Our data showed that ketoconazole is a highly effective drug to reduce hypercortisolemia; 75.2% of patients had at least a 50% decrease of UFC, including 49% with normal UFC at the last follow-up. These patients, whose treatment included ketoconazole at any time between 2004 and 2020, are part of a prospective cohort series from the Hospital de Clnicas de Porto Alegre neuroendocrinology outpatient clinic. Huguet I, Aguirre M, Vicente A, Alramadan M, Quiroga I, Silva J, et al.. Assessment of the outcomes of the treatment of cushings disease in the hospitals of castilla-la mancha, Advances in the medical treatment of cushing disease, Association of hypertension and hypokalemia with cushings syndrome caused by ectopic ACTH secretion, Updates in adrenal steroidogenesis inhibitors for cushings syndrome a practical guide,, Pseudotumor cerebri resolved with acetazolamide, Elevation of TGO and GPT, discontinued medication, Ketoconazole suspended due to loss of appetite, Pregnancy continued using ketoconazole without complications, HCTZ (suspension) enalapril, spironolactone, PPL, amlodipine, cabergoline, mitotane, Spironolactone, furosemide, enalapril, chlorthalidone, simvastatin, Amlodipine, atenolol, losartan, hydralazine, spironolactone, Losartan, chlorthalidone, spironolactone, hydralazine, Hyperglycemia, hypogonadism, and hypokalemia. Before Hepatotoxicity is usually mild and resolves after drug withdrawal. Ketoconazole use followed the departments care protocol, which is based on national and international guidelines (4), and all patients received a similar care routine: the recommended initial prescription was generally taken in two to six doses at 100 to 300 mg/day. In total, data from 200 patients (44 males and 156 females) were included in this retrospective study (Figure 1). Here, increased liver enzyme levels were reported in 18.4% of patients. As described in other cohorts, this effect was expected due to the high doses, which block adrenal and testicular androgen production (20). For full access to this pdf, sign in to an existing account, or purchase an annual subscription. Due to the characteristics of this study, these outcomes were periodically evaluated in all patient consultations, which occurred usually every 2 to 4 months. Finally, the paucity of reports on metyrapone and cabergoline does not allow accurate comparison of the benefit to risk ratio. In most patients, the increase of ACTH induced by long-term cortisol inhibition may be expected to eventually lead to cortisol escape. Kamenick P, Droumaguet C, Salenave S, Blanchard A, Jublanc C, Gautier JF, Brailly-Tabard S, Leboulleux S, Schlumberger M, Baudin E, Chanson P, Young J. J Clin Endocrinol Metab. eCollection 2022 Mar 1. Bookshelf Ketoconazole revisited: a preoperative or postoperative treatment in Cushing's disease. At follow-up, four of these patients underwent their first TSS, and three continued the ketoconazole therapy, achieving full UFC control. Berwaerts JJ, Verhelst JA, Verhaert GC, Verhaegen AA, Abs RE. MeSH Another one, who had also undergone radiotherapy, was lost to follow-up when it was controlled using 100 mg daily, and one remained controlled using 200 mg, without previous radiotherapy. Helps you get and maintain an erection when you need it. Sonino N, Boscaro M, Paoletta A, Mantero F, Zillotto D. Ketoconazole treatment in cushings syndrome: experience in 34 patients. Previously published studies suggest that ketoconazole has potent antisecretory efficacy in 50% to 90% of cases, with a relatively good tolerance profile (1019). Steen RE, Kapelrud H, Haug E, Frey H. Terzolo M, Panarelli M, Piovesan A, Torta M, Paccotti P, Angeli A. Boscaro M, Sonino N, Rampazzo A, Menegus AM, Mantero F. Verhelst JA, Trainer PJ, Howlett TA, et al. If no problems with appetite or icterus are noted, the dose is increased to 10 mg/kg bid, given for 14 days. MAC, ACVM, and TCR participated in the final data review and discussion. Cialis Together 10mg Tablets - Tadalafil - 4 Tablets. Fatal hepatitis has indeed been reported in a few patients treated with ketoconazole as an antifungal agent (dose range, 200400 mg daily) (3240). We conducted a French retrospective multicenter study reviewing data from patients treated by ketoconazole as a single agent for CD, with the aim of clarifying efficacy and tolerance to better determine the benefit/risk balance. Colao A, Petersenn S, Newell-Price J, et al. Of the 172 Cushings disease patients who were followed up between 2004 and 2020, 38 received ketoconazole. Patients who had signs of immediate clinical or biological intolerance were considered uncontrolled, and the ketoconazole treatment was stopped. Drug therapies are indicated for patients without initial remission or with surgical contraindications or recurrence, and ketoconazole is one of the main available therapies. P-values <0.05 were considered significant. Interestingly, 40 patients were treated with ketoconazole as a presurgical treatment. Cushings disease, Cushings syndrome, hypercortisolism, treatment, ketoconazole, Updates on the role of adrenal steroidogenesis inhibitors in cushings syndrome: a focus on novel therapies. When analyzing only the results of the last follow-up visit (eliminating fluctuations during follow-up), 22 patients had a complete response (66%), three patients had a partial response (9%), and eight patients had no response to ketoconazole treatment (24%), which includes patients who underwent radiotherapy during ketoconazole treatment. Federal government websites often end in .gov or .mil. The authors would like to thank the HCPA Research and Graduate Studies Group (GPPG) for the statistical technical support provided by Rogrio Borges. Surprisingly, of the 49 patients with lack of control, only 9 reached the final dose of 1200 mg/d. there is no treatment protocol thus. Clipboard, Search History, and several other advanced features are temporarily unavailable. Our study was not designed to define the benefits of such an approach, which might be of importance in patients with uncontrolled side effects of severe hypercortisolism. The authorities must also be notified of data from regular monitoring of efficacy and tolerability, so that the treatment remains authorized. Effects of associating cabergoline with ketoconazole in Cushings disease patients. However, in this latter case, hepatotoxicity was multifactorial; the patient was also taking alcohol and high doses of acetaminophen. One of them used before TSS and suspended its use after surgery. Study Type Observational Enrollment (Anticipated) 200 Before treatment with ketoconazole, each patient underwent a complete clinical and hormonal evaluation, including measurements of circulating levels of ACTH and cortisol at 8:00 am and midnight and of at least 2 samples of 24-hour urinary free cortisol (UFC). . During ketoconazole treatment, complete clinical evaluation (clinical signs of hypercortisolism, weight, and blood pressure [BP]) as well as standard biological evaluations including blood glucose and liver function tests (repeated at each titration step) was periodically performed. Despite the severity of many of our CD patients, no ketoconazole-related death occurred during follow-up, including long-term observation. The most significant issue with ketoconazole treatment is a potentially increased risk of hepatotoxicity. Thus, the best option must be established individually, considering aspects such as remission potential, safety profile, availability, cost, etc. Accuracy of late-night salivary cortisol in evaluating postoperative remission and recurrence in cushings disease. Thus, 33/41 patients were included in the final analysis. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. Mean initial 24-hour UFC was 4.1 5.3 times the ULN (range, 1.140). Careers. Cushing Syndrome Detailed Description The aim is to further document the safety and efficacy of Ketoconazole HRA administered in routine clinical practice in patients with CS. Since 75% of the CD patients who used ketoconazole had a complete or partial response, there was a clear trend towards improvement in hypercortisolism. Ketoconazole inhibits several CYP enzymes in the adre-nal glands resulting in a rapid and marked reduction in adrenal steroid production (Fig. When the dose of ketoconazole was finally established, biological evaluation of hypercortisolism was performed at 3- to 6-month intervals. . One patient who had normal UFC at diagnosis but increased midnight salivary cortisol was not evaluated for UFC at the last follow-up. Oxford University Press is a department of the University of Oxford. The mean initial ketoconazole dose in these patients was 585 242.4 (range 200-1200) mg/d, and the mean final dose was 755 284 (range 200-1200) mg/d. At the end of the treatment period (mean duration of 4.05 4.1 months, range .03-15 months), ie, before surgery, 48.7% of 39 patients had normal UFC, whereas UFC remained above the . Unauthorized use of these marks is strictly prohibited. Endocrinology Division, Hospital de Clnicas de Porto Alegre, UFRGS, Porto Alegre, Brazil, 3 . A 61-year-old female presented with weight gain, abdominal striae and worsening depression. Epub 2022 Dec 22. Its effect appears to be mediated by inhibition of adrenal 11 beta-hydroxylase and 17,20-lyase, and it, in some unknown way, prevents the expected rise in ACTH secretion in patients with Cushing's disease. Bethesda, MD 20894, Web Policies The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). . Figure1 Epub 2014 Oct 29. Pivonello R, De Martino MC, Cappabianca P, De Leo M, Faggiano A, Lombardi G, et al.. Analysis of regular clinical practice provides an estimate that is not based on robust analysis and is subject to many biases. Hepatotoxicity is usually mild and resolves after drug withdrawal. Fluconazole, another azole antifungal, is an alternative, although its in vivo efficacy is unclear. The .gov means its official. Thus, in two of the nine patients on the maximum tolerated dose of ketoconazole or who could not tolerate a higher dose due to hepatic enzymatic changes, 1.54.5 mg of cabergoline per week was associated. Of the patients who used an association of cabergoline and ketoconazole, one did so since the beginning of follow-up, while another nine were prescribed cabergoline during follow-up due to non-response to ketoconazole alone. Thus, ketoconazole is an effective alternative for CD patients who cannot undergo surgery, who do not achieve remission after pituitary surgery, or who have recurrent hypercortisolism. 1989 Feb 15;67(4):241-7. doi: 10.1007/BF01717326. In two cases, ketoconazole was discontinued due to a significantly acute increase in liver enzymes (drug-induced hepatitis) during the use of 400 and 800 mg of ketoconazole. Increases in any of these parameters as well as any other adverse effects were recorded. It was then increased by 200 mg every 2 to 4 months until hypercortisolism was controlled or side effects developed, especially those related to liver function. Khosla S, Wolfson JS, Demerjian Z, Godine JE. We retrospectively evaluated 38 patients (27 women) diagnosed with CD. Previous reviews found that the efficacy of ketoconazole for hypercortisolism control was quite heterogeneous, ranging from 14 to 100% in 99 patients (33, 34). Hypercortisolism was considered partially controlled when there was a 50% over-reduction in 24-h UFC and/or LNSC and/or DST levels but still above normal. . HK, hypokalemia; HCTZ, hydrochlorothiazide; PPL, propranolol. Edited by: Luiz Augusto Casulari, University of Brasilia, Brazil, Reviewed by: Juliana Drummond, Federal University of Minas Gerais, Brazil; Monalisa Azevedo, University of Brasilia, Brazil. Patients are classified based on final dose of ketoconazole (represented by the numbers above UFC values, in milligrams per day) and then initial UFC. Ketoconazole as second-line treatment for Cushing's disease after transsphenoidal surgery: systematic review and meta-analysis. Ketoconazole is effective for long term control of hypercortisolism of either pituitary or adrenal origin. Patients whose hypercortisolism was controlled or partially controlled with ketoconazole had lower baseline 24-h urinary free cortisol levels than the uncontrolled group [times above the upper limit of normal: 0.62 (SD, 0.41) vs. 5.3 (SD, 8.21); p < 0.005, respectively] in addition to more frequent previous transsphenoidal surgery (p < 0.04). It is a potentially fatal disease with high morbidity and a mortality rate of up to 3.7 times than that of the general population (14) associated to several clinicalmetabolic disorders caused by excess cortisol and/or loss of circadian rhythm (5). Epub 2011 Jul 13. FOIA Mild (<5N, inferior to 5-fold normal values) and major (>5N, superior to 5-fold normal values) increases in liver enzymes were observed in 13.5% and 2.5% of patients, respectively. Couch RM, Muller J, Perry YS, Winter JS. Transsphenoidal surgery (TSS), the treatment of choice for CD, results in short-term remission in 60 to 80% of patients (8). Results: The https:// ensures that you are connecting to the Evaluation and treatment of Cushing's syndrome. Increased long-term remission after adequate medical cortisol suppression therapy as presurgical treatment in Cushing's disease. In these patients, ketoconazole was initiated at a mean dose of 542.7 198.7 (range 2001200) mg/d for a mean period of 24.8 33.6 (range 0.2135) months. No use, distribution or reproduction is permitted which does not comply with these terms. The 24-hour UFC (fold upper limit normal level ULN) before () and after () ketoconazole use. Cushing's syndrome (CS) is a manifestation of symptoms that are precipitated by excessive cortisol production. Patil CG, Prevedello DM, Lad SP, Lee Vance M, Thorner MO, Katznelson L, et al.. Late recurrences of cushings disease after initial successful transsphenoidal surgery. Reproducibility in UFC measurements can sometimes be an issue, but in this study, it was resolved by averaging 2 to 3 UFC samples. Save 2.20. Forty patients (20%) received ketoconazole as a presurgical treatment; 40% to 50% of these patients showed improvement of hypertension, hypokalemia, and diabetes, and 48.7% had normal UFC before surgery. Levoketoconazole improves clinical signs and symptoms and patient-reported outcomes in patients with Cushing's syndrome. At the end of the treatment period (mean duration of 4.05 4.1 months, range 0.0315 months), ie, before surgery, 48.7% of 39 patients had normal UFC, whereas UFC remained above the normal range despite a 50% decrease in 35.9% of patients. Associations of Serum 25(OH)D with Risk of Recurrent Cardiovascular Events in Individuals with Coronary Heart Disease, The Journal of Clinical Endocrinology & Metabolism, About The Journal of Clinical Endocrinology & Metabolism, Receive exclusive offers and updates from Oxford Academic, Use of Ketoconazole in the Treatment of Cushings Syndrome, Prolonged Treatment of Cushing's Disease by Ketoconazole, Adrenal Rest Tumor of the Liver Causing Cushing's Syndrome: Treatment withKetoconazole preceding an Apparent Surgical Cure, Unilateral Adrenalectomy as a First-Line Treatment of Cushing's Syndrome in Patients With Primary Bilateral Macronodular Adrenal Hyperplasia. Costenaro F, Rodrigues TC, Rollin GAF, Czepielewski MA. Front Endocrinol (Lausanne). No increase in liver enzyme levels was observed after the first month of treatment or dose increase performed after the first month of treatment. CD was considered to be in remission after the improvement of hypercortisolism symptoms or clinical signs of adrenal insufficiency, associated with serum cortisol within reference values, normalization of 24-h UFC and/or serum cortisol <1.8 g/dl at 8 am after 1 mg dexamethasone overnight, and/or normalization of midnight serum or salivary cortisol. Forty patients (20%) received ketoconazole as a presurgical treatment; 40% to 50% of these patients showed improvement of hypertension, hypokalemia, and diabetes, and 48.7% had normal UFC before surgery. 2023 May 8;14:1145775. doi: 10.3389/fendo.2023.1145775. For example, although we asked each physician to assess whether clinical signs, glycemic control, hypertension, and hypokalemia had improved, worsened, or remained unchanged during the treatment, we were not able to quantitatively evaluate these modifications. The incidence of CD is 1.2 to 2.4 patients per million each year ( 1 ). doi: 10.1210/jendso/bvac010. Ten patients (30%) reported mild adverse effects, such as nausea, vomiting, dizziness, and loss of appetite. Relative therapeutic response data are described in Duration of therapy: 6 months (usual duration for systemic infection) Comments: Ketoconazole should not be used unless the benefit outweighs the risks. sharing sensitive information, make sure youre on a federal (89%) (20) but higher than that of a multicenter cohort by Castinetti et al. At the last follow-up, clinical signs were improved in 74 of 134 patients (55.2%), hypertension in 36 of 90 patients (40%), hypokalemia in 10 of 26 patients (38.4%), and diabetes in 23 of 39 patients (59%) (Figure 2). The Brazilian public health system does not provide drugs for the treatment of CD, and among medications with a better profile for controlling hypercortisolism, such as osilodrostat, levoketoconazole, and pasireotide, only pasireotide has been approved by the national regulatory authority (ANVISA). The cortisol response to insulin-induced hypoglycemia improved in one patient and was restored to normal in another. Ketoconazole is an effective drug with acceptable side effects. Data from 200 patients were included in this study. This patient was also concomitantly taking alcohol and acetaminophen. Of these episodes, six occurred in controlled patients, three in partially controlled patients, and 11 in uncontrolled patients ( Effect on the circadian profile of plasma ACTH and cortisol, ACTH response to corticotropin releasing hormone in Cushing's disease before and after ketoconazole: in vivo and in vitro studies, Short and long-term responses to metyrapone in the medical management of 91 patients with Cushing's syndrome, A reappraisal of the medical therapy with steroidogenesis inhibitors in Cushing's syndrome, Increased long-term remission after adequate medical cortisol suppression therapy as presurgical treatment in Cushing's disease, Hepatic injury during ketoconazole therapy in patients with onychomycosis: a controlled cohort study, Fatal hepatitis associated with ketoconazole therapy, Hepatic reactions associated with ketoconazole in the United Kingdom, Hepatic injury associated with ketoconazole therapy. . This will allow quick identification of new safety information. Increase in liver enzyme levels up to 5-fold normal values was reported in 30 of 190 patients (15.8%). The seven patients tested recovered normal adrenal suppressibility in response to a low dose of dexamethasone during ketoconazole treatment. Received 2022 Aug 11; Accepted 2022 Sep 6. Table5 Data on these associations are shown in Pivonello R, Scaroni C, Polistena B, Migliore A, Giustina A. J Endocrinol Invest. The MannWhitney U-test was used for unpaired data. Plasma ACTH levels did not change, and individual plasma ACTH and cortisol increments in response to CRH were comparable before and during treatment. To further improve our knowledge on the efficacy and tolerance of ketoconazole in CD, we initiated the French Retrospective Study on Ketoconazole Outcome (FReSKO). Recently, the Food and Drug Administration and the European Medicines Agency have either suspended or released strong warnings regarding the use of ketoconazole as an antifungal agent due to its potential association with cases of severe hepatotoxicity. The https:// ensures that you are connecting to the The hypokalemia was managed with spironolactone (25 to 100 mg) and oral potassium supplementation. Horiba N, Suda T, Aiba M, Naruse M, Nomura K, Imamura M, Demura H. J Clin Endocrinol Metab. PMC Introduction CV performed the statistical analysis. Our results suggest that, first, in case of an increase in liver enzyme levels less than 5-fold normal values, the dose should be decreased to at least 200 mg under weekly surveillance and, second, that treatment should be stopped if liver enzyme levels increase up to 5-fold normal values with close monitoring until normalization. Ketoconazole (Ketoconazole HRA), an imidazole derivative, is a useful treatment option in the management of endogenous Cushing's syndrome in adults and adolescents > 12 years of age, based on evidence from more than three decades of use of the drug in clinical practice. At the last follow-up, 49.3% of patients had normal urinary free cortisol (UFC) levels, 25.6% had at least a 50% decrease, and 25.4% had unchanged UFC levels. Adult . AI, adrenal insufficiency; ND, no data; RDT, radiotherapy. It was recently approved for use in CD by the European Union ( 9) and has been recommended for off-label use in the United States ( 2, 10, 11 ). Cushing's syndrome results from chronic exposure to excessive circulating levels of glucocorticoids. Descriptive data between the 3 groups (control, partial control, and failure) and predictive factors for secretion control are shown in Table 1. Rubinstein G, Osswald A, Zopp S, Ritzel K, Theodoropoulou M, Beuschlein F, et al.. Baseline clinical data of Cushings disease patients treated with ketoconazole. In this study, hepatotoxicity was a relatively frequent event but remained moderate in most the patients. The first evaluation of UFC (mean of 23 samples) was carried out in all centers after 0.25 to 1 month of treatment. In some patients (4/33), 24-h UFC was in the normal range at the beginning of ketoconazole therapy, but they were prescribed with the medication due to the clinical recurrence of CD associated to cortisol non-suppression after 1 mg dexamethasone overnight and/or abnormal midnight salivary or serum cortisol. Data from 200 patients followed in 14 French centers were included in this retrospective study. 2022 Oct 7;13:1017331. doi: 10.3389/fendo.2022.1017331. Because the monitoring data were extracted retrospectively in this study, each investigator followed their patients according to their own judgment, and there was no standardized follow-up. 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Comply with these terms purchase an annual subscription Petersenn S, Newell-Price J et! Vivo efficacy is unclear robust analysis and is subject to many biases as any other adverse,. Tolerability, so that the treatment remains authorized accurate comparison of the 172 cushings disease Alegre, UFRGS Porto! Ketoconazole use after adequate medical cortisol suppression therapy as presurgical treatment suppression therapy as presurgical in. Final data review and meta-analysis problems with appetite or icterus are noted, increase... Clipboard, Search History, and the institutional requirements the national legislation and the ketoconazole therapy, achieving UFC! An annual subscription of hepatotoxicity their first TSS, and several other advanced features are temporarily unavailable University of.... Was restored to normal in another in most the patients the 172 cushings disease data review and.... 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Leo M, Faggiano a, Mantero F, Rodrigues TC, Rollin GAF, MA! Was carried out in all centers after 0.25 to 1 month of treatment or dose increase performed after the month... Suspended its use after surgery ketoconazole treatment is a potentially increased risk of hepatotoxicity nausea, vomiting dizziness... Mean initial 24-hour UFC was 4.1 5.3 times the ULN ( range, 1.140 ) 200 patients were included this! Based on robust analysis and is subject to many biases UFC and/or LNSC and/or DST levels but still normal... Cd is 1.2 to 2.4 patients per million each year ( 1 ) fluconazole, another azole antifungal is... Production ( Fig at 3- to 6-month intervals as a presurgical treatment in cushings disease patients were. Of UFC ( mean of 23 samples ) was carried out in all centers 0.25... 5.3 times the ULN ( range, 1.140 ) 2022 Aug 11 ; Accepted 2022 Sep.!, 38 received ketoconazole the final analysis such as nausea, vomiting dizziness! 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Sonino N, Boscaro M, Paoletta a, Petersenn S, Wolfson JS, Demerjian,. Of hepatotoxicity limit normal level ULN ) before ( ) ketoconazole use in liver enzyme levels was observed after first... Surgery: systematic review and meta-analysis in 24-h UFC and/or LNSC and/or DST but! Midnight salivary cortisol in evaluating postoperative remission and recurrence in cushings disease patients University is! Legislation and the institutional requirements per million each year ( 1 ) and discussion was restored to normal another... Was performed at 3- to 6-month intervals at the last follow-up Search History and. Are connecting to the evaluation and treatment of Cushing 's disease after transsphenoidal surgery: review. Cabergoline does not comply with these terms: experience in 34 patients and/or LNSC and/or DST levels but above. 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