26/19. Istradefylline - (NOURIANZ)-@- (Aug-2019)- Parkinsons Disease
Drug Name:26/19. Istradefylline - (NOURIANZ)-@- (Aug-2019)- Parkinsons 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
1. Effect of Other Drugs on NOURIANZ
Strong CYP3A4 Inhibitors Coadministration of NOURIANZ with a strong CYP3A4 inhibitor (ketoconazole) increased istradefylline AUCinf by 2.5-fold
Therefore, the recommended maximum dosage of NOURIANZ in patients concomitantly using strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, clarithromycin) is 20 mg once daily
Strong CYP3A4 Inducers
Coadministration of NOURIANZ with a strong CYP3A4 inducer (rifampin) decreased istradefylline Cmax and AUCinf by 45% and 81%, respectively
Therefore, it is recommended to avoid use of NOURIANZ with strong CYP3A4 inducers (e.g., carbamazepine,rifampin, phenytoin, St. John’s wort)
2. Effect of NOURIANZ on Other Drugs
CYP3A4 Substrates Coadministration of NOURIANZ 20 mg with a CYP3A4 substrate (midazolam) did not affect the CYP3A4 substrate exposure, while concomitant administration of NOURIANZ 40 mg increased the CYP3A4 substrate (atorvastatin) Cmax and AUCinf by 1.5-fold
Monitor for an increase in adverse reactions of concomitant drugs that are CYP3A4 substrates when coadministering with NOURIANZ 40 mg.
P-glycoprotein (P-gp) Substrates
Coadministration of NOURIANZ with a P-gp substrate (digoxin) increased the P-gp substrate Cmax and AUCinf by 33% and 21%, respectively
Monitor for an increase in adverse reactions of concomitant drugs that are P-gp substrates when coadministering with NOURIANZ.
Indication:
BRIEF SUMMARY
ISTRADEFYLLINE -(Aug 2019)
Indn- To treat adult patients with Parkinsons disease experiencing "off" episodes
Comp- Tablets: 20 mg and 40 mg The recommended dosage is 20 mg orally once daily. The dosage may be increased to a maximum of 40 mg once daily .
May be taken with or without food
ADR- The most common adverse reactions (at least 5% and more frequent than placebo) were dyskinesia, dizziness, constipation, nausea, hallucination, and insomnia
CI- None
WARNINGS-
Dyskinesia: Monitor patients for dyskinesia or exacerbation of existing dyskinesia
Hallucinations / Psychotic Behavior: Consider dosage reduction or stopping if occurs
Pat Inform-
Dyskinesia
Advise patients that may cause dyskinesia or exacerbate pre-existing dyskinesia
Hallucinations / Psychotic Behavior
Advise patients that may cause hallucinations or psychotic behavior and they should report any of these adverse reactions to their healthcare provide
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U.S. FDA APPROVED DRUGS DURING 2019
Sr.No.26.
Name of the Drug- NOURIANZ
Active Ingredient - Istradefylline
Pharmacological Classification-
To treat adult patients with Parkinsons disease experiencing
"off" episodes
Date of Approval - 8/27/2019
(Ref- FDA approved List 2019
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
NOURIANZ safely and effectively.
See full prescribing information for NOURIANZ. NOURIANZ™ (istradefylline) tablets, for oral use
Initial U.S. Approval: 2019
INDICATIONS AND USAGE
NOURIANZ is an adenosine receptor antagonist indicated as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson’s disease (PD) experiencing “off” episodes
Adverse Reaction:
ADVERSE REACTIONS
The most common adverse reactions (at least 5% and more frequent than placebo) were dyskinesia, dizziness, constipation, nausea, hallucination, and insomnia
Contra-Indications:
CONTRAINDICATIONS
None
WARNINGS AND PRECAUTIONS
Dyskinesia: Monitor patients for dyskinesia or exacerbation of existing dyskinesia (5.1).
Hallucinations / Psychotic Behavior: Consider dosage reduction or stopping NOURIANZ if occurs
Impulse Control / Compulsive Behaviors: Consider dosage reduction or stopping NOURIANZ if occurs
Dosages/ Overdosage Etc:
INDICATIONS AND USAGE
NOURIANZ is an adenosine receptor antagonist indicated as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson’s disease (PD) experiencing “off” episodes
DOSAGE AND ADMINISTRATION
The recommended dosage is 20 mg orally once daily. The dosage may be increased to a maximum of 40 mg once daily .
May be taken with or without food
Patients with hepatic impairment:
Maximum recommended dosage with moderate hepatic impairment is 20 mg once daily; use of NOURIANZ in patients with severe hepatic impairment should be avoided
Patients who smoke 20 or more cigarettes per day (or the equivalent of another tobacco product):
Recommended dosage is 40 mg once daily
DOSAGE FORMS AND STRENGTHS
Tablets: 20 mg and 40 mg
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Dyskinesia
Advise patients that NOURIANZ may cause dyskinesia or exacerbate pre-existing dyskinesia
Hallucinations / Psychotic Behavior
Advise patients that NOURIANZ may cause hallucinations or psychotic behavior and they should report any of these adverse reactions to their healthcare provider
Impulse Control / Compulsive Behaviors
Inform patients that they may experience intense urges to gamble, increased sexual urges, and other intense urges and the inability to control these urges while taking NOURIANZ and one or more medication(s) for the treatment of Parkinson’s disease (including levodopa).
Advise patients that they should report any of these adverse reactions to their healthcare provider [see Warnings and Precautions (5.3)].
Concomitant Medications
Certain medications can cause an interaction with NOURIANZ.
Advise patients to inform their healthcare provider about their smoking status and about all of the medicines they are taking or plan to take, including over-the-counter medicines, dietary supplements, and herbal products.
Manufactured by:
Kyowa Kirin, Inc.
Bedminster, NJ 07921 15
Reference ID: 4483120
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action
The precise mechanism by which istradefylline exerts its therapeutic effect in Parkinson disease isunknown. In in vitro studies and in in vivo animal studies, istradefylline was demonstrated to be an adenosine A2A receptor antagonist.
2. Pharmacodynamics
Cardiac Electrophysiology
The effect of NOURIANZ (40 mg or 160 mg [4 times the maximum recommended dosage] oncedaily for 14 days) on the QTc interval was evaluated in a randomized, placebo and moxifloxacincontrolled,multiple-dose, blinded, parallel group study.
There was no clinically significant prolongation of QTc interval or relationship between changes in QTc and concentrations of
istradefylline.
3. Pharmacokinetics
Istradefylline exhibits dose-proportional pharmacokinetics after multiple oral doses from 20 mg to 80 mg (2 times the maximum recommended dosage).
Steady-state was reached within 2 weeks of once-daily dosing. The pharmacokinetics of istradefylline were similar in PD patients and healthy subjects.
Absorption
The median time to reach the maximum concentration (Tmax) for istradefylline was about 4 hours under fasted dosing conditions.
Effect of Food
Istradefylline exposure, represented by the area under the curve over time to infinity (AUCinf), increased 1.25-fold when NOURIANZ was coadministered with a standard high-fat meal, compared with administration in a fasted state.
Istradefylline maximum plasma concentrations (Cmax) increased by 1.64-fold and Tmax was shortened by 1 hour when NOURIANZ was administered with a high-fat meal.
These differences in pharmacokinetic parameters are not expected to be clinically significant
Distribution
The plasma protein binding of istradefylline was approximately 98%. The apparent volume of distribution (Vd/F) of istradefylline is approximately 557 liters.
Elimination
The total clearance of istradefylline is approximately 4.6 L/hour. The mean terminal half-life (t1/2) for istradefylline at steady-state is approximately 83 hours.
Metabolism
In humans, istradefylline is exclusively eliminated via metabolism. In vitro studies indicate that istradefylline is primarily metabolized via CYP1A1 and CYP3A4, with minor contribution from CYP1A2, 2B6, 2C8, CYP2C9, CYP2C18, and 2D6.
Six metabolites have been identified in human plasma. These metabolites each account for less than 10% of the exposure of the parent drug.
Excretion
Approximately 48% of a 40-mg oral dose of 14C-istradefylline was eliminated in feces, and 39% in urine. Unchanged istradefylline was not detected in urine.
Specific Populations
In patients with moderate hepatic impairment (Child-Pugh B), the steady-state exposure (AUC0-24) of istradefylline is predicted to be 3.3-fold higher relative to healthy subjects, based on the estimated mean terminal half-life
Based on population pharmacokinetic analyses, no clinically relevant changes in the pharmacokinetics of istradefylline were observed based on age, sex, weight, or race.
No clinically relevant changes in istradefylline exposure were observed in patients with severe renal impairment (CrCL 15-29 mL/min) or mild hepatic impairment
NOURIANZ has not been studied in patients with ESRD (CrCL < 15 mL/min), ESRD patients requiring hemodialysis, or severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (8.6, 8.7)].
Steady-state systemic exposure to istradefylline (40 mg) is 38% to 54% lower in tobacco smokers (who smoke 20 or more cigarettes per day) when compared with non-smokers matched for age, gender, and body weight
Drug Interaction Studies
In Vitro Assessment of Drug Interactions
Drug-Metabolizing Enzyme Inhibition
Istradefylline is a weak inhibitor of CYP3A4, but not an inhibitor of CYP1A2, 2B6, 2C9, 2C19, or 2D6 in vitro.
Drug-Metabolizing Enzyme Induction
Istradefylline was a weak inducer of CYP3A4 but not an inducer of CYP1A2 and 2B6 when tested in vitro. However, clinical drug-drug interaction studies with a CYP3A4 substrate (i.e., midazolam) showed no induction of CYP3A4.
Transporters
Istradefylline was not a substrate for drug transporters P-gp, BCRP, OATP1B1, or OATP1B3 when tested in vitro. Istradefylline was a weak inhibitor for P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OCT2, MATE1, and MATE2-K, but not an inhibitor of OAT3 when tested in vitro.
In Vivo Assessment of Drug Interactions
Effect of Other Drugs on Istradefylline
Strong CYP3A4 Inhibitors
Coadministration of ketoconazole (200 mg twice daily for 4 days) with a single dose of istradefylline (40 mg) increased the AUCinf of istradefylline by 2.5-fold, but had no effect on Cmax
Strong CYP3A4 Inducers
Coadministration of rifampin (600 mg daily for 20 days) with a single dose of istradefylline (40 mg) reduced the Cmax and AUCinf of istradefylline by 45% and 81% respectively, when compared with istradefylline administered alone
Effect of Istradefylline on Other Drugs
CYP3A4 Substrates
Coadministration of istradefylline at higher than the recommended doses (80 mg for 14 days) with a single dose of midazolam (10 mg) increased midazolam AUCinf 2.4-fold, and Cmax by 1.6-fold, when compared with midazolam administered alone.
Coadministration of lower doses of istradefylline (5 mg and 20 mg) with midazolam (7.5 mg) did not have these effects
Coadministration of istradefylline (40 mg daily for 17 days) with a single dose of atorvastatin (40 mg) increased the Cmax and AUCinf of atorvastatin by 1.5-fold, compared with atorvastatin alone
P-glycoprotein Substrates
Coadministration of istradefylline (40 mg daily for 21 days) with a single dose of digoxin (0.4 mg) increased the Cmax and AUCinf of digoxin by 33% and 21%, respectively, when compared with digoxin alone
Carbidopa/Levodopa
Coadministration of istradefylline (80 mg [two times the recommended maximum dosage] daily for 14 days) with a single dose of carbidopa/levodopa (50/200 mg) did not affect the pharmacokinetics of carbidopa/levodopa.
Also, coadministration of istradefylline (20 mg or 40 mg daily for 14 days) with carbidopa/levodopa (25/100 mg three times a day for 14 days) did not affect the systemic exposure of carbidopa/levodopa.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy
Risk Summary
There are no adequate data on the developmental risk associated with the use of NOURIANZ in pregnant women.
In animal studies ,oral administration of istradefylline during pregnancy resulted in teratogenicity (increased incidences of fetal structural abnormalities, embryofetal and offspring mortality and growth deficits) at clinically relevant exposures and in the absence of maternal toxicity.
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 risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.
2. Lactation
Risk Summary
There are no data on the presence of istradefylline in human milk, the effects of istradefylline on the breastfed infant, or the effects of istradefylline on milk production. Istradefylline was present in the milk of lactating rats at concentrations up to 10 times that in maternal plasma.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NOURIANZ, and any potential adverse effects on the breastfed infant from NOURIANZ or from the underlying maternal condition.
3. Females and Males of Reproductive Potential
Contraception Use of NOURIANZ during pregnancy is not recommended. Women of childbearing potential should be advised to use contraception during treatment with NOURIANZ
4. Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
5. Geriatric Use
No adjustment of NOURIANZ dosage is recommended on the basis of age. Of the total number of PD patients who received NOURIANZ in clinical trials, 53% were =65 years and 13% were =75 years of age. No overall differences in effectiveness were observed between these patients and younger patients.
6. Renal Impairment
No adjustment of NOURIANZ dosage is needed in patients with mild renal impairment (estimated creatinine clearance (CrCL) by Cockcroft-Gault equation: 60-89 mL/min), moderate renal impairment (CrCL 30-59 mL/min), or severe renal impairment (CrCL 15-29 mL/min).
NOURIANZ has not been evaluated in patients with end-stage renal disease (ESRD) (CrCL <15 mL/min) or ESRD requiring hemodialysis [see Clinical Pharmacology (12.3)].
7. Hepatic Impairment
No adjustment of NOURIANZ dosage is needed in patients with mild hepatic impairment (Child-Pugh Class A).
In patients with moderate hepatic impairment (Child-Pugh B), the steady-state exposures (AUC0-24h) were predicted to be 3.3-fold higher than in healthy subjects, based on the estimated mean terminal half-life.
Therefore, the maximum recommended dosage of NOURIANZ in patients with moderate hepatic impairment (Child-Pugh B) is 20 mg once daily
Closely monitor patients with moderate hepatic impairment for adverse events when on NOURIANZ treatment
NOURIANZ has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Avoid use of NOURIANZ in patients with severe hepatic impairment
8 .Tobacco Smokers
Tobacco smoking decreased NOURIANZ steady-state systemic exposures by 38% to 54% [see Clinical Pharmacology (12.3)], which may decrease efficacy.
Therefore, the recommended NOURIANZ dosage in patients who smoke 20 or more cigarettes per day (or the equivalent amount of another tobacco product) is 40 mg once daily.
OVERDOSAGE
1. Human Experience
There is limited clinical experience regarding human overdosage with NOURIANZ. In clinical trials, one patient took 6 tablets (120 mg, 3 times the maximum recommended dosage) of istradefylline with alcoholic beverages and developed hallucinations, agitation, and worsening dyskinesia.
2. Management of Overdose
There are no known specific antidotes for NOURIANZ nor any specific treatment for istradefylline overdose. If an overdose occurs, NOURIANZ treatment should be discontinued and supportive treatment should be administered as clinically indicated.
Consider the long terminal half-life of istradefylline (about 83 hours) and the possibility of multiple drug involvement.
Consult a Certified Poison Control Center for up-to-date guidance and advice.
