For example, using a dose of dienogest 2 mg daily, the reduction of endometriosis-related pain was significant; however, in 95% of cases spotting was reported. A mouse model of endometriosis shows that dienogest reduces lesion size better than duphaston and Esmya, although all three were effective. Safety and tolerability of dienogest in endometriosis: pooled analysis from the European clinical study program Thomas Strowitzki,1 Thomas.
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Endometriosis is a chronic disease primarily affecting women of childbearing age, in which endometriotic lesions form outside the uterus, typically leading to painful symptoms, fatigue, and infertility. The symptoms of endometriosis may cause significant impairment in quality of life and represent a substantial economic burden to patients, families, and society. There is no cure for endometriosis; management consists of alleviating pain and other symptoms, reducing endometriotic lesions, and improving quality of life.
Recurrence after surgical intervention is common, while the clinical evidence to support the efficacy and safety of many medications currently used in endometriosis is limited. Dienogest is an oral progestin that has been investigated extensively in the treatment of endometriosis in two clinical programs performed in Europe and Japan, including dose-ranging, placebo-controlled, active comparator-controlled, and long-term up to 65 weeks studies. These studies demonstrated that dienogest 2 mg daily effectively alleviates the painful symptoms of endometriosis, reduces endometriotic lesions, and improves indices of quality of life.
Dienogest showed a favorable safety and tolerability profile in these studies, with predictable adverse effects, high rates of patient compliance, and low withdrawal rates. This review article describes the clinical trial evidence that characterizes the efficacy and safety of dienogest in endometriosis, including two studies characterizing dienogest in long-term use. The relevance of these findings to the management of endometriosis in clinical practice is discussed.
New drugs: Dienogest
These lesions cause a dirnogest, inflammatory reaction, which can lead to the formation of scar tissue and adhesions. Endometriosis places a considerable economic burden on families and on society. Due to the variable presentation of endometriosis, there is typically a delay between the first appearance of symptoms and an accurate diagnosis. An diennogest survey reported that this delay is, on average, seven years.
Errors in diagnosis, with the potential for inappropriate therapy, are also common, creating anxiety and frustration, and contributing dienoegst to the burden of endometriosis.
A definitive diagnosis of endometriosis requires laparoscopy, ideally combined with confirmatory histology, to characterize endometriotic lesions. There is no permanent cure for endometriosis. The main aims of treatment are to alleviate pain and other symptoms, reduce endometriotic lesions, and improve the quality of life of affected individuals.
A number of medical and surgical therapies are available to treat endometriosis, which may, on occasion, be used in combination. No single treatment is ideal for all patients and the management approach chosen should be directed to the individual needs of each patient. As endometriosis is a chronic disease, consideration should be given not only to the efficacy but also to the long-term safety and tolerability of the treatment options that are available.
Surgical intervention includes ablation of endometriotic lesions, removal of endometriotic cysts, and division of adhesions. Nonsteroidal anti-inflammatory drugs are frequently used by women with endometriosis in an attempt to achieve analgesia, although clinical trial evidence to support the efficacy of these agents in endometriosis is lacking.
Specific medical therapies that are approved for the treatment of endometriosis include gonadotropin-releasing hormone GnRH agonists, danazol, and certain progestins. These agents and the combined oral contraceptives COCs share a common difnogest mechanism of action in endometriosis.
COCs are widely used to treat the symptoms of endometriosis, although they are not approved for this indication in the majority of countries because of the absence of supportive trial evidence.
However, a common problem with long-term continuous COC regimens is breakthrough bleeding. This is often treated by discontinuing the COC for a few days and then restarting therapy. GnRH agonists are an established therapy for endometriosis that can be administered via either intramuscular, subcutaneous, or intranasal routes. Although GnRH agonists provide effective pain relief and reduce the progression of endometriotic implants, 29 the hypoestrogenic state that they induce is associated with effects endometrjosis as accelerated bone mineral density loss, hot flushes, and vaginal dryness.
The optimal regimens for add-back therapy are not yet established. Danazol is an androgenic steroid that is effective in treating the signs and symptoms of endometriosis, but its use is limited by adverse effects on lipid metabolism and by weight gain, edema, acne, vaginal dryness, hot flushes, oily skin, hirsutism, liver toxicity, and breast atrophy.
Oral, parenteral, intrauterine, or implantable progestins have been used for decades in the treatment of endometriosis, although for many of these agents there is a lack of supportive evidence from controlled clinical trials.
Dose-finding data are lacking for most progestins, and there are few comparative data to indicate the benefits of one progestin over another. The progestins that are approved for use in endometriosis vary between countries.
This medication carries a black box warning concerning possible bone mineral loss. The preparation is not available in Europe. When administered continuously, progestins are effective in many women for the management of pain and other symptoms of endometriosis, with endomrtriosis effects also relating to amenorrhea and anovulation. However, certain progestins are effective in endometriosis only at high doses when compared with use in other indications, 3334 which may increase the likelihood of adverse dienogesf, such as weight gain and androgenic effects, and elevate the risk of cardiovascular adverse events.
Endomefriosis is an oral progestin that has been investigated systematically for the treatment of endometriosis in dose-ranging, placebo-controlled, active comparator-controlled, and long-term trials performed in Europe and Japan Figure 1. Based on this trial evidence, dienogest has received approval as a monotherapy for the treatment of endometriosis in Europe, Japan, Australia, and Singapore.
Structural formula of the progestin, dienogest, compared with naturally occurring progesterone. Dienogest demonstrates a number of characteristics in preclinical studies that are relevant to its use in endometriosis. Pharmacologically, dienogest combines the advantages of the norprogestin and the progesterone derivative classes. Unlike other agents in the norprogestin class, dienogest lacks androgenic effects; rather, dienogest has beneficial antiandrogenic properties typical of dieenogest progesterone derivatives, which are associated with minimal ddienogest in lipid and carbohydrate levels.
Dienogest is almost completely absorbed, and has a high bioavailability after oral administration, similar to other norprogestins. Its relatively short half-life of 10 hours means there is no risk of accumulation after repeated dosing.
The majority dienogeet orally administered dienogest is excreted within 24 hours, mainly in urine. Dienogest reduces endometriotic lesions through a number of biological mechanisms. Dienogest is associated with relatively moderate inhibition of gonadotropin secretion, leading to a modest reduction in the endogenous production of estradiol.
Animal studies indicate that dienogest may also reduce plasma estradiol levels directly, through inducing apoptosis of granulosa cells in the ovary. A recent pharmacokinetic study confirmed the moderate suppression of estradiol levels, remaining within the lower end of the normal physiological range, in women volunteers administered dienogest at doses of 0.
In exploratory models of endometriosis, dienogest also demonstrates antiproliferative, anti-inflammatory, and antiangiogenic effects.
Oral administration of dienogest significantly suppressed angiogenesis in a mouse model. Clinical studies of rienogest with durations between 12 endometriosus 24 weeks have provided information on optimal dosing and on efficacy and safety characteristics that are relevant to the long-term management of endometriosis. The optimal daily dose of dienogest for treating endometroisis was investigated in an open-label, randomized, multicenter, week, dose-ranging study in Europe. Randomization to the 1 mg group was halted prematurely because of unsatisfactory bleeding patterns.
Laparoscopy showed that dienogest at 2 mg and 4 mg daily significantly reduced endometriotic lesions. In addition, dienogest at both these doses improved patient-reported symptoms, including the intensity of dyspareunia, dysmenorrhea, and diffuse pelvic pain. The 2 mg and 4 mg dienogest doses were generally well tolerated and rates of discontinuations due to endometiosis events were low. Irregular uterine bleeding was experienced by Based on these outcomes, dienogest at 2 mg endomertiosis daily was recommended as the optimal dose in the treatment of dienovest.
In support of these findings, a Japanese study investigated dienogest at daily doses of 1 mg, 2 mg, and 4 mg for 24 weeks in women with endometriosis. While safety assessments indicated no dose-related differences, reductions in estradiol levels associated with endlmetriosis 4 mg dose indicated that 2 mg daily may offer least potential for adverse effects on bone mineral density.
Mean serum estradiol concentrations at between eight weeks and the end of treatment in this study were The effectiveness of dienogest at the 2 mg daily dose was compared against placebo in a week, randomized trial using a range of tools for measuring changes in symptoms and quality of life. The study enrolled women with stage I—IV ie, minimal to severe endometriosis and an endometriosis-associated pelvic pain score of at least 30 mm on a visual analog scale measured on a scale of 0— mmwhich represents a well validated tool for the measurement of endomteriosis.
Biberoglu and Endometriosi scale scores supported the visual analog scores by demonstrating dienogesg reductions in the intensity of symptoms and signs in the dienogest group compared with placebo. The Clinical Global Impression scale, a measure of overall improvement, showed that Dienogest was generally well tolerated in this trial, with no serious or unexpected adverse events, and few events related to therapy.
Estradiol levels were modestly suppressed, and profiles of uterine bleeding in the dienogest group were comparable with the placebo group.
Dienogest Better to Treat Endometriosis than Esmya, Duphaston, Study Says
By week 24, reductions in mean visual analog score were Consistent with the visual analog score changes, dienogest and leuprolide acetate induced similar decreases in the intensity of symptoms and physical findings assessed by Biberoglu and Behrman scores. Short Form 36 Health Survey scores showed a trend to greater improvement in both physical and mental health in the dienogest than the leuprolide acetate group. Dienogest 1 mg twice daily was compared with triptorelin 3. Hot flushes were reported in Irregular bleeding was the most common complication in the dienogest group Greatest changes in quality of life assessed by Short Form 36 Health Survey score in both groups were improvements in bodily pain, with a trend to greater improvement in the dienogest group.
Consistent with the other comparative trials, dienogest was associated more frequently with irregular bleeding but less frequently with hot flushes than the GnRH agonist. Notably, each of the trials that investigated dienogest 2 mg daily described adverse effects of generally mild to moderate intensity which were associated with low rates of treatment discontinuation eg, 5.
Bleeding episodes decreased in number and intensity over time, and were associated with no discontinuations in these trials. An open-label pilot study of dienogest at the higher dose of 10 mg twice daily for 24 weeks provides additional information on the safety of this medication.
In addition, dienogest at this high dose had no adverse effects on lipid metabolism, liver enzymes, fasting insulin, or glucose. No menopausal symptoms and no adverse androgen-related effects were reported. These dienogfst, demonstrating that dienogest has a favorable safety and tolerability profile even at 20 mg daily ie, 10 times the recommended dosesupport the conclusion that the recommended dose of 2 mg once daily will have a similar beneficial profile.
The majority of women suffering from endometriosis are of reproductive age and so may require contraception. Based on the available dienogeat, dienogest provides complete ovulation inhibition at a daily dose of 2 mg.
Women with endometriosis may desire pregnancy once sufficient pain relief is achieved. Recent pharmacodynamic data in volunteers indicate that ovarian activity resumes rapidly range 1—43 days after cessation of dienogest. As with other progestins, there are limited data on the use of dienogest in pregnant women. The available data do not indicate harmful effects for dienogest with respect to reproductive toxicity and reveal no special risks on pregnancy.
Dienogest Treatment Reduces Endometriosis Lesions Better than Duphaston or Esmya, Mouse Study Shows
However, dienogest should not be administered to pregnant women because there is no need to treat endometriosis during pregnancy. Effective management of endometriosis over the longer term is an important objective.
The painful symptoms and impairment in quality of life associated with endometriosis may persist or deteriorate in the absence of effective treatment.
dienogesy Recurrence is frequent even after successful surgery, while there are only limited trial data to confirm the efficacy and safety of long-term treatment for many medications endometroosis in endometriosis.
Dienogest has been investigated as a long-term treatment of endometriosis in two large trials performed in Europe and Japan, which included assessments of efficacy, change in quality of life, safety, and tolerability.
Women who completed the week placebo-controlled study in Europe 54 were offered the opportunity to enter an open-label extension study of dienogest for up to 53 additional weeks, providing envometriosis overall treatment period of up to 65 weeks.
The intensity of pain showed significant, sustained improvements during the long-term study, in addition to the improvements associated with dienogest during the placebo-controlled phase.
Mean visual analog scores decreased from During a week treatment-free period following the long-term study, visual analog scores increased only moderately, suggesting that dienogest induces a beneficial effect that may persist after treatment cessation.