Isturisa (Page 2 of 6)

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.

A total of 137 Cushing’s disease patients were exposed to ISTURISA in the study [see Clinical Studies ( 14)] . The adverse reactions that occurred with frequency higher than 10% during the core 48-week period are shown in Table 1.

Table 1: Adverse Reactions With a Frequency of More Than 10% in 48-week Clinical Study in Cushing’s Disease Patients)
a Adrenal insufficiency includes glucocorticoid deficiency, adrenocortical insufficiency acute, steroid withdrawal syndrome, cortisol free urine decreased, cortisol decreased. One-third of the subjects with this event had low cortisol levels indicative of Adrenal Insufficiency. The majority of subjects had normal cortisol levels suggesting a cortisol withdrawal syndrome. b Fatigue includes lethargy, asthenia. c Headache includes head discomfort. d Edema includes edema peripheral, generalized edema, localized edema. e Rash includes rash erythematous, rash generalized, rash maculopapular, rash papular. f Dizziness includes dizziness postural. g Abdominal pain includes abdominal pain upper, abdominal discomfort h Hypokalaemia includes blood potassium decreased. i Hypotension includes orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased.

Adverse Reaction Type

(N = 137) %

Adrenal insufficiency a

43.1

Fatigue b

38.7

Nausea

37.2

Headache c

30.7

Edema d

21.2

Nasopharyngitis

19.7

Vomiting

19

Arthralgia

17.5

Back pain

15.3

Rash e

15.3

Diarrhea

14.6

Blood corticotrophin increased

13.9

Dizziness f

13.9

Abdominal pain g

13.1

Hypokalaemia h

12.4

Myalgia

12.4

Decreased appetite

11.7

Hormone level abnormal

11.7

Hypotension i

11.7

Urinary tract infection

11.7

Blood testosterone increased

10.9

Pyrexia

10.9

Anemia

10.2

Cough

10.2

Hypertension

10.2

Influenza

10.2

Other notable adverse reactions which occurred with a frequency less than 10% were: hirsutism (9.5%), acne (8.8%), dyspepsia (8%), insomnia (8%), anxiety (7.3%), depression (7.3%), gastroenteritis (7.3%), malaise (6.6%), tachycardia (6.6%), alopecia (5.8%), transaminases increased (4.4%), electrocardiogram QT prolongation (3.6%), and syncope (1.5%).

Description of Selected Adverse Reactions

Gastrointestinal Disorders

Gastrointestinal disorders, predominantly nausea, vomiting, diarrhea and abdominal pain were reported in 69% of patients. In many cases, the episodes were of short duration (1-2 days) and the severity was mild to moderate.

Hypocortisolism

Hypocortisolism was reported at a rate of 31% up to 12 weeks, and 18% from Weeks 12 to 26. The majority of cases were manageable by reducing the dose of ISTURISA and/or adding low-dose, short-term glucocorticoid therapy.

Changes in Pituitary Tumor Volume

An increase in the pituitary corticotroph tumor volume by greater than 20% from baseline was observed in 21/137 (15%) patients, while a decrease in tumor volume by greater than 20% from baseline was observed in 24/137 (18%) patients at Week 48. Eight patients discontinued because of an increase in tumor volume. There was no correlation between tumor volume increase and increase in adrenocorticotrophic hormone (ACTH). There was no specific pattern of timing of the tumor volume increase and no relationship with the total and the last dose of ISTURISA used in the study.

QTc Interval Prolongation

Adverse reactions of QT prolongation and clinically relevant ECG findings were reported. Five (4%) patients had an event of QT prolongation, 3 (2%) patients had a QTcF increase of > 60 ms from baseline, and 18 (13%) had a new QTcF value of > 450 ms [see Clinical Pharmacology ( 12.2)] .

Accumulation of Adrenal Hormone Precursors

CYP11B1 inhibition by ISTURISA is associated with adrenal steroid precursor accumulation and testosterone increases [see Warnings and Precautions ( 5.3)] . The incidence of adverse reactions potentially related to accumulation of adrenal hormone precursors was 42%. Hypertension and hypokalemia were the most common adrenal hormone precursor-related adverse reactions and occurred in 14% of patients and 17% of patients, respectively; edema was reported in 7% of patients, elevated blood pressure in 15% of patients. All cases of hypokalemia responded to treatment with potassium supplementation and/or mineralocorticoid antagonist therapy (e.g., spironolactone). One patient discontinued the study because of hypokalemia. In male patients testosterone levels generally increased but remained within normal limits; all patients were asymtomatic with no values above upper limit of normal (ULN) at last available value. In female patients, mean testosterone levels increased above the normal range from baseline and reversed when treatment was interrupted. The testosterone increase was associated with mild to moderate cases of hirsutism (12%) or acne (11%) in a subset of female patients.

Other Abnormal Laboratory Findings

Decreased Absolute Neutrophil Count

Of the 137 patients from the 48-week study, 18 patients had at least one measured absolute neutrophil count below the normal limit, 2 patients had an adverse reaction of neutropenia. No concomitant infections and/or fever were reported in patients with decreased absolute neutrophil count.

Elevated Liver Function Tests

Liver enzyme elevations in patients treated with ISTURISA were infrequent, typically mild and reversed spontaneously or following dose adjustment. Most liver abnormal parameters occurred during the dose-titration period and no patients discontinued ISTURISA drug due to abnormal liver chemistry parameters. Five (4%) patients had ALT or AST > 3 x ULN during the 48-week clinical study.

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