Approval Date.
Instructions for Denogestrel Tablets
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic Name: Denogestrel Tablets
Trade name: Visanen® / Visanne®
English Name: Dienogest Tablets
Hanyu Pinyin：Dinuoyunsu Pian
Ingredients
The main ingredient of this product is denogest.
Chemical name: 17-hydroxy-3-oxo-19-nor-17α-pregna-4,9-dien-21-carbonitrile
Chemical structure formula.
Molecular formula: C20H25NO2
Molecular weight: 311.42
Properties
This product is white or off-white tablet.
【Indications】.
Treatment of endometriosis.
Specification
2mg
Dosage]
Take orally, one tablet daily without interruption, preferably at the same time every day, with water when needed. This product can be taken after meals or on an empty stomach.
The tablets must be taken continuously, with or without vaginal bleeding. If you finish taking one box, start taking the next box without interruption.
Treatment with this product may be started on any day of the menstrual cycle.
Any hormonal contraceptive method needs to be stopped before starting treatment. If contraception is needed, a non-hormonal method of contraception (e.g. barrier method) should be used.
Management of missed pill doses
The efficacy of Denogestrel tablets is diminished in the event of missed doses, vomiting and/or diarrhea (if occurring within 3 to 4 hours of dosing). In the case of one or more missed tablets, the patient should take one tablet as soon as remembered and then should continue to take it the next day at the previous dosing schedule. If a tablet is not absorbed due to vomiting or diarrhea, a supplementary tablet should also be taken.
[Adverse reactions].
Adverse reactions to Denogestrel Tablets are most common in the first month after the start of treatment and gradually decrease with the continuation of treatment. Changes in bleeding patterns, such as spotting, irregular bleeding or amenorrhea, may occur. The following adverse reactions have been reported in users of Denogestrel Tablets.
The most frequently reported adverse reactions during treatment with Denogestrel Tablets were headache (9.0%), breast discomfort (5.4%), depression (5.1 %), and acne (5.1 %).
In addition, the majority of patients taking denogestrel tablets for treatment experienced a change in menstrual bleeding pattern. The assessment of menstrual bleeding patterns was performed using patient logs and analyzed using the WHO 90-day reference period method. During the first 90 days of treatment with denogestrel tablets, the following bleeding patterns were observed (n=290; 100%): amenorrhea (1.7%), decreased bleeding (27.2%), frequent bleeding (13.4%), irregular bleeding (35.2%), prolonged bleeding (38.3%), and normal bleeding, i.e., not any of the above classifications (19.7%). During the 4th reference period, the following bleeding patterns were observed (n=149; 100%): amenorrhea (28.2%), decreased bleeding (24.2%), frequent bleeding (2.7%), irregular bleeding (21.5%), prolonged bleeding (4.0%), and normal bleeding, i.e., not any of the above classifications (22.8%). However, changes in menstrual bleeding patterns were only occasionally reported by patients as adverse events (see Table 1: Adverse Reactions Table).
See the table below for a summary of the incidence of adverse drug reactions (ADRs) to denogestrel tablets reported by MedDRA Systematic Organ Classification (MedDRA SOCs). Within each frequency group, ADRs are listed in order of decreasing frequency of occurrence. Frequencies were defined as common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100). Frequencies were based on pooled data from 4 clinical trials including 332 patients (100%).
Table 1, Adverse Reaction Table, Phase III Clinical Trials, N= 332
System Organ Classification Common Uncommon Blood and lymphatic system disorders Anemia Metabolic and nutritional disorders Weight gain Weight loss, increased appetite Psychiatric disorders Mood depression Sleep disturbances Nervousness
Loss of libido Mood changes Anxiety
Depression
Mood swings Various neurological disorders Headache
Migraine headache Autonomic nervous system imbalance
Attention disorders Eye disorders Dry eyes Ear and vagus disorders Tinnitus Heart disorders Non-specific circulatory disorders
Palpitations Vascular disorders Hypotension Respiratory, thoracic and mediastinal disorders Respiratory difficulties Gastrointestinal disorders Nausea
Abdominal pain
Gastrointestinal flatulence
Abdominal distention
Vomiting Diarrhea
Constipation Abdominal discomfort
Inflammation of the gastrointestinal tract
Gingivitis Skin and subcutaneous tissue disorders Acne
Hair loss dry skin hyperhidrosis
Itching
Hirsutism
Fractured nails Dandruff
Dermatitis
Abnormal hair growth
Photosensitivity reaction
Pigmentation disorders various musculoskeletal and connective tissue disorders back pain bone pain
Muscle spasms
Limb pain
Limb heaviness Kidney and urinary tract disorders Urinary tract infections Reproductive system and breast disorders Breast discomfort
Ovarian cysts
Hot flashes
Uterine/vaginal bleeding
（Vaginal candidiasis (including spotting) Vulvovaginal dryness Genital discharge Pelvic pain Atrophic vulvovaginitis Breast lumps Breast fibrocystic changes Breast hardness Systemic diseases and various reactions at the site of administration Weakness Irritable edema The following adverse reactions have also been reported in monoformulations containing denogestrel in general: common: dizziness, fever, abnormal liver function tests, including AST (GOT), ALT (GPT), γ-GTP (GOT), ALT (GPT), γ-GTP, and elevated bilirubin. Unusual: leukopenia, drowsiness, numbness, frozen shoulder, arthralgia, lactation, elevated blood glucose, elevated blood cholesterol (see [Drug Interactions] Laboratory Tests).
Risk of reduced bone mineral density in adolescents
In a non-controlled clinical trial, 111 adolescent female patients (12-18 years of age) were given denogestrel tablets, of which bone mineral density was measured in 103 patients. After 12 months of administration, approximately 72% of the subjects developed reduced bone mineral density in the lumbar spine (L2-L4) (see [Caution])
[Contraindication
Denogestrel Tablets should not be used under the circumstances listed below, which are derived in part from information material on other progestin preparations. If any of the following conditions occur during the use of Denogestrel Tablets, the drug should be discontinued immediately
Active venous thromboembolic disease
Current or previous arterial and cardiovascular disease (e.g. myocardial infarction, cerebrovascular accident, ischemic heart disease)
Diabetes mellitus presenting with vasculopathy
Current or prior severe liver disease in which liver function values have not returned to normal
Current or previous liver tumor (benign or malignant)
Known or suspected sex hormone-dependent malignancy
Vaginal bleeding of unknown origin
Hypersensitivity to active substances or excipients
Denogestrel tablets are contraindicated in patients with current or previous severe hepatic disease.
For patients with renal impairment, there are no data suggesting the need for dose adjustment.
Precautions]
Since Denogestrel Tablets is a monoprogestational formulation, it can be assumed that the warnings and precautions for the use of other monoprogestational formulations are also applicable to Denogestrel Tablets, but not all warnings and precautions are based on the results of the corresponding clinical studies of Denogestrel Tablets.
The risk-benefit of patients should be assessed before starting or continuing the use of Denogestrel Tablets if the following diseases/risk factors are present or worsened
Severe uterine bleeding
For example, in women with adenomyosis or uterine smooth muscle tumors, uterine bleeding may worsen with the use of Denogestrel Tablets. If the bleeding is heavy or continuous, it may lead to anemia (severe anemia occurs in some cases). Discontinuation of Denogestrel Tablets should be considered in the event of anemia.
Changes in bleeding pattern
Changes in menstrual bleeding patterns have occurred in most patients treated with Denogestrel Tablets (see [Adverse Reactions]).
Circulatory disorders
Based on epidemiological studies, there is little evidence of an association between single progestin preparations and an increased risk of myocardial infarction or cerebral thromboembolism. However, the risk of cardiovascular and cerebrovascular events has been significantly associated with increasing age, hypertension, and smoking. Among hypertensive women, single progestin drugs may slightly increase the risk of stroke.
Some studies have shown a slightly increased risk of venous thromboembolism (deep vein thrombosis, pulmonary embolism) in combination with single progestin drug use, but the increase is not statistically significant. Risk factors for venous thromboembolism (VTE) are generally considered to include: a personal or family history (venous thromboembolism in a sibling or parent at a relatively young age), age, obesity, prolonged braking, major surgery or severe trauma. In cases of prolonged braking, it is advisable to discontinue the use of denogestrel tablets (at least 4 weeks in advance if elective surgery is to be performed) and to resume their use only after 2 weeks of full re-activity.
Elevated risk of thromboembolism in the puerperium must be taken into account.
Treatment should be discontinued immediately if symptoms of arterial or venous thrombosis are present or suspected.
Oncology
A meta-analysis of 54 epidemiologic studies reported a slightly elevated relative risk of breast cancer (RR=1.24) in women currently using oral contraceptives (OCs), primarily estrogen-progestin combinations. This elevated risk tapered off over a 10-year period after discontinuation of compounded oral contraceptives (COCs). Because breast cancer is relatively rare in women under the age of 40, the increase in breast cancer among women who are currently using and have recently used COCs is not actually significant relative to the overall risk of breast cancer. The degree of risk of breast cancer diagnosis in single progestin drug users may be similar to the risk of breast cancer associated with COC use. The evidence for single progestin drugs, however, is based on small sample populations and, therefore, is less conclusive than that for COCs. These studies do not provide evidence for a causality determination. The observed increased risk may be explained by the earlier diagnosis of breast cancer in OC users, and the biological effects of OC or COCs. Clinically, there is a trend toward earlier staging of breast cancer diagnosed in OC users than in patients who have not used OC.
Rare cases of benign liver tumors and even rarer cases of malignant liver tumors have been reported among users of hormonal drugs such as substances contained in denogestrel tablets. In isolated cases, these tumors have caused life-threatening intra-abdominal bleeding. The presence of liver tumors needs to be considered in the differential diagnosis when women taking denogestrel tablets present with severe upper abdominal pain, liver enlargement, or signs of intra-abdominal hemorrhage.
Osteoporosis
Changes in bone mineral density (BMD)
In a non-controlled clinical trial, 111 adolescent female patients (12-18 years of age) taking denogestrel tablets experienced a decrease in lumbar spine bone mineral density (BMD) over a 12-month treatment period.
From baseline to the end of treatment, the mean reduction in BMD of the lumbar spine (L2-L4) was 1.2%, with changes ranging from -6% to +5% (95% confidence interval: -1.70% to -0.78%, n=103.) The subgroup of patients with reduced BMD at the end of treatment was re-measured at month 6 after the end of treatment and showed a trend toward recovery (this subgroup had a mean reduction of 2.3% at the end of treatment compared to baseline). mean reduction of 2.3% from baseline at the end of treatment and 0.6% from baseline at 6 months after the end of treatment, ranging from -9% to +6% (95% confidence interval: -1.20% ~0.06%, n=60).
Reduced BMD is a concern to consider during this critical period of bone growth in adolescence and early adulthood. It is not clear whether reduced BMD in this population reduces peak bone mass and increases the risk of future fractures.
Because endogenous estrogen levels decrease with the administration of denogestrel, physicians should weigh the benefits and potential risks before prescribing it to each patient at risk for fracture.
Adequate intake of calcium and vitamin D, whether through food or supplements, is important for the bone health of women of all ages.
No effect of denogestrel on bone mineral density has been observed in adult women.
Other conditions
Patients with a history of depression should be carefully monitored and the drug discontinued if depression recurs to a severe degree.
Denogestrel tablets generally do not affect blood pressure in women with normal blood pressure. However, when persistent clinically significant hypertension occurs during the use of Denogestrel Tablets, Denogestrel Tablets should be discontinued and the hypertension should be treated.
Cholestatic jaundice and/or pruritus that previously occurred during pregnancy or during previous use of sex hormone analogs and recurred while taking Denogestrel Tablets require discontinuation of Denogestrel Tablets.
Denogestrel Tablets may have a slight effect on peripheral insulin resistance and glucose tolerance. Women with diabetes, especially those with a history of gestational diabetes, should be carefully monitored during the use of Denogestrel Tablets.
Melasma may sometimes develop, especially in women with a history of melasma during pregnancy. Women who have a tendency to develop melasma should avoid exposure to sunlight or ultraviolet radiation while using Denogestrel Tablets.
Ectopic pregnancies are more likely to occur in users of monoprogestational formulations of contraception than in users of compounded oral contraceptives. Therefore, in women with a history of ectopic pregnancy or impaired tubal function, the decision to use Denogestrel Tablets should be made only after careful weighing of the benefits and risks.
Persistent follicles (often called functional ovarian cysts) can occur during the administration of Denogestrel Tablets. Most of these follicles are asymptomatic, but some are associated with pelvic pain.
Lactose
Each tablet of Denogestrel tablets contains 62.8 mg of lactose monohydrate. The lactose content of Denogestrel tablets should be considered in patients with rare hereditary galactose intolerance, laprolactase deficiency or glucose-galactose malabsorption and receiving a lactose-free diet.
Effects on driving and mechanical handling ability
No effects on driving and mechanical handling ability have been observed in users of denogestrel-containing products.
Pregnant women and nursing mothers
Use during pregnancy
Pregnancy should be excluded before starting to take Denogestrel tablets.
Data on the use of denogestrel in pregnant women are limited.
Animal studies have not suggested direct or indirect harmful effects in terms of reproductive toxicity (see [Pharmacological Toxicology] section).
However, since treatment of endometriosis is not required during pregnancy, denogestrel tablets should not be given to pregnant women.
Use during lactation
Treatment with Denogestrel Tablets is not recommended during breastfeeding.
It is not known whether denogestrel is secreted into human breast milk. Animal data suggest that denogestrel can be secreted in rat milk.
The benefits of breastfeeding to the infant must be weighed against the benefits of treatment with Denogestrel Tablets to the mother to decide whether to discontinue breastfeeding or to discontinue/discontinue treatment with Denogestrel Tablets.
Fertility
According to available data, ovulation is suppressed in most patients during treatment with Denogestrel. However, Denogestrel tablets are not a contraceptive.
If contraception is required, non-hormonal methods of contraception should be used (see [Dosage]).
According to available data, the menstrual cycle returns to normal after 2 months of stopping treatment with Denogestrel Tablets.
Use in children
Denogestrel Tablets are not indicated for use in children before the onset of menstruation.
The safety and efficacy of denogestrel has been studied in a non-controlled clinical trial in 111 adolescent female patients (12-18 years of age) with endometriosis for more than 12 months (see Precautions).
Therefore, physicians should prescribe it to adolescent female patients after weighing the benefits and potential risks.
[Geriatric Use].
Denogestrel Tablets do not include elderly patients in the relevant indication population.
Drug Interactions]
Note: Consult your doctor for combined medication information to determine potential drug interactions.
Effects of other drugs on Denogestrel
Progestins, including denogestrel, are mainly metabolized by the cytochrome P450 3A4 system (CYP3A4) located in the intestinal mucosa and the liver. Therefore, inducers or inhibitors of CYP3A4 may affect progestin drug metabolism.
Increased clearance of sex hormones due to enzyme induction may reduce the efficacy of denogestrel tablets and may lead to adverse effects such as altered uterine bleeding patterns.
Decreased clearance of sex hormones due to enzyme inhibition may increase the exposure to denogestrel and may lead to adverse reactions.
Substances that increase sex hormone clearance (by enzyme-induced reduction in potency) such as.
Phenytoin, barbiturates, paracetamol, carbamazepine, rifampin, and oxcarbazepine, topiramate, felbamate, ashwagandha, and drugs containing St. John’s Wort [onychomycetin].
Enzyme-inducing effects occur a few days after dosing, with maximal enzyme-inducing effects occurring within a few weeks and may persist for at least 4 weeks after discontinuation of treatment.
The effects of the CYP 3A4-inducing agent rifampicin have been studied in postmenopausal women. Combined administration of rifampicin with estradiol/dinogestrel tablets resulted in significantly lower steady-state blood concentrations and systemic exposure to dinogestrel and estradiol. Systemic exposure to denogestrel and estradiol, as measured by AUC (0-24), decreased by 83% and 44%, respectively.
Substances causing changes in sex hormone clearance.
When used in combination with sex hormones, many HIV protease inhibitors,non-nucleoside reverse transcriptase inhibitors, including HCV inhibitors, increase or decrease blood concentrations of estrogen and progestin, and such changes may be clinically meaningful in some cases.
Substances that decrease the clearance of sex hormones.
Denogestins are substrates of cytochrome P450 3A4 (CYP3A4) and the clinical relevance of potential interactions with enzyme inhibitors is unknown.
When used in combination with strong CYP3A4 inhibitors, blood concentrations of denogestrel may be increased.
Combination with the strong CYP3A4 inhibitor ketoconazole increased the AUC (0-24h) of denogestrel to reach steady state by 2.9-fold. Co-administration with the moderately strong inhibitor erythromycin increased the AUC (0-24h) of denogestrel to reach steady state by 1.6-fold.
Action of denogestrel on other drugs
Based on in vitro inhibition studies, denogestrel is unlikely to interact clinically relevant with other drugs with cytochrome P450 enzyme-mediated metabolism.
Interaction with food
A standardized high-fat diet does not affect the bioavailability of denogestrel tablets.
Laboratory Tests
The use of progestins may affect the results of certain laboratory tests, including liver, thyroid, adrenal and renal function as well as (carrier) protein plasma level biochemical parameters such as corticosteroid-binding globulin and lipid/lipoprotein composition, carbohydrate metabolism parameters, and coagulation parameters and fibrinolysis parameters. The changes that occur remain largely within the normal laboratory range.
[Drug Overdose].
Acute toxicity studies with denogestrel have not suggested a risk of acute adverse reactions in the event of accidental administration of several times the daily therapeutic dose. There is no specific antidote. Denogestrel 20-30 mg (10 to 15 times the dose in denogestrel tablets) administered once daily for 24 weeks was well tolerated.
【Clinical trials】.
Global clinical trials
A 3-month study including 198 patients with endometriosis confirmed the superior efficacy of denogestrel tablets compared to placebo. Endometriosis-associated pelvic pain (EAPP) was measured by a visual analog scale (0-100 mm), and there was a statistically significant difference after 3 months of treatment with denogestrel tablets compared to placebo (Δ = 12.3 mm; 95% CI: 6.4 – 8.1; p< 0.0001); the reduction in pain compared to baseline was clinically significant (mean reduction = 27.4 mm ± 22.9).
After 3 months of treatment, endometriosis-related pelvic pain was reduced by 50% or more in 37.3% (placebo: 19.8%) of patients taking denogestrel tablets, with no corresponding increase in combined analgesic medications; endometriosis-related pelvic pain (EAPP) was reduced by 75% or more in 18.6% (placebo 7.3%) of patients taking denogestrel tablets, with no corresponding increase in combined There was no corresponding increase in analgesic medication.
This placebo-controlled plus 15-month open extension study demonstrated sustained improvement in endometriosis-associated pelvic pain during treatment.
Results from a study using GnRH agonists as positive controls in 252 patients with endometriosis support these placebo-controlled findings.
Three studies enrolling a total of 252 patients receiving denogestrel 2 mg daily confirmed a significant reduction in endometriosis lesions after 6 months of treatment.
A small study (per dosing group: n=8) showed that denogestrel 1 mg daily induced anovulatory status after 1 month of treatment. The contraceptive efficacy of denogestrel tablets has not been evaluated in large studies.
Clinical trials completed in China
A multicenter study of the efficacy and safety of denogestrel tablets was completed in Chinese subjects with endometriosis in two parts: a 24-week, double-blind, randomized, placebo-controlled, parallel-group study part (double-blind study part) and a 28-week, single-arm, open-label, active study drug treatment part (open study part). The primary efficacy metric was absolute change from baseline after 24 weeks of treatment based on visual analog scale (VAS) scores to evaluate pelvic pain.
The double-blind part of the study enrolled 262 patients aged 18 to 45 years with surgically confirmed endometriosis and pelvic pain (130 in the denogestrel tablet group and 132 in the placebo group). The full analysis set (FAS) for effectiveness analysis was entered with 255 patients (126 in the denogestrel tablet group and 129 in the placebo group) and 225 patients (112 in the denogestrel tablet group and 113 in the placebo group) completing the double-blind phase of the study.
At the end of 24 weeks of treatment, VAS scores in the subjects taking denogestrel tablets were significantly different from those in the placebo group (D = 24.54 mm; 95% confidence interval: -29.93 to -19.15; p<0.0001), with a clinically significant reduction in pain compared with baseline values (mean VAS reduction of 38.7 ± 25.07 mm).
At the end of 24 weeks of treatment, pelvic pain was reduced by more than 50% in 60.3% of patients in the denogestrel tablet group and without an increase in remedial medication, compared with 17.8% in the placebo group; pelvic pain was reduced by more than 75% in 43.7% of patients in the denogestrel tablet group and without an increase in remedial medication, compared with 10.1% in the placebo group.
Analysis of secondary efficacy indicators at the end of the double-blind phase also demonstrated the superiority of denogestrel tablets over placebo, including percentage response rate, change from baseline in VAS corrected for remedial medication, remedial medication intake, B&B severity score, investigator and patient scores on CGI, subject PGI-C scores, pelvic pain scores using patient electronic logs, and improvement in quality of life. pain scores, and improvement in quality of life.
Two hundred and twenty patients chose to participate in the open portion of the study. This included 109 subjects previously taking placebo (placebo-denogestrel tablet group) and 111 subjects previously receiving denogestrel tablets (denogestrel tablet-denogestrel tablet group). All subjects received denogestrel tablets during the open portion. At the end of the open treatment period, 203 (92.3%) subjects had completed this part of the study (99 from the placebo-denogestrel tablet group and another 104 from the denogestrel tablet-denogestrel tablet group).
The results of the open study phase of the effectiveness study also support the conclusions on the effectiveness of denogestrel tablets obtained from the double-blind phase study. Subjects who switched from placebo to denogestrel tablets showed a trend toward a decrease in pelvic pain and other endometriosis-related symptoms between week 24 and week 52 and were generally consistent with the degree of symptom reduction in subjects previously taking denogestrel tablets. In addition, patients who continued to take denogestrel tablets were able to maintain the level of symptom reduction during the open study phase.
At the end of the open treatment, the proportion of responders was significantly higher in the placebo-denogestrel tablet group from the end of the double-blind treatment to the end of the open treatment than at the end of the double-blind period. In the denogestrel tablet- denogestrel tablet group, the proportion of responders at the end of open treatment remained approximately the same as at the end of double-blind treatment.
In the 24-week double-blind study, vaginal bleeding occurred more frequently in the denogestrel tablet group (10 [7.9%] subjects) compared to the placebo group (3 [2.3%] subjects). There were no subjects with excessive menstruation, depressed mood, or ectopic pregnancy in the denogestrel tablet group. Denogestrel tablets had a moderate inhibitory effect on estradiol levels.
BMD of the lumbar L2-L4 spine was assessed in 140 subjects (72 in the denogestrel group and 68 in the placebo group) and showed minimal and no difference in BMD from baseline values to the end of 24 weeks in either group. This shows that after 24 weeks of dosing, denogestrel tablets had no effect on BMD in adult women.
In the 28-week open-phase study, the most common adverse events were vaginal bleeding (7.3%), nasopharyngitis (4.5%), and upper respiratory tract infection (4.1%). Vaginal bleeding was more common in the placebo-denogestrel tablet group (12.8%) than in the denogestrel tablet-denogestrel tablet group (1.8%), a finding that suggests that the frequency of vaginal bleeding decreases with longer duration of denogestrel tablet use.
Pharmacology and toxicology]
Pharmacological effects
Denogestrel is a 19-nortestosterone derivative, which does not have androgenic activity, but has anti-androgenic activity, and its activity is about one-third of that of cyproterone acetate. The binding affinity of denogestrel with human uterine progesterone receptors is only 10% of that of progesterone, and although its affinity with progesterone receptors is low, it has potent progestogenic effects in vivo. Denogestrel has no significant androgenic, salicorticoid, or glucocorticoid activity in vivo.
Denogestrel acts on endometriosis by reducing the endogenous production of estradiol, thereby inhibiting the stimulatory effect of estradiol on the normally located and ectopic endometrium. When administered continuously, denogestrel leads to an endocrine environment of low estrogen and high progesterone, causing methylation of endometrial tissue, which in turn leads to a reduction in the size of endometriotic lesions.
Toxicological studies
Genotoxicity
The results of Ames test for denogestrel, in vitro chromosome aberration test for Chinese hamster lung cells and human lymphocytes, mouse lymphoma cell test, and in vivo bone marrow micronucleus test for mice were negative.
Reproductive toxicity
In the rat fertility and early embryonic development test, the
Female rats were given dinoprogesterone 0.3, 1.0 and 3.0 mg/kg/day from 15 days before mating to day 7 of gestation, and the dose of 3.0 mg/kg/day decreased the fertility index, decreased the mean number of implantation and increased the rate of post-implantation loss in female rats.
In the rat embryo-fetal development toxicity test, no embryotoxicity or teratogenicity was observed at a dose of 3.0 mg/kg/day of denogestrel; in the rabbit embryo-fetal development toxicity test, no teratogenicity was observed at a dose of 3.0 mg/kg/day of denogestrel, and the post-implantation loss rate increased at a dose of 3.0 mg/kg/day, while no significant effect was observed at a dose of 1.0 mg/kg/day.
In the perinatal toxicity test in rats, dinogestrel at 1 mg/kg/day reduced the frequency of estrus, mating index and fertility index of the F1 generation, and decreased the number of fertility and the number of F2 generation, but no significant effect was observed at 0.3 mg/kg/day.
The above fertility inhibition is the result of ovulation inhibition and pregnancy prolongation, which is related to the progestational activity of denogestrel.
Carcinogenicity
In the mouse 104-week carcinogenicity test, mice given denogestrel orally at 5, 15, and 50 mg/kg/day (males) and 10, 30, and 100 mg/kg/day (females) were exposed to 1.1, 3.5, and 10.6 times the dose given to women at 3 mg, and the incidence of interstitial uterine polyps was increased in females at the 100 mg/kg dose.
In a 104-week carcinogenicity test in rats, oral administration of denogestrel at 1, 3, and 10 mg/kg/day in female rats was 0.2, 1.4, and 6.1 times the exposure in women given 3 mg, and no carcinogenicity was observed.
It should be kept in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.
Pharmacokinetics
Absorption
After oral administration, denogestrel is rapidly and almost completely absorbed. The peak serum concentration (47 ng/mL) is reached about 1.5 hours after a single dose. The bioavailability is approximately 91%. The pharmacokinetic properties of denogestrel are dose proportional in the 1 – 8 mg dose range.
Distribution
Denogestrel binds to serum albumin, but not to sex hormone binding protein (SHBG) or adrenocorticotropin binding protein (CBG). 10 % of the total serum drug concentration is present as free steroids and 90 % is bound non-specifically to albumin.
The apparent volume of distribution (Vd/F) of denogestrel is 40 L.
Metabolism
Denogestrel is completely metabolized by known steroid metabolic pathways, mainly forming metabolites without endocrinological activity. Based on in vitro and in vivo studies, CYP3A4 is the main metabolic enzyme involved in the metabolism of denogestrel. Metabolite excretion is very rapid and therefore plasma is predominantly pro-formed dinogestrel.
The metabolic clearance rate as determined by serum CL/F was 64 mL/min.
Elimination
The serum level of denogestrel decreases in two periods. The half-life of the terminal elimination phase is approximately 9 to 10 hours. After oral administration of denogestrel at 0.1 mg/kg, its metabolites are excreted in urine and feces in a ratio of 3:1. The half-life of urinary metabolite excretion is 14 hr. After oral administration, 86% of the administered dose is cleared within approximately 6 days, most of which is excreted primarily in the urine within 24 hours.
Steady state
The pharmacokinetics of denogestrel are not affected by SHBG levels. After daily dosing, serum concentration levels of the drug increase approximately 1.24-fold, reaching steady state after 4 days of treatment. The pharmacokinetic profile of denogestrel after repeated administration of denogestrel tablets can be predicted based on the pharmacokinetics of a single dose.
Pharmacokinetics in special populations
Denogestrel Tablets have not been specifically studied in subjects with renal impairment. Denogestrel Tablets have not been studied in subjects with hepatic impairment.
There are no clinically significant differences in systemic exposure after steady state of denogestrel in Asian (Chinese and Korean) and Caucasian females.
[Storage].
Do not exceed 25°C and store airtight in the original packaging.
Packaging
Aluminum-plastic (polyvinyl chloride covered with polyvinyl chloride green transparent film/aluminum foil) packaging, 28 tablets/box, 84 tablets/box.
Expiration date
60 months
Standard】Imported drug registration standard: JX20170016
【Imported drug registration certificate number
【Manufacturer
Licensee’s name: Jenapharm GmbH & Co. KG
Address: Otto-Schott-Strasse 15, 07745 Jena, Germany
Production plant: Bayer Weimar GmbH und Co.
Production address: Döbereinerstrasse 20, 99427 Weimar, Germany
Tel: 0049 3643 4331354
Fax: 0049 3643 4332611354
Domestic Contact Unit
Company name: Bayer Healthcare Ltd.
Address: No. 7 Rongjing East Street, Beijing Economic and Technological Development Zone, Beijing, China
Postal Code: 100176
Telephone number: 010-59218282
Fax number: 010-59218181