Istradefylline is a xanthine derivative and an oral adenosine A2A receptor antagonist. Istradefylline is approved for use as an adjuvant to levodopa-carbidopa therapy in adult patients with Parkinson's disease (PD) experiencing 'off' episodes. The efficacy of istradefylline was established in 4 placebo-controlled, randomized trials. In these trials, patients continued levodopa treatment with or without concomitant PD medications, including dopamine agonists, COMT inhibitors, MAO-B inhibitors, anticholinergics, and/or amantadine, provided these medications were stable. In all trials, istradefylline significantly improved daily awake "off" time relative to placebo. Decreases from baseline in the mean percentage of awake "off" hours were observed during treatment with istradefylline 20 mg/day (-4.57%, p = 0.025) and istradefylline 40 mg/day (-6.78%, p = 0.007). Awake "off" hours were reduced from baseline, with mean differences of -0.65 hours (p = 0.028) and -0.76 hours (p = 0.006) for istradefylline 20 mg daily regimens and -0.92 hours (p = 0.002) and -0.74 (p = 0.008) for istradefylline 40 mg daily regimens. Patients treated with istradefylline experienced additional increases from baseline in "on" time without troublesome dyskinesia compared to patients treated with placebo. There is a potential for the drug to cause or exacerbate hallucinations or psychosis. Istradefylline was approved by the FDA in August 2019.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-May administer tablets with or without food.
A few changes in laboratory investigations were reported during 4 randomized, placebo-controlled clinical trials of istradefylline in patients with Parkinson's disease taking a stable dose of levodopa and a DOPA carboxylase inhibitor. The incidence of increased alkaline phosphatase was 1% among patients treated with istradefylline 20 mg, 2% with istradefylline 40 mg, and 1% with placebo. The incidence of increased blood glucose was 1% during treatment with istradefylline 20 mg, 2% with istradefylline 40 mg, and 0% with placebo. The incidence of increased blood urea was 1% during treatment with istradefylline 20 mg, 2% with istradefylline 40 mg, and 0% with placebo.
Istradefylline in combination with levodopa may cause dyskinesia or exacerbate pre-existing dyskinesia. During 4 randomized, placebo-controlled clinical trials of istradefylline in patients with Parkinson's disease taking a stable dose of levodopa and a DOPA carboxylase inhibitor (e.g., carbidopa), dyskinesia occurred in 15% of patients treated with istradefylline 20 mg, 17% of patients treated with istradefylline 40 mg, and 8% of patients treated with placebo. Dyskinesia was the most common reason for drug discontinuation. Dizziness occurred in 3% of patients treated with istradefylline 20 mg, 6% of patients treated with istradefylline 40 mg, and 4% of patients treated with placebo.
Istradefylline may exacerbate psychosis, and patients with a major psychotic disorder should not be treated with the drug. During 4 randomized, placebo-controlled clinical trials of istradefylline in patients with Parkinson's disease taking a stable dose of levodopa and a DOPA carboxylase inhibitor (e.g., carbidopa), hallucinations occurred in 2% of patients treated with istradefylline 20 mg, 6% of patients treated with istradefylline 40 mg, and 3% of patients treated with placebo. Hallucinations were visual, oflactory, somatic, and auditory. Abnormal thinking and behavior (including paranoia, delusions, confusion, mania, disorientation, aggressive behavior, agitation, or delirium) occurred in 1% of patients treated with istradefylline 20 mg, 2% of patients treated with istradefylline 40 mg, and 1% of patients treated with placebo. Consider dose reduction or discontinuation if a patient develops hallucinations or psychotic behaviors while taking istradefylline. Insomnia occurred in 1% of patients treated with istradefylline 20 mg, 6% of patients treated with istradefylline 40 mg, and 4% of patients treated with placebo.
Intense urges to gamble, increased sexual urges, intense urges to spend money, binge or compulsive eating, or other urges may occur in patients treated with istradefylline and other medications for Parkinson's disease, including levodopa. Patients may lack the ability to control urges. During 4 randomized, placebo-controlled clinical trials of istradefylline in patients with Parkinson's disease taking a stable dose of levodopa and a DOPA carboxylase inhibitor, impulse control symptoms occurred in 1 patient treated with istradefylline 40 mg (0.3%) compared to no patients treated with istradefylline 20 mg or placebo. In some reported postmarketing cases, urges stopped when the dose of istradefylline was reduced or the medication was discontinued. Ask patients and caregivers about the development of new or increased impulse control symptoms or compulsive behaviors. Consider dose reduction or discontinuation of istradefylline if the patient develops such urges.
During 4 randomized, placebo-controlled clinical trials of istradefylline in patients with Parkinson's disease taking a stable dose of levodopa and a DOPA carboxylase inhibitor, constipation occurred in 5% of patients treated with istradefylline 20 mg, 6% of patients treated with istradefylline 40 mg, and 3% of patients treated with placebo. Nausea occurred in 4% of patients treated with istradefylline 20 mg, 6% of patients treated with istradefylline 40 mg, and 5% of patients treated with placebo. The incidence of diarrhea was 1% during treatment with istradefylline 20 mg, 2% with istradefylline 40 mg, and 1% with placebo. The incidence of decreased appetite was 1% during treatment with istradefylline 20 mg, 3% with istradefylline 40 mg, and 1% with placebo.
During 4 randomized, placebo-controlled clinical trials of istradefylline in patients with Parkinson's disease taking a stable dose of levodopa and a DOPA carboxylase inhibitor, rash (unspecified) occurred in 1% of patients treated with istradefylline 20 mg, 2% of patients treated with istradefylline 40 mg, and 1% of patients treated with placebo.
During 4 randomized, placebo-controlled clinical trials of istradefylline in patients with Parkinson's disease taking a stable dose of levodopa and a DOPA carboxylase inhibitor, upper respiratory tract inflammation or infection occurred in 1% of patients treated with istradefylline 20 mg, 2% of patients treated with istradefylline 40 mg, and no patients treated with placebo.
Libido increase has been reported during postmarketing experience with istradefylline.
As with other medications used for Parkinson's disease, istradefylline in combination with levodopa-carbidopa therapy may cause dyskinesia or exacerbate pre-existing dyskinesia. Educate patients to contact their healthcare provider if dyskinesia occurs or worsens during treatment.
Patients with a major psychotic disorder should not be treated with istradefylline because of the risk of exacerbating psychosis. Patients have reported hallucinations and abnormal thinking or behavioral changes (including paranoid ideation, delusions, confusion, mania, disorientation, aggressive behavior, agitation, or delirium) during istradefylline treatment. Consider dose reduction or discontinuation if a patient develops psychotic behaviors or hallucinations while taking istradefylline.
Patients treated with istradefylline or other medications for Parkinson's disease have reported intense and uncontrollable impulse control symptoms, such as urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, binge or compulsive eating, or other intense urges. Advise patients and caregivers that they may experience impulsive and/or compulsive behaviors and to inform their physician or health care provider if they experience new or increased symptoms of this type while taking this medication. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges during treatment. Consider dose reduction or discontinuation if a patient develops such urges during treatment.
Use istradefylline with caution in patients with hepatic disease. Patients with moderate hepatic impairment (Child-Pugh B) require lower maximal daily doses of istradefylline than normal subjects due to increased drug exposure; monitor these patients for increased adverse reactions to istradefylline. The use of istradefylline in patients with severe hepatic impairment (Child-Pugh C) has not been studied and use in these patients should be avoided.
Tobacco smoking produces polycyclic aromatic hydrocarbons that induce hepatic microsomal enzymes, particularly CYP1A enzymes, and this induction increases the systemic clearance of istradefylline. Those who use or smoke tobacco at the equivalent of 20 cigarettes per day or more have significantly decreased steady-state systemic exposure to istradefylline. Therefore, these patients should be initiated and maintained with a dose of istradefylline 40 mg PO once daily. If the patient's smoking status changes, and the patient pursues smoking cessation, the practitioner should monitor the patient for adverse effects and the need for downward dose adjustments.
There are no adequate data on the developmental risk associated with istradefylline use during human pregnancy. Use of istradefylline during pregnancy is not recommended due to teratogenicity observed during animal studies during pregnancy. Fetal malformations, including skeletal and visceral variations, reduced fetal body weight, and embryofetal death occurred in the offspring of pregnant rabbits given oral istradefylline during organogenesis. Plasma exposure at the lowest dose tested (50 mg/kg/day) is less than the plasma exposure in humans at the maximum recommended human dose (MRHD) of 40 mg/day. Increases in embryofetal death and malformations (limb reduction, craniofacial, and cardiovascular) occurred in the offspring of rabbits given oral istradefylline in combination with levodopa/carbidopa (80/20 mg/kg/day). Plasma exposure at the lowest dose of istradefylline tested (50 mg/kg/day) was less than plasma exposure in humans at the MRHD. There was a marked increase in malformations at the highest dose of istradefylline (400 mg/kg/day) when given in combination with levodopa/carbidopa. No increase in fetal malformations occurred with levodopa/carbidopa alone. Fetal body weight was reduced by istradefylline alone and in combination with levodopa/carbidopa. Oral administration of istradefylline to female rats throughout gestation and lactation resulted in decreased pup survival and reduced body weight which persisted into adulthood. No adverse effects were observed on physical or neurobehavioral development or reproductive function. Plasma exposure at the no-effect dose for adverse effects on pre- and postnatal development in rats (6 mg/kg/day) is less than that in humans at the MRHD.
Istradefylline poses a reproductive risk and use is not recommended during pregnancy. While there are no adequate data on the developmental risks associated with use in pregnant women, teratogenicity occurred at clinically relevant exposures during animal studies. Discuss the recommended contraception requirements with the patient. Contraception should be used by females of childbearing potential during treatment with istradefylline.
Use caution when considering istradefylline therapy in a woman who is breast-feeding. There are no data on the presence of istradefylline in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for istradefylline and any potential adverse effects on the breast-fed infant from istradefylline or the underlying maternal condition.
Safe and effective use of istradefylline has not been established in pediatric patients. Juvenille Parkinson's disease is rare in children and adolescents. There is no identified potential use of istradefylline in infants.
For the treatment of "off" episodes in Parkinson's disease as an adjunct to carbidopa/levodopa:
Oral dosage:
Adults: 20 mg PO once daily, initially. May increase the dose to 40 mg PO once daily based on clinical response and tolerability. Initial dose titration is not required. Max: 40 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Maximum Dosage Limits:
-Adults
40 mg/day PO.
-Geriatric
40 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Use not indicated.
Patients with Hepatic Impairment Dosing
Mild hepatic impairment (Child-Pugh A): No dose adjustment needed.
Moderate hepatic impairment (Child-Pugh B): The maximum recommended dose is 20 mg PO once daily.
Severe hepatic impairment (Child-Pugh C): Avoid use.
Patients with Renal Impairment Dosing
CrCl 15 mL/minute or more: No dosage adjustments are needed.
CrCl less than 15 mL/minute: Data are not available. Istradefylline has not been studied in patients with end-stage renal disease (ESRD) or ESRD requiring hemodialysis.
*non-FDA-approved indication
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of istradefylline 40 mg daily is necessary. If istradefylline is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with istradefylline may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If istradefylline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Istradefylline administered as 40 mg daily is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with istradefylline 40 mg daily may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of istradefylline could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If istradefylline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor; there was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of istradefylline 40 mg daily is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If istradefylline is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of istradefylline 40 mg daily is necessary. If istradefylline is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. Coadministration can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If istradefylline is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Adagrasib: (Major) Do not exceed 20 mg once daily of istradefylline if administered with adagrasib as istradefylline exposure and adverse effects may increase. Istradefylline is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong CYP3A inhibitor in a drug interaction study.
Afatinib: (Moderate) If the concomitant use of istradefylline and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of istradefylline. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate. Istradefylline inhibits P-gp. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of istradefylline 40 mg daily is necessary. If istradefylline is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. Coadministration can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If istradefylline is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Alprazolam: (Major) Avoid coadministration of alprazolam and istradefylline due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with istradefylline, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and istradefylline is a weak CYP3A4 inhibitor. Coadministration with another weak CYP3A4 inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
Amlodipine; Atorvastatin: (Moderate) Monitor for atorvastatin-related adverse reactions (i.e., myopathy/rhabdomyolysis) if coadministration of istradefylline 40 mg daily is necessary as atorvastatin exposure may be increased. Atorvastatin is a CYP3A4 and P-gp substrate; istradefylline administered as 40 mg daily is a weak inhibitor of CYP3A4 and P-gp. Coadministration of atorvastatin and istradefylline 40 mg daily increased the atorvastatin exposure by 1.5-fold.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Do not exceed 20 mg once daily of istradefylline if administered with clarithromycin as istradefylline exposure and adverse effects may increase. Clarithromycin is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Apalutamide: (Major) Avoid coadministration of istradefylline with apalutamide as istradefylline exposure and efficacy may be reduced. Apalutamide is a strong inducer. Istradefylline exposure was decreased by 81% when administered with a strong inducer in a drug interaction study.
Aripiprazole: (Moderate) Monitor for aripiprazole-related adverse reactions during concomitant use of istradefylline. Patients receiving both a CYP2D6 inhibitor plus istradefylline may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP3A and CYP2D6 substrate; istradefylline is a weak CYP3A inhibitor.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with istradefylline 40 mg daily may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of istradefylline could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If istradefylline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor; there was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of istradefylline 40 mg daily is necessary. If istradefylline is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. Coadministration can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If istradefylline is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Atazanavir: (Major) Do not exceed 20 mg once daily of istradefylline if administered with atazanavir as istradefylline exposure and adverse effects may increase. Atazanavir is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Atazanavir; Cobicistat: (Major) Do not exceed 20 mg once daily of istradefylline if administered with atazanavir as istradefylline exposure and adverse effects may increase. Atazanavir is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study. (Major) Do not exceed 20 mg once daily of istradefylline if administered with cobicistat as istradefylline exposure and adverse effects may increase. Cobicistat is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Atorvastatin: (Moderate) Monitor for atorvastatin-related adverse reactions (i.e., myopathy/rhabdomyolysis) if coadministration of istradefylline 40 mg daily is necessary as atorvastatin exposure may be increased. Atorvastatin is a CYP3A4 and P-gp substrate; istradefylline administered as 40 mg daily is a weak inhibitor of CYP3A4 and P-gp. Coadministration of atorvastatin and istradefylline 40 mg daily increased the atorvastatin exposure by 1.5-fold.
Benzhydrocodone; Acetaminophen: (Moderate) Monitor patients for respiratory depression and sedation at frequent intervals if benzhydrocodone is administered with istradefylline 40 mg daily. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Concurrent use may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Discontinuation of istradefylline in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If istradefylline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Betrixaban: (Moderate) Avoid betrixaban use in patients with severe renal impairment receiving istradefylline. In other patients, a betrixaban dosage reduction may be necessary, as betrixaban exposure and risk of bleeding may be increased during concurrent use. Betrixaban is a P-gp substrate and istradefylline is a weak P-gp inhibitor. Coadministration of stronger P-gp inhibitors increased betrixaban exposure by 2 to 3 fold. Based on data with stronger P-gp inhibitors, the betrixaban label recommends a single initial dose of 80 mg followed by 40 mg once daily when administered with P-gp inhibitors.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with istradefylline 40 mg daily may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of istradefylline could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If istradefylline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor; there was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of codeine with istradefylline 40 mg daily may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of istradefylline could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If istradefylline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor; there was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Carbamazepine: (Major) Avoid coadministration of istradefylline with carbamazepine as istradefylline exposure and efficacy may be reduced. Additionally, taking these drugs together may increase carbamazepine plasma concentrations, potentially resulting in adverse events. Carbamazepine is a substrate of CYP3A4 with a narrow therapeutic index and a strong inducer. Istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. Istradefylline exposure was decreased by 81% when administered with a strong inducer in a drug interaction study. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Celecoxib; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with istradefylline 40 mg daily is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of istradefylline 40 mg daily, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Ceritinib: (Major) Do not exceed 20 mg once daily of istradefylline if administered with ceritinib as istradefylline exposure and adverse effects may increase. Ceritinib is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Chloramphenicol: (Major) Do not exceed 20 mg once daily of istradefylline if administered with chloramphenicol as istradefylline exposure and adverse effects may increase. Chloramphenicol is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with istradefylline 40 mg daily may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of istradefylline could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If istradefylline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor; there was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of istradefylline 40 mg daily is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If istradefylline is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Cisapride: (Moderate) Monitor for cisapride-related adverse reactions if coadministration of istradefylline 40 mg daily is necessary. Cisapride is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Clarithromycin: (Major) Do not exceed 20 mg once daily of istradefylline if administered with clarithromycin as istradefylline exposure and adverse effects may increase. Clarithromycin is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with istradefylline 40 mg daily and monitor for adverse reactions. If istradefylline is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Cobicistat: (Major) Do not exceed 20 mg once daily of istradefylline if administered with cobicistat as istradefylline exposure and adverse effects may increase. Cobicistat is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Cobimetinib: (Moderate) Monitor for cobimetinib-related adverse reactions if coadministration of istradefylline is necessary as concurrent use may increase cobimetinib exposure. Cobimetinib is a P-gp substrate and istradefylline is a P-gp inhibitor.
Codeine: (Moderate) Concomitant use of codeine with istradefylline 40 mg daily may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of istradefylline could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If istradefylline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor; there was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with istradefylline 40 mg daily may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of istradefylline could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If istradefylline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor; there was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with istradefylline 40 mg daily may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of istradefylline could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If istradefylline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor; there was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with istradefylline 40 mg daily may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of istradefylline could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If istradefylline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor; there was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with istradefylline 40 mg daily may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of istradefylline could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If istradefylline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor; there was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Colchicine: (Major) Avoid concomitant use of colchicine and istradefylline due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and istradefylline is a P-gp inhibitor.
Cyclosporine: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with istradefylline 40 mg daily. Use of these medications together may result in elevated cyclosporine serum concentrations, causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A4 and P-gp substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor and P-gp inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with istradefylline, a P-gp inhibitor. Although the coadministration of dabigatran and istradefylline may have no effect on the pharmacokinetics of dabigatran or istradefylline in healthy subjects, patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like istradefylline in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with istradefylline, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
Darunavir: (Major) Do not exceed 20 mg once daily of istradefylline if administered with darunavir as istradefylline exposure and adverse effects may increase. Darunavir is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Darunavir; Cobicistat: (Major) Do not exceed 20 mg once daily of istradefylline if administered with cobicistat as istradefylline exposure and adverse effects may increase. Cobicistat is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study. (Major) Do not exceed 20 mg once daily of istradefylline if administered with darunavir as istradefylline exposure and adverse effects may increase. Darunavir is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Do not exceed 20 mg once daily of istradefylline if administered with cobicistat as istradefylline exposure and adverse effects may increase. Cobicistat is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study. (Major) Do not exceed 20 mg once daily of istradefylline if administered with darunavir as istradefylline exposure and adverse effects may increase. Darunavir is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Delavirdine: (Major) Do not exceed 20 mg once daily of istradefylline if administered with delavirdine as istradefylline exposure and adverse effects may increase. Delavirdine is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Dextromethorphan; Quinidine: (Moderate) Monitor for quinidine-related adverse reactions if coadministration of istradefylline 40 mg daily is necessary. Quinidine is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Digoxin: (Moderate) Monitor for digoxin-related adverse reactions if coadministration of istradefylline is necessary as digoxin exposure may be increased. Digoxin is a P-gp substrate; istradefylline is a P-gp inhibitor. Coadministration of digoxin and istradefylline 40 mg daily increased the exposure of digoxin by 21%.
Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with istradefylline 40 mg daily is necessary. Istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with istradefylline is necessary as concurrent use may increase tenofovir exposure. Tenofovir is a P-gp substrate and istradefylline is a P-gp inhibitor.
Doxorubicin Liposomal: (Major) Avoid coadministration of istradefylline with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Istradefylline is a P-gp inhibitor and doxorubicin is a P-gp substrate. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of istradefylline with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Istradefylline is a P-gp inhibitor and doxorubicin is a P-gp substrate. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Edoxaban: (Major) If coadministered with istradefylline, a weak P-gp inhibitor, dosage reduction of edoxaban, a P-gp substrate, may be necessary for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE). An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with istradefylline. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of istradefylline. Increased concentrations of edoxaban may occur during concomitant use of istradefylline; monitor for increased adverse effects of edoxaban.
Efavirenz: (Moderate) Monitor for efavirenz-related adverse reactions if coadministration of istradefylline 40 mg daily is necessary. Efavirenz is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with istradefylline is necessary as concurrent use may increase tenofovir exposure. Tenofovir is a P-gp substrate and istradefylline is a P-gp inhibitor. (Moderate) Monitor for efavirenz-related adverse reactions if coadministration of istradefylline 40 mg daily is necessary. Efavirenz is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with istradefylline is necessary as concurrent use may increase tenofovir exposure. Tenofovir is a P-gp substrate and istradefylline is a P-gp inhibitor. (Moderate) Monitor for efavirenz-related adverse reactions if coadministration of istradefylline 40 mg daily is necessary. Efavirenz is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Eliglustat: (Major) In poor CYP2D6 metabolizers (PMs), coadministration of istradefylline 40 mg daily and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration of eliglustat with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias) in these patients. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Do not exceed 20 mg once daily of istradefylline if administered with cobicistat as istradefylline exposure and adverse effects may increase. Cobicistat is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Do not exceed 20 mg once daily of istradefylline if administered with cobicistat as istradefylline exposure and adverse effects may increase. Cobicistat is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with istradefylline is necessary as concurrent use may increase tenofovir exposure. Tenofovir is a P-gp substrate and istradefylline is a P-gp inhibitor.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with istradefylline is necessary as concurrent use may increase tenofovir exposure. Tenofovir is a P-gp substrate and istradefylline is a P-gp inhibitor.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with istradefylline is necessary as concurrent use may increase tenofovir exposure. Tenofovir is a P-gp substrate and istradefylline is a P-gp inhibitor.
Encorafenib: (Major) Avoid coadministration of istradefylline with encorafenib as istradefylline exposure and efficacy may be reduced. Istradefylline is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Istradefylline exposure was decreased by 81% when administered with a strong CYP3A inducer in a drug interaction study.
Enzalutamide: (Major) Avoid coadministration of istradefylline with enzalutamide as istradefylline exposure and efficacy may be reduced. Enzalutamide is a strong inducer. Istradefylline exposure was decreased by 81% when administered with a strong inducer in a drug interaction study.
Ethosuximide: (Moderate) Monitor for ethosuximide-related adverse reactions if coadministration of istradefylline 40 mg daily is necessary. Ethosuximide is a CYP3A substrate; istradefylline administered as 40 mg daily is a weak CYP3A inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A substrate.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with istradefylline is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and Istradefylline is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
Felodipine: (Moderate) Concurrent use of felodipine and istradefylline 40 mg daily should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate. Concurrent use of another weak CYP3A4 inhibitor increased felodipine AUC and Cmax by approximately 50%.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of istradefylline 40 mg daily is necessary. If istradefylline is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. Coadministration can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If istradefylline is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or istradefylline; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and istradefylline is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including istradefylline 40 mg daily, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the potential outcomes of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient. Istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Fosamprenavir: (Major) Do not exceed 20 mg once daily of istradefylline if administered with fosamprenavir as istradefylline exposure and adverse effects may increase. Fosamprenavir is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Fosphenytoin: (Major) Avoid coadministration of istradefylline with fosphenytoin as istradefylline exposure and efficacy may be reduced. Fosphenytoin is a strong inducer. Istradefylline exposure was decreased by 81% when administered with a strong inducer in a drug interaction study.
Grapefruit juice: (Major) It may be advisable for patients to avoid grapefruit juice or grapefruit-containing foods while taking istradefylline as istradefylline exposure and adverse effects may increase. Grapefruit juice is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of istradefylline 40 mg daily is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If istradefylline is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of istradefylline 40 mg daily is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If istradefylline is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of istradefylline 40 mg daily is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. Coadministration can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If istradefylline is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of istradefylline 40 mg daily is necessary. If istradefylline is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. Coadministration can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If istradefylline is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Idelalisib: (Major) Do not exceed 20 mg once daily of istradefylline if administered with idelalisib as istradefylline exposure and adverse effects may increase. Idelalisib is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Indinavir: (Major) Do not exceed 20 mg once daily of istradefylline if administered with indinavir as istradefylline exposure and adverse effects may increase. Indinavir is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of istradefylline with rifampin as istradefylline exposure and efficacy may be reduced. Rifampin is a strong inducer. Istradefylline exposure was decreased by 81% when administered with rifampin in a drug interaction study.
Isoniazid, INH; Rifampin: (Major) Avoid coadministration of istradefylline with rifampin as istradefylline exposure and efficacy may be reduced. Rifampin is a strong inducer. Istradefylline exposure was decreased by 81% when administered with rifampin in a drug interaction study.
Itraconazole: (Major) Do not exceed 20 mg once daily of istradefylline if administered with itraconazole as istradefylline exposure and adverse effects may increase. Itraconazole is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of istradefylline is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and istradefylline is a weak CYP3A inhibitor.
Ketoconazole: (Major) Do not exceed 20 mg once daily of istradefylline if administered with ketoconazole as istradefylline exposure and adverse effects may increase. Ketoconazole is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with ketoconazole in a drug interaction study.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with istradefylline is necessary as concurrent use may increase tenofovir exposure. Tenofovir is a P-gp substrate and istradefylline is a P-gp inhibitor.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Do not exceed 20 mg once daily of istradefylline if administered with clarithromycin as istradefylline exposure and adverse effects may increase. Clarithromycin is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Lapatinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with istradefylline is necessary. Lapatinib is a P-gp substrate and istradefylline is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
Lefamulin: (Major) Avoid coadministration of istradefylline with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; istradefylline may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and istradefylline is a P-gp inhibitor. Istradefylline administered as 40 mg daily is also a weak CYP3A4 inhibitor.
Lemborexant: (Major) Limit the dose of lemborexant to a maximum of 5 mg PO once daily if coadministered with istradefylline as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; istradefylline is a weak CYP3A4 inhibitor. Coadministration of lemborexant with a weak CYP3A4 inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
Levoketoconazole: (Major) Do not exceed 20 mg once daily of istradefylline if administered with ketoconazole as istradefylline exposure and adverse effects may increase. Ketoconazole is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with ketoconazole in a drug interaction study.
Lomitapide: (Major) Decrease the dose of lomitapide by one-half not to exceed 30 mg/day PO if coadministration with istradefylline 40 mg daily is necessary. Concomitant use may significantly increase the serum concentration of lomitapide. Istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Lonafarnib: (Major) Avoid coadministration of lonafarnib and istradefylline; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, do not exceed 20 mg once daily of istradefylline and reduce to or continue lonafarnib at a dosage of 115 mg/m2; closely monitor patients for adverse reactions from both drugs. Resume previous lonafarnib dosage 14 days after discontinuing istradefylline. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; istradefylline is a CYP3A4 substrate and weak CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Loperamide: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with istradefylline. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and istradefylline is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Loperamide; Simethicone: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with istradefylline. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and istradefylline is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Lopinavir; Ritonavir: (Major) Do not exceed 20 mg once daily of istradefylline if administered with ritonavir as istradefylline exposure and adverse effects may increase. Ritonavir is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of istradefylline with lumacaftor; ivacaftor as istradefylline exposure and efficacy may be reduced. Lumacaftor; ivacaftor is a strong inducer. Istradefylline exposure was decreased by 81% when administered with a strong inducer in a drug interaction study.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of istradefylline with lumacaftor; ivacaftor as istradefylline exposure and efficacy may be reduced. Lumacaftor; ivacaftor is a strong inducer. Istradefylline exposure was decreased by 81% when administered with a strong inducer in a drug interaction study.
Methadone: (Moderate) Concomitant use of methadone with istradefylline 40 mg daily may increase methadone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of methadone until stable drug effects are achieved. Discontinuation of istradefylline could decrease methadone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to methadone. If istradefylline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Methadone is a substrate for CYP3A4; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Midazolam: (Moderate) Monitor for midazolam-related adverse reactions if coadministration of istradefylline 40 mg daily is necessary. Midazolam is a sensitive CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on midazolam exposure when administered with istradefylline 20 mg daily.
Mifepristone: (Major) Do not exceed 20 mg once daily of istradefylline if administered with mifepristone as istradefylline exposure and adverse effects may increase. Mifepristone is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Mitotane: (Major) Avoid coadministration of istradefylline with mitotane as istradefylline exposure and efficacy may be reduced. Mitotane is a strong inducer. Istradefylline exposure was decreased by 81% when administered with a strong inducer in a drug interaction study.
Morphine: (Moderate) Monitor for morphine-related adverse effects if coadministration with istradefylline is necessary as concurrent use may increase morphine exposure. Morphine is a substrate of P-gp and istradefylline is an inhibitor of P-gp.
Morphine; Naltrexone: (Moderate) Monitor for morphine-related adverse effects if coadministration with istradefylline is necessary as concurrent use may increase morphine exposure. Morphine is a substrate of P-gp and istradefylline is an inhibitor of P-gp.
Naldemedine: (Moderate) Monitor for an increase in naldemedine-related adverse reactions if coadministration with istradefylline is necessary as concurrent use may increase naldemedine exposure. Naldemedine is a P-gp substrate and istradefylline is a P-gp inhibitor.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and istradefylline. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and istradefylline is a weak CYP3A and P-gp inhibitor.
Nefazodone: (Major) Do not exceed 20 mg once daily of istradefylline if administered with nefazodone as istradefylline exposure and adverse effects may increase. Nefazodone is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Nelfinavir: (Major) Do not exceed 20 mg once daily of istradefylline if administered with nelfinavir as istradefylline exposure and adverse effects may increase. Nelfinavir is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Nimodipine: (Moderate) Monitor blood pressure and reduce the dose of nimodipine as clinically appropriate if coadministration with istradefylline 40 mg daily is necessary. Nimodipine is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Nirmatrelvir; Ritonavir: (Major) Do not exceed 20 mg once daily of istradefylline if administered with ritonavir as istradefylline exposure and adverse effects may increase. Ritonavir is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with istradefylline 40 mg daily due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of istradefylline 40 mg daily is necessary. If istradefylline is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. Coadministration can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If istradefylline is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Phenobarbital: (Major) Avoid coadministration of istradefylline with phenobarbital as istradefylline exposure and efficacy may be reduced. Phenobarbital is a strong inducer. Istradefylline exposure was decreased by 81% when administered with a strong inducer in a drug interaction study.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of istradefylline with phenobarbital as istradefylline exposure and efficacy may be reduced. Phenobarbital is a strong inducer. Istradefylline exposure was decreased by 81% when administered with a strong inducer in a drug interaction study.
Phenytoin: (Major) Avoid coadministration of istradefylline with phenytoin as istradefylline exposure and efficacy may be reduced. Phenytoin is a strong inducer. Istradefylline exposure was decreased by 81% when administered with a strong inducer in a drug interaction study.
Pimozide: (Moderate) Monitor for pimozide-related adverse reactions if coadministration of istradefylline 40 mg daily is necessary. Pimozide is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Posaconazole: (Major) Do not exceed 20 mg once daily of istradefylline if administered with posaconazole as istradefylline exposure and adverse effects may increase. Posaconazole is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Pralsetinib: (Major) Avoid concomitant use of istradefylline with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a P-gp substrate and istradefylline is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased the overall exposure of pralsetinib by 81%.
Primidone: (Major) Avoid coadministration of istradefylline with primidone as istradefylline exposure and efficacy may be reduced. Primidone is a strong inducer. Istradefylline exposure was decreased by 81% when administered with a strong inducer in a drug interaction study.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and istradefylline due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and istradefylline is a P-gp inhibitor.
Propafenone: (Moderate) Monitor for propafenone-related adverse reactions if coadministration of istradefylline 40 mg daily is necessary. Propafenone is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Quinidine: (Moderate) Monitor for quinidine-related adverse reactions if coadministration of istradefylline 40 mg daily is necessary. Quinidine is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Ranolazine: (Moderate) Monitor for ranolazine-related adverse reactions and titrate according to clinical response if coadministration of istradefylline is necessary. Coadministration may increase the exposure of ranolazine. Ranolazine is a P-gp substrate; istradefylline is a P-gp inhibitor.
Relugolix: (Major) Avoid concomitant use of relugolix and oral istradefylline. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer istradefylline at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-gp substrate and istradefylline is a P-gp inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral istradefylline. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer istradefylline at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-gp substrate and istradefylline is a P-gp inhibitor.
Repotrectinib: (Major) Avoid coadministration of repotrectinib with istradefylline due to increased repotrectinib exposure which may increase the risk for repotrectinib-related adverse effects. Repotrectinib is a P-gp substrate and istradefylline is a P-gp inhibitor.
Ribociclib: (Major) Do not exceed 20 mg once daily of istradefylline if administered with ribociclib as istradefylline exposure and adverse effects may increase. Ribociclib is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Ribociclib; Letrozole: (Major) Do not exceed 20 mg once daily of istradefylline if administered with ribociclib as istradefylline exposure and adverse effects may increase. Ribociclib is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Rifampin: (Major) Avoid coadministration of istradefylline with rifampin as istradefylline exposure and efficacy may be reduced. Rifampin is a strong inducer. Istradefylline exposure was decreased by 81% when administered with rifampin in a drug interaction study.
Rifapentine: (Major) Avoid coadministration of istradefylline with rifapentine as istradefylline exposure and efficacy may be reduced. Istradefylline is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Istradefylline exposure was decreased by 81% when administered with a strong inducer in a drug interaction study.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with istradefylline is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and istradefylline is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with istradefylline; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and istradefylline is a P-gp inhibitor.
Ritonavir: (Major) Do not exceed 20 mg once daily of istradefylline if administered with ritonavir as istradefylline exposure and adverse effects may increase. Ritonavir is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Saquinavir: (Major) Do not exceed 20 mg once daily of istradefylline if administered with saquinavir/ritonavir as istradefylline exposure and adverse effects may increase. Saquinavir boosted with ritonavir is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Silodosin: (Moderate) Monitor for silodosin-related adverse reactions if coadministration with istradefylline is necessary as concurrent use may increase silodosin exposure. Silodosin is a P-gp substrate; istradefylline is a P-gp inhibitor.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of istradefylline. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and istradefylline is a weak CYP3A and P-gp inhibitor.
St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of istradefylline with St. John's Wort as istradefylline exposure and efficacy may be reduced. St. John's Wort is a strong inducer. Istradefylline exposure was decreased by 81% when administered with a strong inducer in a drug interaction study.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if istradefylline 40 mg daily must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of istradefylline 40 mg daily is necessary. If istradefylline is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. Coadministration can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If istradefylline is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with istradefylline 40 mg daily is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with istradefylline is necessary. Talazoparib is a P-gp substrate and istradefylline is a P-gp inhibitor.
Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with istradefylline is necessary as concurrent use may increase temsirolimus exposure. Temsirolimus is a P-gp substrate and istradefylline is a P-gp inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with istradefylline is necessary as concurrent use may increase tenofovir exposure. Tenofovir is a P-gp substrate and istradefylline is a P-gp inhibitor.
Ticagrelor: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with istradefylline as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-gp substrate and istradefylline is a P-gp inhibitor.
Tipranavir: (Major) Do not exceed 20 mg once daily of istradefylline if administered with tipranavir as istradefylline exposure and adverse effects may increase. Tipranavir is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Tobacco: (Major) The initial and maximal recommended istradefylline dosage in patients who smoke 20 or more cigarettes per day (or the equivalent amount of another tobacco product) is 40 mg once daily. Tobacco smoking has been observed to decrease istradefylline overall exposure by 38% to 54% which may reduce its efficacy.
Topotecan: (Major) Avoid coadministration of istradefylline with oral topotecan due to increased topotecan exposure; istradefylline may be administered with intravenous topotecan. Oral topotecan is a substrate of P-gp and istradefylline is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with istradefylline 40 mg daily is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of istradefylline 40 mg daily, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with istradefylline 40 mg daily is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of istradefylline 40 mg daily, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with istradefylline and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and istradefylline is a weak CYP3A inhibitor.
Tucatinib: (Major) Do not exceed 20 mg once daily of istradefylline if administered with tucatinib as istradefylline exposure and adverse effects may increase. Tucatinib is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with istradefylline. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 and P-gp substrate; istradefylline is a weak CYP3A4 inhibitor and a P-gp inhibitor.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with istradefylline due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of istradefylline. Istradefylline is a P-gp inhibitor; venetoclax is a P-gp substrate. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Vincristine Liposomal: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of istradefylline is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and istradefylline is a P-gp inhibitor.
Vincristine: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of istradefylline is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and istradefylline is a P-gp inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with istradefylline 40 mg daily is necessary. Vinorelbine is a CYP3A4 and P-gp substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor and P-gp inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Do not exceed 20 mg once daily of istradefylline if administered with clarithromycin as istradefylline exposure and adverse effects may increase. Clarithromycin is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Voriconazole: (Major) Do not exceed 20 mg once daily of istradefylline if administered with voriconazole as istradefylline exposure and adverse effects may increase. Voriconazole is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with istradefylline is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Istradefylline is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Istradefylline is an adenosine A2A receptor antagonist that acts through a non-dopaminergic mechanism to improve motor function. The precise mechanism by which istradefylline exerts its therapeutic effect in Parkinson's disease is unknown. Blockade of the striatal adenosine A2A receptors on medium spiny neurons located in an indirect pathway between the striatum to the globus pallidus decreases excessive pathway activation. This indirect output pathway is known to be overactive in Parkinson's disease due to dopaminergic cell degeneration in the substantia nigra pars compacta and a lack of inhibition normally mediated by the nigrostriatal pathway. Preclinical data have suggested potential neuroprotective effects of A2A receptor antagonists; however, this potential benefit of these drugs remains to be proven in human subjects.
Istradefylline is administered orally. Plasma protein binding is approximately 98% and the apparent volume of distribution is approximately 557 liters. Istradefylline is primarily metabolized by isoenzymes CYP1A1 and CYP3A4, with a minor contribution from CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C18, and CYP2D6. Six metabolites each account for less than 10% of the exposure of the parent drug. Approximately 39% and 48% of a 40 mg oral dose of C-istradefylline are eliminated in the urine and feces, respectively. The total clearance of istradefylline is 4.6 L/hour. Steady-state is reached within 2 weeks of once-daily dosing. The mean terminal half-life at steady state is approximately 83 hours.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2D6, P-glycoprotein (P-gp), BCRP, OATP1B1, OATP1B3, OAT1, OCT2, MATE1, MATE2-K
Istradefylline is predominantly metabolized by CYP1A1 and CYP3A4. Clinically relevant drug interactions may occur with other drugs that are CYP3A4 inhibitors and inducers, and dose modification of istradefylline is recommended for heavy smokers/users of tobacco (induces CYP1A1). Istradefylline is also a substrate for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C18, and CYP2D6 but does not inhibit or induce these enzymes. Istradefylline is a weak inhibitor of CYP3A4, P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT2, MATE1, and MATE2-K. The drug does not inhibit OAT3. Drug-drug interaction studies suggest that istradefylline may increase the exposure of selected CYP3A4 substrates (e.g., midazolam, atorvastatin) and P-gp substrates (e.g., digoxin). While istradefylline was a weak inducer of CYP3A4 in vitro, clinical drug-drug interaction studies with a CYP3A4 substrate (i.e., midazolam) showed no induction of CYP3A4.
-Route-Specific Pharmacokinetics
Oral Route
Istradefylline exhibits dose-proportional pharmacokinetics after multiple oral doses ranging from 20 mg to 80 mg. Tmax is approximately 4 hours under fasting conditions. AUC increased 1.25-fold when istradefylline was given with a high-fat meal compared to the fasted state. Cmax increased by 1.64-fold and Tmax decreased by 1 hour when istradefylline was given with a high-fat meal. These differences are not expected to be clinically significant.
-Special Populations
Hepatic Impairment
The steady-state exposure (AUC) of istradefylline was found 3.3-fold higher among patients with moderate hepatic impairment (Child-Pugh B) compared to those with normal hepatic function. Istradefylline has not been studied in patients with severe hepatic impairment (Child-Pugh C).
Renal Impairment
No difference in the pharmacokinetics of istradefylline was found among patients with mild, moderate, or severe renal impairment (CrCl 15 mL/minute or more) compared to those with normal renal function. Istradefylline has not been studied in patients with end-stage renal disease (CrCl less than 15 mL/minute) with or without hemodialysis.
Geriatric
The pharmacokinetics of istradefylline were not affected by age.
Gender Differences
The pharmacokinetics of istradefylline were not affected by gender.
Ethnic Differences
The pharmacokinetics of istradefylline were not affected by race.
Obesity
The pharmacokinetics of istradefylline were not affected by body weight.
Other
Tobacco Smoking
Steady-state systemic exposure to a 40 mg dose of istradefylline is 38% to 54% lower in tobacco smokers who smoke 20 or more cigarettes daily compared to non-smokers matched for age, gender, and body weight.