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ISTURISA® (is tur ee' sah) (osilodrostat) is a prescription medicine used to treat elevated levels of cortisol in the blood (endogenous hypercortisolemia) in adults with Cushing's syndrome (CS):
- who cannot have surgery, or
- who have had surgery which did not cure their CS
It is not known if ISTURISA is safe and effective in children.
HOW ISTURISA WORKS
ISTURISA blocks an enzyme that helps your adrenal glands make cortisol. In turn, less cortisol should be released into your bloodstream. ISTURISA is the first FDA-approved medicine for CS that works this way.
Everyone responds to treatment differently, and it may take some time to feel better. The study results below may give you a better idea of what to expect with ISTURISA.
ISTURISA HELPS BRING CORTISOL LEVELS DOWN TO NORMAL
The safety and clinical effects of ISTURISA were assessed in a study called LINC 3.
ABOUT THE LINC 3 STUDY
137 patients diagnosed with Cushing's disease were included. Patients had to be between 18 and 75 years of age to participate. Some patients received prior treatments for Cushing's disease, including surgery, radiation therapy, and/or medication therapy, while others had not. Most patients were female and the average age was 41 years.
The study took place over 48 weeks. It was broken up into different periods.
Period 1
(weeks 1-12): 137 patients received ISTURISA. Doses were adjusted as needed to help each patient work toward achieving mean urinary free cortisol (mUFC) levels in the normal range
Period 2
(weeks 13-24): 130 patients received ISTURISA. By the end of this period, 71 patients were able to achieve normal cortisol levels [mUFC ≤upper limit of normal (ULN)] and maintain the same dose from Period 1. These patients were eligible to enter the randomized withdrawal period during period 3
Period 3
(weeks 26-34): of the 71 patients eligible for the randomized withdrawal period, 36 patients continued to receive ISTURISA and 35 patients were switched to receive placebo
The main goal of the study was to see how many patients in each group maintained normal cortisol levels (mUFC) without increasing their dose during Period 3.
Period 4
(weeks 26- or 34-38): 117 patients received ISTURISA. Those included were the 47 patients not eligible for the randomized withdrawal period at week 26 and the 70 patients who completed the randomized withdrawal period at week 34
Optional extension
(beyond week 48): 106 patients who were benefiting from ISTURISA continued treatment
At the end of the randomized withdrawal period (week 34),
ISTURISA WAS SHOWN
TO HELP A MAJORITY OF PATIENTS MAINTAIN NORMAL CORTISOL LEVELS (mUFC)a
86%
of patients who received ISTURISA hadnormal cortisol levels (mUFC) at week 34 (31 out of 36 patients)
VS
29%
of patients who received placebo hadnormal cortisol levels (mUFC) at week 34 (10 out of 34 patients)
Additional analysis showed
IN A MAJORITY OF PATIENTS, ISTURISA LASTED LONGa
53%*
(72 out of 137 patients)
of patients had normal cortisol levels (mUFC) at week 24 (end of Period 2) without a dose increase beyond week 12
66%*
(91 out of 137 patients)
of patients had normal cortisol levels (mUFC) at week 48 (end of Period 4)
81%*
(86 out of 106 patients)
of patients had normal cortisol levels (mUFC) at week 72 (optional
extension)
106 patients who were benefiting from ISTURISA had the option to
continue treatment beyond 48 weeks
During the study, participants had their cortisol levels measured multiple times with a test called the urinary free cortisol (UFC) test. These measurements refer to how much cortisol is found in a urine sample within a 24-hour collection period. In the LINC 3 study, “normal cortisol levels” were defined as less than or equal to 50 μg/24 h or 138 nmol/24 h.
STUDY LIMITATIONS: The study was not designed to reliably prove ISTURISA effect on these measures; it is not certain if these results are meaningful.
Please see Important Safety Information
below for ISTURISA warnings on serious side effects such as:
LINC 3 SIDE EFFECTS
The list below shows side effects that occurred in 15% or more of the 137 patients who received ISTURISA during the 48-week study.
| Side effects | Approximate % of patients |
|---|---|
| Low cortisol levels (adrenal insufficiency)b | 43% |
| Fatigue | 39% |
| Nausea | 37% |
| Headache | 31% |
| Swelling (edema) | 21% |
| Common cold (nasopharyngitis) | 20% |
| Vomiting | 19% |
| Joint stiffness (arthralgia) | 18% |
| Back pain | 15% |
| Rash | 15% |
Adrenal insufficiency or hypocortisolism was suspected based on clinical signs and symptoms, which may have included nausea, vomiting, fatigue, morning headaches, low blood sugar, or dizziness. About one-third of the patients had low cortisol levels, which is a sign of adrenal insufficiency. However, most patients had normal cortisol levels, suggesting a cortisol withdrawal syndrome.
MORE WAYS ISTURISA MAY HELP
In further LINC 3 analysis, improvements were seen at 48 weeks in:
Cardiovascular Measurements
This includes blood pressure, body weight, waist measurement, blood sugar, and cholesterol.
- This study allowed for the use of blood pressure and diabetes medicines and dose increases in patients already taking these medicines. There was also no control group. So how much ISTURISA or these other medicines contributed to these specific benefits can't be clearly established.
Health-Related Quality of Life
Scores on the CushingQOL questionnaire, used to measure health-related quality of life or how a person with Cushing's disease sees their physical and mental health over time, improved, suggesting a noticeable benefit in patients taking ISTURISA.
Depression Symptoms
Scores on the Beck Depression Inventory, a 21-item self-report questionnaire used to evaluate the severity of depression, decreased, suggesting a noticeable benefit in patients taking ISTURISA.
Additional benefits of ISTURISA include:
- Dosing that can be individualized to your specific needs
- Tablets that can be taken with or without food
Wondering if ISTURISA is right for you?
STUDY LIMITATIONS: The study was not designed to reliably prove ISTURISA effect on these measures; it is not certain if these results are meaningful.
ISTURISA WAS ALSO ASSESSED IN A STUDY CALLED LINC 4
ABOUT THE LINC 4 STUDY
73 patients diagnosed with Cushing's disease were included. Patients had to be between 18 and 75 years of age to participate. Some patients received prior treatments for Cushing's disease, including surgery, irradiation therapy, and/or medication therapy, while others had not. Most patients were female and the averagec age was 41 years.
The study took place over 48 weeks. It was broken up into different periods:
Period 1
(weeks 1-12): Of the 73 patients, 48 received ISTURISA. Doses were adjusted as needed to help each patient work towards achieving cortisol levels (mUFC) in the normal range
The main goal of the study was to see how many patients taking ISTURISA achieved normal cortisol levels (mUFC) at the end of Period 1 compared with those who took placebo.
Period 2
(weeks 13-24): 130 patients received ISTURISA. By the end of this period, 71 patients were able to achieve normal cortisol levels [mUFC ≤upper limit of normal (ULN)] and maintain the same dose from Period 1. These patients were eligible to enter the randomized withdrawal period during period 3
OPTIONAL EXTENSION
(beyond week 48): 60 patients who were benefiting from ISTURISA continued treatment
SEE THE LINC 4 RESULTS
At 12 weeks,
ISTURISA WAS SHOWN TO HELP A MAJORITY OF PATIENTS ACHIEVE NORMAL CORTISOL LEVELS
(mUFC)c
77%
of patients who received ISTURISA had normal cortisol levels (mUFC) at week 12 (37 out of 48 patients)
VS
8%
of patients who received placebo had normal cortisol levels (mUFC) at week 12 (2 out of 25 patients)
At 26 weeks,
4 out of 5 PATIENTS sustained normal cortisol levels in the open‑label
period
81%*
of patients who received ISTURISA maintained normalized mUFC mUFC ≤ULN at week 36 (59 out of 73 patients)
ADDITIONAL ANALYSIS SHOWED THAT WITHIN 5 WEEKS
58%*
of patients who received ISTURISA had normal cortisol levels (mUFC) (28 out of 48 patients)
VS
16%*
of patients who received placebo had normal cortisol levels (mUFC) (4 out of 25 patients)
The median time to achieve normal cortisol levels was 35 days for patients who received ISTURISA.c,d
STUDY LIMITATIONS: The study was not designed to reliably prove ISTURISA effect on these measures; it is not certain if these results are meaningful.
During the study, participants had their cortisol levels measured multiple times with a screening test called the urinary free cortisol (UFC) test. Each participant's individual test results were averaged together. In the LINC 4 study, “normal cortisol levels” were defined as 11-138 nmol/24 h or 4-50 μg/24 h. These measurements refer to how much cortisol is found in a urine sample within a 24-hour collection period.
The median is the middle number in a list of numbers: in this case, the middle time in a range of patient times to normal cortisol levels.
LINC 4 SIDE EFFECTS
The list below shows side effects that occurred in more than 20% of the 73 patients who received ISTURISA during the study.
| Side effects | Approximate % of patients |
|---|---|
| Joint stiffness (arthralgia) | 45% |
| Decreased appetite | 45% |
| Fatigue | 38% |
| Nausea | 37% |
| Headache | 33% |
| Muscle aches and pains (myalgia) | 26% |
| Dizziness | 26% |
| Low cortisol levels (adrenal insufficiency)e,f | 25% |
| Increased blood testosterone | 25% |
| Diarrhea | 23% |
| High blood pressure (hypertension) | 22% |
| Physical weakness or lack of energy (asthenia) | 21% |
| Upper respiratory tract infection | 21% |
Adrenal insufficiency was suspected based on clinical signs and symptoms, which may have included nausea, vomiting, diarrhea, fatigue, dizziness, loss of appetite, joint pain, fever, low blood pressure, or fast heartbeat.
Fewer patients (25%) experienced adrenal insufficiency in the LINC 4 study than in the LINC 3 study (43%). This may have been due to the more gradual dose adjustment schedule in the LINC 4 study (every 3 weeks based on overall health condition) than in the LINC 3 study (every 2 weeks based solely on cortisol levels), and that adrenal insufficiency was defined in the two studies per different clinical signs and symptoms.
WHAT IS ISTURISA?
ISTURISA (osilodrostat) is a prescription medicine used to treat elevated levels of cortisol in the blood (endogenous hypercortisolemia) in adults with Cushing’s syndrome:
- who cannot have surgery, or
- who have had surgery which did not cure their Cushing’s syndrome
It is not known if ISTURISA is safe and effective in children.
ISTURISA is a prescription medicine used to treat elevated levels of cortisol in the blood (known as endogenous hypercortisolemia) in adults with Cushing’s syndrome. Appropriate patients either cannot have surgery, or have had surgery which did not cure their Cushing’s syndrome. It is not known if ISTURISA is safe and effective in children.
IMPORTANT SAFETY INFORMATION
Before starting ISTURISA tell your healthcare provider about all your medical conditions, including if you:
- have or had heart problems, such as an irregular heartbeat, including a condition called prolonged QT syndrome (QT interval prolongation). Your healthcare provider will check the electrical signal of your heart (called an electrocardiogram) before you start taking ISTURISA, 1 week after starting ISTURISA, and as needed after that.
- have a history of low levels of potassium or magnesium in your blood.
- have liver problems.
- are or plan to become pregnant. It is not known if ISTURISA will harm your unborn baby. There are risks to the mother and unborn baby associated with active Cushing’s syndrome during pregnancy.
- are breastfeeding or plan to breastfeed. It is not known if ISTURISA passes into your breast milk. You should not breastfeed if you take ISTURISA and for 1 week after stopping treatment.
Tell your healthcare provider about all the medicines you take, including any prescription and over-the-counter medicines, vitamins, or herbal supplements.
Especially tell your healthcare provider if you take medicines used to treat certain heart problems. Ask your healthcare provider if you are not sure whether your medicine is used to treat heart problems.
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: nausea, vomiting, tiredness (fatigue), low blood pressure, problems with body salt (electrolyte) levels in your blood, stomach (abdominal) pain, loss of appetite, dizziness, low blood sugar.
If you get symptoms of hypocortisolism while taking ISTURISA, your healthcare provider may change your dose or ask you to stop taking it.
- Heart problem or a heart rhythm problem, such as an irregular heartbeat which could be a sign of a heart problem called QT prolongation. Call your healthcare provider right away if you have irregular heartbeats.
-
Increase in other adrenal hormone levels. Your other adrenal hormones may increase when you take ISTURISA. Your healthcare provider may monitor you for the symptoms associated with these hormonal changes while you are taking ISTURISA:
- Low potassium (hypokalemia)
- High blood pressure (hypertension)
- Swelling (edema) in the legs, ankles or other signs of fluid retention
- Excessive facial or body hair growth (hirsutism)
- Acne (in women)
Call your healthcare provider if you have any of these side effects.
The most common side effects of ISTURISA include very low cortisol levels (adrenal insufficiency), tiredness (fatigue), nausea, headache, and swelling of the legs, ankles or other signs of fluid retention (edema), decreased appetite, pain in your joints (arthralgia), muscle pain or soreness (myalgia), weakness (asthenia), and diarrhea.
These are not all the possible side effects of ISTURISA. Call your healthcare provider for medical advice about side effects. You are encouraged to report side effects of prescription drugs to the FDA. Call 1-800-FDA-1088 or visit www.fda.gov/medwatch.
ISTURISA® (osilodrostat) tablets, for oral use, is available as 1 mg and 5 mg tablets.
Please see full Prescribing Information.
PP-IST-US-0576
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