Battysayene
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`Pac=)-leae
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`al-
`AmericanJournal
`of Medicine.
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`Mylan v. Janssen IPR2016-01332
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`4
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`INDEX ISSUE.
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`JANSSEN EXHIBIT 2065
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`JANSSEN EXHIBIT 2065
`Mylan v. Janssen IPR2016-01332
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`

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`CASE REPORTS
`
`Total Suppression of Cortisol Excretion by Ketoconazole in the
`Therapy of the Ectopic Adrenocorticotropic Hormone Syndrome
`
`ALAN P. FARWELL, M.D.
`JOHN T. DEVLIN, M.D., F.A.C.P.
`JAMES A. STEWART, M.D., F.A.C.P.
`Burlington, Vermont
`
`From the Division of Endocrinology, Department
`of Medicine, Vermont Regional Cancer Center,
`Medical Center Hospital of Vermont, Burlington,
`Vermont. Requests for reprints should be ad(cid:173)
`dressed to Dr. Alan P. Farwell, Division of Endo(cid:173)
`crinology and Metabolism, Department of Medi(cid:173)
`cine, University of Massachusetts Medical Cen(cid:173)
`ter, 55 Lake Avenue, North, Worcester,
`Massachusetts 01605. Manuscript submitted
`November 12, 1987, and accepted February 16,
`1988.
`
`Ketoconazole, an antifungal imidazole derivative, has been shown to
`inhibit adrenal steroidogenesis in vitro and in vivo. This has led to its use
`clinically as an effective treatment for various forms of Cushing's
`syndrome. The clinically effective doses have been reported to be
`between 800 to 1,200 mg per day, usually without glucocorticoid
`replacement. Herein is reported the first case of Cushing's syndrome
`due to ectopic adrenocorticotropic production from a metastatic carci(cid:173)
`noid tumor of the thymus that was treated with ketoconazole. Urinary
`cortisol excretion was totally suppressed at the initial dose and optimal
`control was achieved with relatively low doses of ketoconazole (200 to
`400 mg per day), along with dexamethasone replacement. Use of
`glucocorticoid replacement is advisable in this setting to avoid symp(cid:173)
`tomatic hypoadrenalism.
`
`Ketoconazole is an imidazole derivative that until recently had been used
`solely as an antifungal agent. It has been well tolerated overall with very
`few reported side effects, and it is finding more widespread use due to an
`increasing incidence of opportunistic fungal infections, as seen in pa(cid:173)
`tients with the acquired immunodeficiency syndrome. More recently, it
`has been found to be a potent inhibitor of androgen [ 1] and adrenal
`glucocorticoid production [2], and as such, has been used clinically in the
`treatment of hormonally responsive tumors (i.e., prostate cancer) and
`endocrinopathies associated with hypercortisolism (i.e., the Cushing's
`syndromes) [ 3]. It has been suggested that a major role of this drug in the
`future will include the treatment of a variety of endocrine disorders. A
`cautionary note has been sounded recently with several reported deaths
`due to septicemia in patients receiving high-dose ketoconazole ( 1, 200
`mg per day) for the treatment of prostate cancer [ 4].
`We describe a case of Cushing's syndrome due to ectopic production
`of adrenocorticotropic hormone (ACTH) by a metastatic carcinoid tumor
`of the thymus. Medical control of cortisol excretion was achieved with
`lower doses of ketoconazole than reported in the literature and this
`patient was treated prophylactically with dexamethasone to avoid hypoa(cid:173)
`drenalism. We recommend beginning glucocorticoid replacement when
`using ketoconazole to treat the ectopic ACTH syndrome.
`
`CASE REPORT
`A 50-year-old white woman presented in June 1985 with fatigue, intermit(cid:173)
`tent facial flushing, sweating of the back, neck, and face, anorexia, mild
`diarrhea, and an unintentional 10-pound weight loss over the previous four
`to six weeks. Her only pertinent past medical history included hypertension
`since 1980 treated with propranolol and a diuretic. Due to an elevated left
`hemidiaphragm noted on a chest radiograph, a computerized tomographic
`
`June 1988 The American Journal of Medicine Volume 84
`
`1063
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`

`

`KETOCONAZOLE IN THE ECTOPIC ACTH SYNDROME- FARWELL ET AL
`
`~LFC
`
`-
`
`Normal R,.-,ge
`
`...
`
`200
`400
`Ketoconazole Dose (mglday)
`
`•oo
`
`Figure 1. Response of cortisol excretion in the patient
`described, as measured by urine free cortisol ( UFC), to
`varying doses of ketoconazole.
`
`(CT) scan of the chest was performed that revealed a large
`anterior mediastinal mass. There was no pleural or paren(cid:173)
`chymal lung involvement and no abnormality was seen in
`the liver, spleen, or adrenal glands. Biopsy examination of
`the mass via mediastinotomy revealed a carcinoid tumor of
`the thymus. Physical examination revealed a weight of 67.5
`kg and blood pressure of 162/100, but results were other(cid:173)
`wise unremarkable. A 24-hour urine collection for 5-hy(cid:173)
`droxyindoleacetic acid (5-HIAA) was negative. The patient
`was referred to radiation therapy since the tumor was
`deemed unresectable due to the involvement of the chest
`wall. Follow-up CT scans after 6,556 rads to the primary
`tumor mass revealed little, if any, tumor shrinkage but the
`patient showed symptomatic improvement, with only rare
`flushing episodes and with a decrease in the fullness of her
`face. Weight at this time was 62.7 kg. In January 1986, aCT
`scan revealed an increase in the tumor size and the devel(cid:173)
`opment of a left-sided pleural effusion. This was followed
`by serial chest radiographs that showed a slow increase in
`the size of the effusion, with her only symptom at this time
`being mild dyspnea on exertion. In December 1986, a
`biopsy of an enlarging left supraclavicular lymph node was
`performed, with the histology found to be similar to that of
`the patient's primary tumor. Physical examination revealed
`a weight of 70.7 kg, blood pressure of 170/110, facial
`plethora, moon-shaped facies, hyperpigmentation of the
`palmar creases and the extensor surfaces, and a general(cid:173)
`ized increase in body hair. Laboratory examination revealed
`a 24-hour urine collection negative for 5-HIAA and a urine
`free cortisol level of 518 11g per 24 hours (normal: 16 to 80
`11g per 24 hours). A random plasma cortisol level was 43
`11g/dl (normal: 7 to 25 11g/dl) and an 8-mg overnight dexa(cid:173)
`methasone suppression test revealed a morning cortisol
`level of more than 64 11g/dl (normal: less than 5 11g/dl).
`Serum ACTH was 187 pg/liter (normal: less than 100 pg/
`liter). A diagnosis of Cushing 's syndrome due to ectopic
`production of ACTH by a metastatic thymic carcinoid tumor
`was made, and therapy was begun with ketoconazole 400
`mg per day and dexamethasone 1. 0 mg per day, both in
`divided doses. Two weeks later, a 24-hour urine free corti-
`
`sol level was less than 2 11g per 24 hours and the dose of
`ketoconazole was reduced to 200 mg per day (Figure 1).
`Four weeks after beginning treatment, her weight was 66.6
`kg, blood pressure was 140/84, and the patient was feeling
`well with less insomnia, resolution of menorrhagia, and
`improved proximal muscle strength. Serial 24-hour urine
`free cortisol determinations indicate that the optimal dose
`of ketoconazole in this patient is 300 to 400 mg per day.
`
`COMMENTS
`This case represents an example of a metastatic carci(cid:173)
`noid tumor of the thymus producing Cushing 's syndrome
`by ectopic production of ACTH. In retrospect, the patient
`probably had Cushing's syndrome as the cause of her
`clinical symptoms upon initial presentation of her tumor.
`Radiation therapy had little effect on the tumor mass,
`consistent with the slow-growing nature of thymic carci(cid:173)
`noid tumors [5]. However, it most likely did have an effect
`on decreasing probable hormonal production by the tumor
`as her clinical symptoms disappeared and she noted a
`decrease in her facial fullness and her weight. Unfortu(cid:173)
`nately, the only evaluation of hormonal production per(cid:173)
`formed at that time was a 24-hour urine collection for 5-
`HIAA, which was negative, so possible ectopic steroid
`production by the tumor remains undocumented. With
`recurrent disease, she was overtly cushingoid in appear(cid:173)
`ance and the diagnosis was confirmed by an elevated
`plasma cortisol concentration, an elevated 24-hour urine
`free cortisol excretion, an elevated ACTH level, and ab(cid:173)
`sence of suppression of plasma cortisol concentration
`with an 8-mg overnight dexamethasone suppression test.
`She showed quite a remarkable response to the initial
`400 mg per day dose of ketoconazole. Due to the precipi(cid:173)
`tous drop in her cortisol excretion to undetectable levels
`during the first two weeks of therapy, this patient would
`likely have become symptomatic due to hypoadrenalism
`had replacement steroids not been initiated along with the
`ketoconazole. With this therapy, her blood pressure im(cid:173)
`proved, her antihypertensive medications were de(cid:173)
`creased in dosage, and her clinical symptoms resolved .
`To our knowledge, this is the first reported case of a
`thymic carcinoid tumor with ectopic ACTH production
`treated with ketoconazole.
`Ketoconazole was developed in the 1970s as an anti(cid:173)
`fungal agent with oral efficacy. In 1981, DeFelice et al [6]
`observed that gynecomastia developed in three of 40
`patients treated with ketoconazole for fungal infections at
`doses of 200 to 600 mg per day. They initially postulated
`a direct effect of the drug on breast tissue. Similar obser(cid:173)
`vations in two patients by Pont et al [ 1] resulted in further
`investigation and led to the discovery of ketoconazole's
`role as an inhibitor of testosterone synthesis. Description
`of ketoconazole's ability to inhibit adrenal glucocorticoid
`synthesis soon followed [2], as well as delineation of the
`mechanism of these effects, which include inhibition of
`P45o enzymes such as 11-beta-hydroxylase, as well as
`
`1064
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`June 1988 The American Journal of Medicine Volume 84
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`

`

`KETOCONAZOLE IN THE ECTOPIC ACTH SYNDROME-FARWELL ET AL
`
`the side-chain cleavage of cholesterol (7], and the com(cid:173)
`petitive inhibitiion of glucocorticoid activity at the receptor
`level (8]. The first case of symptomatic hypoadrenalism
`due to ketoconazole was reported in 1985 in a patient
`being treated for a fungal infection [9], followed by several
`descriptions of ·similar findings in patients being treated
`with high-dose ( 1 ,200 mg per day) ketoconazole for
`prostatic cancer [ 1 0, 11].
`Ketoconazole's first published use in Cushing's syn(cid:173)
`drome was for preoperative stabilization in a patient with
`an adrenal rest tumor [12]. Subsequent reports have
`described ketoconazole's use in Cushing's disease as an
`adjunct to definitive surgery or radiation therapy (13] and
`as effective primary therapy for short-term [ 14] and long(cid:173)
`term control [ 15]. Effective control has been achieved
`without the expected rise in ACTH seen with other inhibi(cid:173)
`tors of steroidogenesis, by some unknown mechanism
`[14, 15]. Finally, Sheperd et al [16] have described the
`use of ketoconazole for control of the paraneoplastic
`Cushing's syndrome resulting from small cell lung cancer,
`although their patient soon died from the underlying malig(cid:173)
`nancy.
`Ectopic hormone production is the cause of approxi(cid:173)
`mately 15 percent of cases of Cushing's syndrome [ 17].
`Therapy of this paraneoplastic syndrome is usually aimed
`at the primary tumor and prolonged survival with excess
`ACTH is rare due to the highly malignant nature of the
`primary tumors. An exception to this is carcinoid tumors
`where the clinical course is often protracted. Carcinoid
`tumor of the thymus is a rare neoplasm, with less than
`100 cases reported in the literature [ 5]. Cushing's syn(cid:173)
`drome is a common presentation of thymic carcinoids,
`occurring in up to 40 percent of cases. Despite the fact
`that as many as 30 percent of cases will present with
`local invasion (as in our patient) or extrathoracic metasta(cid:173)
`sis, survival is often protracted with a 1 0-year survival rate
`of 35 percent and a median survival of six years [5].
`Aggressive surgical extirpation of the primary, and occa(cid:173)
`sionally the metastatic, tumor offers the best hope for
`either cure or extended survival. Cytotoxic chemotherapy
`response rates are 1 0 to 15 percent at best and radiation
`therapy can be useful in palliating the tumor.
`Prior medical therapy of Cushing's syndrome has been
`limited to essentially two drugs, aminoglutethamide and
`metyrapone, whose high incidence of side effects limits
`their use in up to 50 percent of patients [ 17]. Ketocona(cid:173)
`zole offers the promise of effectively controlling cortisol
`secretion with a much lower incidence of side effects. A
`transient rise in hepatic transaminases, nausea/vomiting,
`slight gynecomastia, and hypocalcemia are seen most
`frequently and are rarely severe enough to alter therapy
`[ 4]. Ketoconazole's antiadrenal effect is related to serum
`drug levels in a direct fashion [2] and Pont et al [2] have
`demonstrated a dramatic decrease in cortisol and testos(cid:173)
`terone levels for six to eight hours after a 400-mg dose.
`
`Despite this observation, clinical doses for adrenal corti(cid:173)
`costeroid and androgen inhibition have been 800 to 1 ,200
`mg per day.
`The use of replacement glucocorticoids during keto(cid:173)
`conazole therapy has generally been avoided in the litera(cid:173)
`ture, since the recommendation has been to decrease the
`ketoconazole dose if symptoms of hypoadrenalism occur
`(13]. A lower dose (400 mg per day) has been reported as
`probably safe based on six patients with leukemia treated
`prophylactically with the drug [ 18]. Most cases of symp(cid:173)
`tomatic hypoadrenalism have been described with the use
`of high-dose ( 800 to 1, 200 mg per day) ketoconazole [ 9-
`11 ], while only one of these reports suggests treating
`simultaneously with steroids, and then only in times of
`stress [ 1 0]. Most recently, Pont [ 19] utilized prophylactic
`replacement-dose steroids in a study on the use of high(cid:173)
`dose ketoconazole in patients with stage D2 prostatic
`cancer and recommends their use in this setting. Few
`data are available regarding the details of the reported
`deaths from sepsis in patients receiving high-dose keto(cid:173)
`conazole (4], but it is possible that hypoadrenalism was
`partly responsible.
`Our patient demonstrates a greatly increased sensitiv(cid:173)
`ity of adrenal glucocorticoid synthesis to inhibition by
`ketoconazole as compared with that described previous(cid:173)
`ly. She would have been at great risk for symptomatic
`hypoadrenalism had she not been simultaneously treated
`with dexamethasone, given her near total suppression of
`cortisol excretion with the initial dose. Because of this, we
`recommend the use of glucocorticoid replacement thera(cid:173)
`PY at the time of initiation of ketoconazole for the treat(cid:173)
`ment of the ectopic ACTH syndrome in order to eliminate
`the risk of hypoadrenalism in these patients. By using
`serial assessments of adrenal function (i.e., 24-hour urine
`free cortisol excretion), the optimal antiadrenal effect can
`be determined at the lowest dose of ketoconazole with
`the least risk to the patient, at which time the steroids can
`be discontinued if desired. Additional steroids, however,
`would be required in times of stress.
`In summary, ketoconazole's activity as a potent inhibi(cid:173)
`tor of steroidogenesis can be effectively utilized in the
`management of the ectopic ACTH syndrome. In addition
`to continuing to be an important antifungal drug, ketocon(cid:173)
`azole, because of its low incidence of side effects and
`twice-a-day dosing schedule, should be a very attractive
`drug in the treatment of several forms of Cushing's syn(cid:173)
`drome. The increasing use of ketoconazole in a variety of
`disorders will require closer monitoring for possible drug(cid:173)
`induced hypoadrenalism. Future investigations into the
`long-term efficacy and possible toxicities of this drug are
`indicated.
`
`ACKNOWLEDGMENT
`
`We wish to thank Dr. John Lantman for referral of this
`patient.
`
`June 1988 The American Journal of Medicine Volume 84
`
`1065
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`

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`KETOCONAZOLE IN THE ECTOPIC ACTH SYNDROME- FARWELL ET AL
`
`REFERENCES
`
`1. Pont A, Williams PL, Azhar S, et al : Ketoconazole blocks
`testosterone synthesis. Arch Intern Med 1982; 142:
`1237-1240 .
`2. Pont A, Williams PL, Loose OS, et al: Ketoconazole blocks
`adrenal steroid synthesis. Ann Intern Med 1982; 97: 370-
`372 .
`3. Sonino N: The use of ketoconazole as an inhibitor of steroid
`production . N Engl J Med 1987; 317 : 812-818.
`4. Williams G, Ware H, Kerle OJ, et al : Objective responses to
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`
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`13. Sonino N, Boscaro M, Merola G, Mantero F: Prolonged treat(cid:173)
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