5.1
Hypocortisolism
Additions
and/or revisions underlined:
ISTURISA lowers cortisol
levels and can lead to hypocortisolism and sometimes life-threatening adrenal
insufficiency. Lowering of cortisol can cause nausea, vomiting, fatigue,
abdominal pain, loss of appetite, dizziness. Significant lowering of serum cortisol
may result in hypotension, abnormal electrolyte levels, and hypoglycemia [see
Adverse Reactions (6)].
Hypocortisolism can occur
at any time during ISTURISA treatment. Evaluate patients for precipitating
causes of hypocortisolism (infection, physical stress, etc.). Monitor 24-hour
urine free cortisol, serum or plasma cortisol, and patient’s signs and symptoms
periodically during ISTURISA treatment.
Decrease or temporarily
discontinue ISTURISA if urine free cortisol levels fall below the target range,
there is a rapid decrease in cortisol levels, and/or patients report symptoms
of hypocortisolism. Stop ISTURISA and administer exogenous glucocorticoid
replacement therapy if serum or plasma cortisol levels are below target range
and patients have symptoms of adrenal insufficiency. After interruption or
discontinuation of ISTURISA, cortisol suppression may persist beyond the 4 hour
half-life. Monitor patients regularly and re-initiate ISTURISA at a
lower dose when urine free cortisol, serum or plasma cortisol levels are within
target range, and/or patient symptoms have resolved.
Educate patients on the
symptoms associated with hypocortisolism and advise them to contact a
healthcare provider if they occur.
6.1
Clinical Trials Experience
Additions
and/or revisions underlined:
. . .
The safety of
ISTURISA was evaluated in two clinical trials in adults with Cushings disease.
Study 1 (NCT02180217) was a 4-period, multicenter study with a 12-week
open-label titration period, 12-week open-label maintenance period, 8- week
double-blind, placebo-controlled period, and 14 to 24-week open label treatment
period in 137 patients with Cushing’s disease. Study 2 (NCT02697734) was a
2-period, multicenter study with a 12-week randomized, double-blind,
placebo-controlled period and a 36-week open-label treatment period in 74
patients with Cushing’s disease [see Clinical Studies (14)].
Study 1
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 1
in Adults with Cushing’s Disease
. . .
Description of
Select Adverse Reactions from the Core 48-week Period of Study 1
Revised
subheading; please refer to label for complete information.
. . .
Study 2
The adverse
reactions that occurred with frequency higher than 10% and greater than placebo
during the 12-week placebo controlled period are shown in Table 2.
Table 2:
Adverse Reactions With a Frequency of More Than 10% and Greater Than Placebo in
the 12-week Placebo Controlled Period of Clinical Study 2 in Adults with Cushing’s
Disease
Newly
added table; please refer to label for complete information.
Description of
Selected Adverse Reactions from the 12-week Placebo-Controlled Period of Study
2
Hypocortisolism
Hypocortisolism
was reported at a rate of 15% in ISTURISA arm and no subjects in placebo arm.
The majority of cases were manageable by interrupting/reducing the dose of
ISTURISA and/or adding low-dose, short-term glucocorticoid therapy.
QTc Interval Prolongation
One (2%)
patient in ISTURISA arm had a new QTcF value of > 450ms versus none in
placebo arm.
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 44% in ISTURISA arm and 36% in placebo arm. Hypertension, blood
testosterone increase, peripheral edema, acne and hypokalemia were the most
common adrenal hormone precursor-related adverse reactions and occurred in 17%
10%, 10%, 4% and 2% of patients in ISTURISA arm, and in 32%, 0%, 4%, 0% and 0%
of patients in the placebo arm. Most 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.
Other Abnormal
Laboratory Findings
Decreased Absolute Neutrophil Count
Three (6%)
patients in ISTURISA arm had at least one measured absolute neutrophil count
below the normal limit and one (2%) of these was classified as Grade 3 by
Common Terminology Criteria for Adverse Events (CTCAEs) grading. No patients in
placebo arm had absolute neutropil count below normal limit.
Elevated Liver Function Tests
Liver enzyme
elevations in patients treated with ISTURISA were infrequent, typically mild
and reversed spontaneously. No patient had concurrent increases in AST, ALT and
total bilirubin and/or ALP. No patient met the criteria for Hy’s Law. Two (4%)
patients in ISTURISA arm versus none in placebo arm had ALT or AST > 3 x
ULN.
6.2
Postmarketing Experience
Newly
added subsection:
Additional adverse
reactions have been identified during postapproval use of ISTURISA. Because
these reactions are reported voluntarily from a population of uncertain size,
it is generally not possible to reliably estimate their frequency or establish
a causal relationship to drug exposure.
- Neutropenia
associated with fever and infection
PATIENT
INFORMATION
Additions
and/or revisions underlined:
ISTURISA® (is tur ee' sah) (osilodrostat) tablets, for oral use
What is the most important information I should
know about ISTURISA? ISTURISA can cause serious side effects, including:
- Low
cortisol levels in your blood (hypocortisolism).
Tell your healthcare
provider right away if you experience any
of the following symptoms, as these may be symptoms of very low cortisol
level, known as adrenal insufficiency:
. . .
The most common side effects of ISTURISA include:
. . .
- decreased
appetite
- pain in
your joints (arthralgia)
- muscle
pain or soreness (myalgia)
- weakness
(asthenia)
- diarrhea
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