10/20. Osilostat-(ISTURIA) @ (Mar 2020) - To treat Cushings disease
Drug Name:10/20. Osilostat-(ISTURIA) @ (Mar 2020) - To treat Cushings disease
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS
• CYP3A4 Inhibitor: Reduce the dose of ISTURISA by half with concomitant use of a strong CYP3A4 inhibitor
• CYP3A4 and CYP2B6 Inducers: An increase of ISTURISA dosage may be needed if ISTURISA is used concomitantly with strong CYP3A4 and CYP2B6 inducers.
A reduction in ISTURISA dosage may be needed if strong CYP3A4 and CYP2B6 inducers are discontinued while using ISTURISA
Indication:
U.S. FDA APPROVED DRUGS DURING 2020
Sr.No- 10
Adverse Reaction:
ADVERSE REACTIONS
Most common adverse reactions (incidence > 20%) are adrenal insufficiency, fatigue, nausea, headache, edema
Contra-Indications:
WARNINGS AND PRECAUTIONS
• Hypocortisolism: Monitor patients closely for hypocortisolism and potentially life-threatening adrenal insufficiency. Dosage reduction or interruption may be necessary • QTc Prolongation: Perform electrocardiogram in all patients Use with caution in patients with risk factors for QTc prolongation • Elevations in Adrenal Hormone Precursors and Androgens: Monitor for hypokalemia, worsening of hypertension, edema, and hirsutism
Dosages/ Overdosage Etc:
Patient Information:
PATIENT COUNSELING INFORMATION
Advise patients to read the FDA-approved patient labeling (Patient Information).
Monitoring- Instruct patients on the importance of laboratory monitoring and adhering to their return visit schedule
Hypocortisolism- Advise patients that ISTURISA is associated with hypocortisolism-related events. Advise patients to report symptoms of hypercortisolism to their healthcare provider
QT Prolongation- Advise patients of the signs and symptoms of QT prolongation. Advise patients to contact their healthcare provider immediately for signs or symptoms of QT prolongation.
Advise patients that an ECG will be taken before treatment and periodically thereafter.
Advise patients with cardiac disease and risk factors for QT prolongation that adjustments in cardiac medications may be made and electrolyte disturbances may require correction
Adrenal Hormone Precursors/Androgens- Advise patients that elevation of adrenal hormone precursors may occur and lead to low potassium levels, worsening of hypertension, and edema.
Advise patients to report the occurrence of these symptoms to their healthcare provider. Advise patients that elevations of androgens may occur and may lead to hirsutism, hypertrichosis, and acne (in females).
Advise patients to report the occurrence of these symptoms to their healthcare provider
Lactation- Advise females not to breastfeed during treatment with ISTURISA and for at least one week after treatment
Distributed by: Recordati Rare Disease, Inc. Lebanon, NJ USA 08833 © Recordati
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action- Osilodrostat is a cortisol synthesis inhibitor. It inhibits 11beta-hydroxylase (CYP11B1), the enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland.
In a Chinese hamster lung cell line V79-4 that overexpresses human CYP11B1, adrenodoxin and adrenodoxin reductase, osilodrostat inhibited the activity of human CYP11B1 dosedependently with IC50 values of 2.5 ± 0.1 nM (n = 4).
2. Pharmacodynamics- A dose dependent increase was observed in 11-deoxycortisol, the cortisol precursor, and ACTH levels in patients with Cushing’s disease.
Cardiac Electrophysiology- A thorough QT study in 86 male and female healthy volunteers showed a maximum mean placebo-corrected QTcF interval increase of 1.73 ms [90% confidence interval (CI): 0.15, 3.31] at a 10 mg dose, and 25.38 ms (90% CI: 23.53, 27.22) at a 150 mg dose (up to 2.5 times the maximum recommended dosage)
3. Pharmacokinetics- Absorption- Osilodrostat is absorbed with a time of maximum observed concentration (Tmax) of approximately 1 hour. Exposure (AUCinf and Cmax) slightly increases over dose-proportionally within the therapeutic dose range of 1 mg to 30 mg.
Effect of Food- In a healthy volunteer study (N = 20), subjects administered with a single, 30 mg oral dose of ISTURISA film-coated tablets with a high-fat meal resulted in reduction of AUC by 11% and Cmax by 21%, respectively.
The median Tmax was delayed from 1 to 2.5 hours. These changes are not considered to be clinically significant, therefore ISTURISA can be administered with or without food.
Distribution- The median apparent volume of distribution of osilodrostat is approximately 100 L. Protein binding is low (36.4%). The osilodrostat blood-to-plasma concentration ratio is 0.85.
Elimination- The elimination half-life of osilodrostat is approximately 4 hours. In an absorption, distribution, metabolism, and excretion study, the majority of the radioactivity dose of osilodrostat is eliminated in the urine (mean: 90.6% of administered dose) with only a minor amount eliminated in the feces (1.58% of dose).
The low percentage of the dose eliminated in the urine as unchanged osilodrostat (5.2%) indicates that metabolism is the major clearance pathway in humans.
Metabolism- Multiple CYP enzymes (i.e., CYP3A4, CYP2B6, and CYP2D6) and UDP-glucuronosyltransferases contribute to osilodrostat metabolism and no single enzyme contributes greater than 25% to the total clearance.
The metabolites are not expected to contribute to the pharmacological effect of osilodrostat.
Specific Populations- Age and gender have no significant impact on osilodrostat exposure in adults. Race/Ethnicity The relative bioavailability in Asian patients is approximately 20% higher compared to that of non-Asian, along with higher Tmax and Cmax, compared to other ethnicities. However, the difference is not clinically significant.
Patients with Renal Impairment- Osilodrostat exposure was similar in the three renal function groups [normal, severe, and end stage renal disease (ESRD) groups] and thus a study was not conducted in mild and moderate renal impairment groups.
The results showed that the PK of osilodrostat was not influenced by varying degrees of renal impairment to any clinically significant extent.
Patients with Hepatic Impairment- There was a trend of increasing AUC of osilodrostat in moderate and severe hepatic impaired subjects (geo-mean ratios are 1.44 and 2.66, respectively) as compared to normal subjects.
Exposures (Cmax and AUC) of osilodrostat in the mild hepatic impairment group were similar to those in the normal group
Drug Interaction- In a healthy volunteer study (N = 20) using a single dose of osilodrostat (50 mg) and a probe drugs cocktail, osilodrostat showed inhibition potential on CYP1A2, CYP2C19, CYP2D6, and CYP3A4/5 isozymes with 2.5-, 1.9-, 1.5- and 1.5-fold increase in caffeine, omeprazole, dextromethorphan, and midazolam exposure, respectively.
There was no significant impact of osilodrostat (30 mg twice daily for 12 days) on the exposure of oral contraceptives containing 0.03 mg estradiol and 0.15 mg levonorgestrel in healthy female subjects.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1 Pregnancy Risk Summary- There are no available data on osilodrostat use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
There are risks to the mother and fetus associated with active Cushing’s Syndrome during pregnancy
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.
2.Lactation- There are no available data on the presence of osilodrostat in human or animal milk, the effects on the breastfed infant, or the effects on milk production.
Because of the potential for serious adverse reactions (such as adrenal insufficiency) in the breastfed infant, advise patients that breastfeeding is not recommended during treatment with ISTURISA and for one week after the final dose.
3.Pediatric Use-
The safety and effectiveness of ISTURISA in pediatric patients have not been established.
4.Geriatric Use- Of the 167 patients in clinical trials with ISTURISA, 10 (6%) were 65 years and older. There were no patients above 75 years of age. Based on the available data on the use of ISTURISA in patients older than 65 years, no dosage adjustment is required
5.Renal Impairment- No dosage adjustment of ISTURISA in patients with impaired renal function is required
In patients with moderate to severe renal impairment, UFC levels should be interpreted with caution due to reduced UFC excretion.
6. Hepatic Impairment- Dosage adjustment is not required in patients with mild hepatic impairment (Child-Pugh A) but is required for patients with moderately impaired hepatic function (Child-Pugh B) and for patients with severe hepatic impairment (Child-Pugh C)
More frequent monitoring of adrenal function may be required during dose titration in all patients with hepatic impairment.
10 OVERDOSAGE
Overdosage may result in severe hypocortisolism. Signs and symptoms suggestive of hypocortisolism may include nausea, vomiting, fatigue, low blood pressure, abdominal pain, loss of appetite, dizziness, and syncope.
In case of suspected overdosage, ISTURISA should be temporarily discontinued, cortisol levels should be checked, and if necessary, corticosteroid supplementation should be initiated.
Close surveillance may be necessary, including monitoring of the QT interval, blood pressure, glucose, fluid, and electrolyte until the patient’s condition is stable.