after beginning oral anticoagulant therapy physicians found antiphospholipid antibodies (ie, the presence of lupus anticoagulant and increased levels of anticardiolipin antibodies). She later developed other thrombotic events despite anticoagulant therapy. The second case (age 35) first experienced a thrombotic event at the age of 29 after about 18 cycles of a sequential 3-phase combined OC. She was not put on long-term anticoagulant therapy at the time. 2 years later, she again experienced thrombosis in the same leg. She was put on oral anticoagulant therapy until age 33, when she wanted to become pregnant. She was then put on acenocumarol therapy. Her pregnancy ended in miscarriage at 8-10 weeks gestation. She developed thrombosis in the left leg 6 months later. Hospital staff detected antiphospholipid antibodies. Case 3 (age 48) had had 2 full-term, normal pregnancies and no miscarriages. She developed thrombosis in the left leg after 12 cycles of OC use (0.03 mg ethinyl estradiol and 0.075 mg gestodene). She discontinued OC use and began anticoagulant therapy. Laboratory findings indicated antiphospholipid antibodies. All 3 cases had or had had a false positive reading for syphilis. They were diagnosed with primary antiphospholipid syndrome (PAPS). These findings suggest that normal women who develop thrombosis during OC use might have undetected PAPS.

For more Human Toxicity Excerpts (Complete) data for GESTODENE (32 total), please visit the HSDB record page.

Oral contraceptives have been reported to produce harmful ocular effects in myopic women. In women who developed myopia at or near puberty and in whom myopia became stable in adulthood, the drugs have reportedly increased the refractive error 2- to 3-fold, usually after 6 months of use. In women who are myopic and have considerable astigmatism, oral contraceptives may produce marked changes in the astigmatic error, possibly leading to frank keratoconus. In addition, oral contraceptives may produce a rapid advancement of the ocular disorder in patients with a family history of marked myopic astigmatism or keratoconus. Contact lens wearers receiving estrogen-progestin contraceptives may have more difficulties with their contact lenses than do nonusers who wear contact lenses. Contact lens wearers who develop visual disturbances or changes in lens tolerance during estrogen-progestin contraceptive use should be assessed by an ophthalmologist; temporary or permanent cessation of contact lens wear should be considered./Estrogen-Progestin Combination/

Mental depression may occur in women receiving oral contraceptives. In a few cases, mental depression has been severe and has led to suicidal behavior. Mental depression appears to occur most frequently in patients with a history of depression, including premenstrual depression; however, relief of premenstrual tension occurs in some women. Patients with a history of mental depression should be observed carefully and the estrogen-progestin contraceptive discontinued if severe depression recurs during use. /Estrogen-Progestin Combination/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

This estrogen-progestogen combination acts by inhibiting ovulation by suppression of the mid-cycle surge of luteinizing hormone, the inspissation of cervical mucus so as to constitute a barrier to sperm, and the rendering of the endometrium unreceptive to implantation.

Gestodene, one of three new gonane progestins, is the most potent on a per weight basis in regard to progestational effects and has little or no estrogenic effect. In in vivo animal studies, gestodene also has less androgenic activity compared with progestins found in older combination oral contraceptive formulations. It binds to mineralocorticoid receptors and consequently is a competitive aldosterone inhibitor, leading to speculation that it may be beneficial in hypertensive patients. ...In general, studies show that the incidence of side effects associated with the progestin and estrogen components tends to be low, with very little impact on lipid and carbohydrate metabolism. ...

Gestodene (17 alpha-ethynyl-13 beta-ethyl-17 beta-hydroxy-4, 15-gonadien-3-one) is the most potent synthetic progestin currently available and it is widely used as a fertility regulating agent in a number of contraceptive formulations because of its high effectiveness, safety and acceptability. The observation that contraceptive synthetic progestins exert hormone-like effects other than their progestational activities, prompted us to investigate whether gestodene (GSD) administration may induce estrogenic effects, even though the GSD molecule does not interact with intracellular estrogen receptors (ER). To assess whether GSD may exert estrogenic effects through some of its neutral metabolites, a series of experimental studies were undertaken using GSD and three of its A-ring reduced metabolites. Receptor binding studies by displacement analysis confirmed that indeed GSD does not bind to the ER, whereas its 3 beta,5 alpha-tetrahydro reduced derivative (3 beta GSD) interacts with a relative high affinity with the ER. The 3 alpha,5 alpha GSD isomer (3 alpha GSD) also binds to the ER, though to a lesser extent. The ability of the A-ring reduced GSD derivatives to induce estrogenic actions was evaluated by the use of two different molecular bioassays: (a) transactivation of a yeast system co-transfected with the human ER alpha (hER alpha) gene and estrogen responsive elements fused to the beta-galactosidase reporter vector and (b) transactivation of the hER alpha-mediated transcription of the chloramphenicol acetyl transferase (CAT) reporter gene in a HeLa cells expression system. The estrogenic potency of 3 beta GSD was also assessed by its capability to induce estrogen-dependent progestin receptors (PR) in the anterior pituitary of castrated female rats. The results demonstrated that 3 beta GSD and 3 alpha GSD were able to activate, in a dose-dependent manner, the hER alpha-mediated transcription of both the beta-galactosidase and the CAT reporter genes in the yeast and HeLa cells expression systems respectively. In both assays the 3 beta derivative of GSD exhibited a significantly greater estrogenic effect than its 3 alpha isomer, while unchanged GSD and 5 alpha GSD were completely ineffective. Neither 3 beta GSD nor 3 alpha GSD exhibited estrogen synergistic actions. Interestingly, the pure steroidal anti-estrogen ICI-182,780 diminished the transactivation induced by 3 beta GSD and 3 alpha GSD in the yeast expression system. Furthermore, administration of 3 beta GSD resulted in a significant increase of estrogen-dependent PR in the anterior pituitaries of castrated rats in comparison with vehicle-treated animals. The characteristics of the 3 beta GSD-induced PR were identical to those induced by estradiol benzoate. The overall results demonstrate that 3 beta GSD and its 3 alpha isomeric alcohol specifically bind to the ER and possess a weak intrinsic estrogenic activity, whereas unmodified GSD does not. The data contribute to a better understanding of the GSD mechanism of action and allow the hypothesis to be advanced that the slight estrogenlike effects attributable to GSD are mediated by its non-phenolic, tetrahydro reduced metabolites.

Studies on the highly progestogenic compound gestodene have demonstrated that its progestogenic activity in an in-vivo system is far lower than those of its in-vitro binding or receptor activation; however, its androgenic activity in vitro has been confirmed and it appears to have weak binding activity to the glucocorticoid receptor . Its weak estrogenic activity (transactivation of estrogen receptor-mediated gene expression in model cells) appears to derive from its metabolism to the A-ring-reduced metabolites, 3beta- and 3alpha,5alpha-tetrahydrogestodene, and is probably mediated by the activity of 5alpha-reductase. These metabolites appeared to be selective agonists of estrogen receptor-alpha but not of estrogen receptor-beta. The parent compound did not activate estrogen receptors-alpha or -beta.

For more Mechanism of Action (Complete) data for GESTODENE (6 total), please visit the HSDB record page.

16 to 18 hrs.

Gestodene serum levels decrease in two phases, characterised by half-lives of 0.1 hours and about 18 hours.

The half-life of elimination of gestodene was shown to range from 12 to 14 hr for the three doses studied (0.025, 0.075 or 0.125 mg gestodene).

Gestodene is not excreted in unchanged form but as metabolites, which are eliminated with a half-life of about 1 day.

The biotransformation follows the known pathways of steroid metabolism. No pharmacologically active metabolites are known.

Gestodene is metabolized primarily in the liver by CYP 3A4 and is a strong inducer of this enzyme. Although ethinylestradiol is also metabolized by CYP 3A4, gestodene does not appear to inhibit its metabolism. Known metabolites of gestodene include dihydrogestodene, 3,5-tetrahydrogestodene and hydroxygestodene.

There is limited information on the metabolism of levonorgestrel, norethindrone and structurally related contraceptive steroids. Both levonorgestrel and norethindrone undergo extensive reduction of the alpha, beta-unsaturated ketone in ring A. Levonorgestrel also undergoes hydroxylation at carbons 2 and 16. The metabolites of both compounds circulate predominantly as sulfates. In urine, levonorgestrel metabolites are found primarily in the glucuronide form, whereas norethindrone metabolites are present in approximately equal amounts as sulfates and glucuronides. Of the progestogens structurally related to norethindrone, norethindrone acetate, ethynodiol diacetate, norethindrone enanthate, and perhaps lynestrenol, undergo rapid hydrolysis and are converted to the parent compound and its metabolites. There is no convincing evidence that norethynodrel is converted to norethindrone. Of the progestogens structurally related to levonorgestrel, it appears that neither desogestrel nor gestodene are transformed to the parent compound. However, there is evidence that norgestimate can be, at least partly, converted to levonorgestrel. ...

Oral contraceptives which owe their effectiveness to hormonal preparations.

Oral contraceptives which owe their effectiveness to synthetic preparations.

Compounds that interact with PROGESTERONE RECEPTORS in target tissues to bring about the effects similar to those of PROGESTERONE. Primary actions of progestins, including natural and synthetic steroids, are on the UTERUS and the MAMMARY GLAND in preparation for and in maintenance of PREGNANCY.

in vitro 99% using 3H=R5020 / in vivo similar to progesterone

Orally administered gestodene is rapidly and completely absorbed.

The absolute bioavailability of gestodene was determined to be 99% of the dose administered.

For gestodene, an apparent volume of distribution of 0.7 L/kg and a metabolic clearance rate from serum of about 0.8 mL/min/kg were determined.

Following ingestion of 0.1 mg gestodene together with 0.03 mg ethinylestradiol (which represents the combination with the highest gestodene content of the tri-step formulation), maximum drug serum levels of about 5.6 ng/mL are reached at 0.5 hour.

For more Absorption, Distribution and Excretion (Complete) data for GESTODENE (8 total), please visit the HSDB record page.

MEDICATION

... a progestogen hormonal contraceptive

Use (kg) in Switzerland (2009): >1

Prepn: Belg. pat. 847,090; H. Hofmeister et al., U.S. pat. 4,081,537 (1977, 1978 both to Schering AG).

It can be prepared from the 17-keto steriod [18-methylestrone methyl ether] in a multistep synthesis involving palladium-catalysed conversion of its enol ether to an enone, reduction to the corresponding allylic alcohol, partial reduction of the aromatic ring, regeneration of the enone and ethinylation.

Oral: Tablets: 30 ug ethinylestradiol and 50 ug gestodene, Triadene (Bayer plc).

Gestodene is available commercially as a component of combination tablets with ethinylestradiol.

...manufactured or formulated in Argentina, Austria, Belgium, Brazil, Finland, France, Germany, Mexico, the Netherlands, New Zealand, Portugal, South Africa, Spain, Switzerland and the United Kingdom.

...used only in combination with ethinyloestradiol as an oral contraceptive, at a dose of 0.075mg gestodene and 20 or 30 ug ethinyloestradiol, and in a triphasic regimen at 0.05, 0.07 and 0.1mg and 30, 40 and 30 ug ethinyloestradiol.

Combination preparation with ethinyl estradiol: Femovan (Schering AG).