Idhifa (enasidenib mesylate)
Antineoplastic - Isocitrate Dehydrogenase-2 Inhibitor (IDH2) Oral Tablet
Last reviewed · Source: First Databank (FDB) drug data
Overview
Enasidenib, a potent and selective inhibitor of isocitrate dehydrogenase-2 (IDH2), is an antineoplastic agent.
Enasidenib, a potent and selective inhibitor of isocitrate dehydrogenase-2 (IDH2), is an antineoplastic agent. Isocitrate dehydrogenases (IDH) are metabolic enzymes in the citric acid cycle responsible for the oxidative decarboxylation of isocitrate to alpha-ketoglutarate, which is essential for normal cellular processes. Approximately 15-20% of acute myeloid leukemia (AML) cases carry IDH2 mutations.
The most common IDH2 mutation is a point mutation at codon R140Q; a less frequently occurring IDH2 mutation is a point mutation at codon R172K. IDH2 mutations cause a reduction of alpha-ketoglutarate to the oncometabolite 2-hydroxyglutarate, which competitively inhibits alpha-ketoglutarate-dependent dioxygenases resulting in epigenetic dysregulation and subsequent histone and DNA hypermethylation and differentiation arrest of hematopoietic stem cells. In vitro studies indicate that enasidenib inhibits IDH2 with R140Q, R172S, or R172K mutation at approximately 40-fold lower concentrations than IDH2 wild-type enzymes.
Enasidenib has demonstrated decreased 2-hydroxyglutarate levels and induction of myeloid cell differentiation in vitro and in mice bearing tumor xenografts that expressed IDH2 mutation. Enasidenib also has demonstrated decreased 2-hydroxyglutarate levels, reduced blast cell counts, and increased percentages of mature myeloid cells in patients with AML that expressed IDH2 mutation. In the phase 1/2 study evaluating enasidenib in patients with relapsed or refractory AML, mature granulocytes retained baseline IDH2 mutations and cytogenetic abnormalities in patients who achieved remission, indicating continued differentiation of abnormal myeloblast cells into mature granulocytes.
Following oral administration of enasidenib, the absolute bioavailability of the drug is 57%. Area under the serum concentration-time curve (AUC) of enasidenib is dose proportional over the enasidenib dosage range of 50-450 mg daily. Following oral administration of a single dose, median time to peak plasma concentrations of enasidenib is 4 hours.
Repeated administration of enasidenib resulted in an approximately tenfold mean enasidenib accumulation ratio. Steady-state concentrations are reached within 29 days. Systemic exposure of enasidenib was increased by 50% when enasidenib was administered with a high-fat meal; however, this effect is not considered clinically important.
Enasidenib is metabolized to the active AGI-16903 metabolite by cytochrome P-450 (CYP) isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 and by uridine diphosphate-glucuronosyl transferases (UGT) 1A1, 1A3, 1A4, 1A9, 2B7, and 2B15. AGI-16903 is subsequently metabolized by CYP isoenzymes 1A2, 2C19, and 3A4 and by UGT1A1, 1A3, and 1A9. Enasidenib and AGI-16903 are highly bound (98.5 and 96.6%, respectively) to plasma proteins.
The terminal half-life of enasidenib is 7.9 days. Following administration of a radiolabeled dose of enasidenib, 89% of the radioactivity was recovered in feces (34% of the dose as unchanged drug) and 11% was recovered in urine (0.4% of the dose as unchanged drug).
The pharmacokinetics of enasidenib do not appear to be affected substantially by age (19-100 years), gender, race, body weight (39-136 kg), or body surface area.
USES: This medication is used to treat a certain type of blood cell cancer (acute myeloid leukemia-AML). Enasidenib works by helping your bone marrow grow normal blood cells so you will need fewer blood transfusions. This drug has been withdrawn from the Canadian market due to problems with effectiveness.
Generic name: enasidenib mesylate
Pronunciation: (EN-a-SID-a-nib)
Drug class: Antineoplastic - Isocitrate Dehydrogenase-2 Inhibitor (IDH2)
Therapeutic class: Antineoplastics
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Idhifa
Indications
The following indications are listed for Idhifa:
- Acute Myeloid Leukemia With Isocitrate Dehydrogenase-2 (Idh2) Mutation
Also known as: Idh2 Mutated Aml, Idh2 Mutation-Positive Acute Myeloid Leukemia.
Dosing
Dosage of enasidenib mesylate is expressed in terms of enasidenib.
Enasidenib is administered orally without regard to meals. The drug should be taken at approximately the same time each day. The tablets should be swallowed whole with a glass of water; they shouldnot be chewed, crushed, or split.
If a dose is vomited, missed, or not taken at the usual time, administer the dose as soon as possible on the same day, and then return to the normal schedule the following day. Do not take 2 doses to make up for a missed dose.
Store enasidenib tablets in the original container with the desiccant at 20-25oC (excursions permitted between 15-30oC).
| Drug label | Dosing type | Instructions |
|---|---|---|
| Idhifa 50 Mg Tablet | Maintenance | Take 2 tablets (100 mg) by oral route once daily. |
| Idhifa 100 Mg Tablet | Maintenance | Take 1 tablet (100 mg) by oral route once daily. |
No dosing information is available for this tab.
Drug interactions
Metabolism of enasidenib to the active AGI-16903 metabolite is mediated by cytochrome P-450 (CYP) isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 and by uridine diphosphate-glucuronosyl transferases (UGT) 1A1, 1A3, 1A4, 1A9, 2B7, and 2B15. AGI-16903 is subsequently metabolized by CYP isoenzymes 1A2, 2C19, and 3A4 and by UGT1A1, 1A3, and 1A9.
In vitro, enasidenib inhibits CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4; enasidenib also inhibits UGT1A1. In vitro, AGI-16903 inhibits CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6. In vitro studies show that enasidenib induces CYP isoenzymes 2B6 and 3A4.
In vitro studies indicate that enasidenib inhibits P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter (OAT) 1, organic anion transport protein (OATP) 1B1, OATP1B3, and organic cation transporter (OCT) 2, but does not inhibit multidrug resistance protein 2 (MRP2) or OAT3. In vitro, AGI-16903 inhibits BCRP, OAT1, OAT3, OATP1B1, and OCT2, but does not inhibit P-gp, MRP2, or OATP1B3. In vitro, AGI-16903 is a substrate of efflux transporters P-gp and BCRP; enasidenib is not a substrate of these transporters. Neither enasidenib nor AGI-16903 is a substrate of MRP2, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.
Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
Bcrp Inhibitors/Topotecan
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Inhibitors of the BCRP transporter may increase the intestinal absorption and hepatic uptake of topotecan.(1)
CLINICAL EFFECTS: The concurrent administration of topotecan with an inhibitor of BCRP may result in elevated levels of topotecan and signs of toxicity. These signs may include but are not limited to anemia, diarrhea, and thrombocytopenia.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of topotecan states that the use of topotecan and BCRP inhibitors should be avoided. If concurrent use is warranted, carefully monitor patients for adverse effects.(1)
DISCUSSION: In clinical studies, the combined use of elacridar (100 mg to 1000 mg), a BCRP and P-gp inhibitor, increased the area-under-curve (AUC) of topotecan approximately 2.5-fold.(1) BCRP inhibitors linked to this monograph include: capmatinib, clopidogrel, curcumin, danicopan, dasabuvir, elbasvir, enasidenib, ensitrelvir, febuxostat, fostamatinib, fostemsavir, glecaprevir, grazoprevir, lazertinib, oteseconazole, pacritinib, paritaprevir, pibrentasvir, pirtobrutinib, regorafenib, resmetirom, ritonavir, roxadustat, tafamidis, ticagrelor, tolvaptan, turmeric, vadadustat, velpatasvir, voxilaprevir, and zongertinib.(2,3)
Cyp1a2 Inhibitors/Fezolinetant
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of fezolinetant.(1-4)
CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from fezolinetant.(1-4)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Recommendations for concurrent use of fezolinetant with CYP1A2 inhibitors differ in different regions. The US manufacturer of fezolinetant states that concurrent use with strong, moderate, and weak CYP1A2 inhibitors is contraindicated.(1) The Australian, Canadian, and UK manufacturers of fezolinetant state that concurrent use with strong and moderate CYP1A2 inhibitors is contraindicated, while weak CYP1A2 inhibitors are not predicted to cause clinically relevant changes in fezolinetant exposure.(2-4)
DISCUSSION: In a study, fluvoxamine, a strong CYP1A2 inhibitor, increased fezolinetant maximum concentration (Cmax) and area-under-curve (AUC) by 80% and 840%, respectively. Mexiletine (400 mg every 8 hours), a moderate CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 40% and 360%, respectively. Cimetidine (300 mg every 6 hours), a weak CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 30% and 100%, respectively.(1) Strong CYP1A2 inhibitors linked to this monograph include angelica root, ciprofloxacin, enasidenib, enoxacin, fluvoxamine, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include capmatinib, centanafadine, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine. Weak CYP1A2 inhibitors linked to this monograph include acyclovir, allopurinol, artemisinin, belumosudil, caffeine, cannabidiol, cimetidine, curcumin, dan-shen, deferasirox, disulfiram, Echinacea, famotidine, ginseng, norfloxacin, obeticholic acid, parsley, piperine, propafenone, propranolol, ribociclib, simeprevir, thiabendazole, ticlopidine, triclabendazole, valacyclovir, verapamil, and zileuton.(5-7)
Enasidenib/Rosuvastatin (> 10 Mg)
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Enasidenib is an inhibitor of the BCRP and OATP1B1 transporters and may increase the absorption and/or decrease the elimination of rosuvastatin.(1)
CLINICAL EFFECTS: Concurrent use of enasidenib may result in increased levels and side effects from rosuvastatin, including rhabdomyolysis.(1)
PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy.
PATIENT MANAGEMENT: The US manufacturer of rosuvastatin states that the dose of rosuvastatin should not exceed 10 mg daily when used concurrently with enasidenib. Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(1) The Australian manufacturer of rosuvastatin states that the starting dose of rosuvastatin should not exceed 5 mg daily when used with enasidenib.(2)
DISCUSSION: In a study, enasidenib 100 mg daily increased the maximum concentration (Cmax) and area-under-curve (AUC) of rosuvastatin 10 mg by 3.7-fold and 3.4-fold, respectively.(1-2)
Oatp1b3 Inhibitors/Zavegepant
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Zavegepant is a substrate of the organic anion transporting polypeptide 1B3 (OATP1B3) transporter. Inhibitors of OATP1B3 may increase zavegepant exposure.(1)
CLINICAL EFFECTS: Concurrent use of OATP1B3 inhibitors may result in increased levels of and toxicity from zavegepant.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Concurrent administration of zavegepant with OATP1B3 inhibitors should be avoided.(1)
DISCUSSION: In a study, rifampin (an OATP1B3 and NTCP inhibitor) at steady state increased the area-under-curve (AUC) and maximum concentration (Cmax) of zavegepant by 2.3-fold and 2.2-fold. Since rifampin is also a CYP3A4 inducer and zavegepant is metabolized by CYP3A4, concurrent use of zavegepant with other OATP1B3 inhibitors that are not CYP3A4 inducers may have an even more significant effect on zavegepant exposure.(1) OATP1B3 inhibitors include: atazanavir, belumosudil, cobicistat, cyclosporine, darolutamide, enasidenib, encorafenib, fostemsavir, glecaprevir/pibrentasvir, leflunomide, leniolisib, letermovir, lopinavir/ritonavir, paritaprevir, resmetirom, rifampin, ritonavir, teriflunomide, velpatasvir, voclosporin, and voxilaprevir.(2-9)
Select Bcrp Inhibitors/Aumolertinib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Aumolertinib is a substrate for BCRP. Inhibitors of the BCRP transporter may increase the intestinal absorption and decrease hepatic elimination of aumolertinib.(1)
CLINICAL EFFECTS: Concurrent use with selected BCRP inhibitors may result in higher systemic concentrations of aumolertinib, which may increase the risk for cardiac failure, rhabdomyolysis, thrombosis, elevated LFTs, hyponatremia, hematologic toxicity, and QT prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsade de pointes (TdP).(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Patients with risk factors for thrombosis may be at higher risk of adverse events, including those with advanced age, obesity (BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable state, history of venous thromboembolism, malignancy, and major surgery. The risk for rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of rhabdomyolysis.
PATIENT MANAGEMENT: The manufacturer of aumolertinib states concomitant administration of aumolertinib should be avoided with BCRP inhibitors.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Based on in vitro data, aumolertinib is a substrate of BCRP.(1) BCRP inhibitors linked to this monograph include: asciminib, clopidogrel, darolutamide, elbasvir/grazoprevir, eltrombopag, enasidenib, febuxostat, fostemsavir, lazertinib, leniolisib, momelotinib, oteseconazole, regorafenib, rolapitant, roxadustat, tafamidis, ticagrelor, vadadustat, and zongertinib.(3,4)
Selected Cyp1a2 Inhibitors/Rasagiline (> 0.5 Mg)
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of rasagiline.(1)
CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from rasagiline.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of rasagiline states that patients receiving concurrent therapy with an inhibitor of CYP1A2 should receive no more than 0.5 mg of rasagiline daily.(1) Concurrent therapy with vemurafenib may require extended monitoring for interaction onset and severity because steady-state levels of vemurafenib are not attained for approximately 15 days.(2)
DISCUSSION: In a study in 12 healthy subjects, ciprofloxacin (500 mg twice daily) increased the area-under-curve (AUC) of rasagiline (2 mg twice daily) by 83%.(1) Strong CYP1A2 inhibitors linked to this monograph include angelica root, ciprofloxacin, enasidenib, enoxacin, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include capmatinib, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, and vemurafenib.(3-5)
Selected Dual Cyp1a2 And Cyp3a4 Inhibitors/Alosetron
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Dual inhibitors of CYP1A2 and CYP3A4 may inhibit the metabolism of alosetron.(1,2)
CLINICAL EFFECTS: Concurrent administration with dual CYP1A2 and CYP3A4 inhibitors may result in 6-fold increases in alosetron levels and toxicity.(1,2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturers of alosetron states that concurrent use is contraindicated.(1)
DISCUSSION: In a study in 40 healthy females, pretreatment with fluvoxamine (escalating doses from 50 mg to 200 mg daily for 16 days) increased the area-under-curve (AUC) and half-life of alosetron by 6-fold and 3-fold, respectively.(1,2) Selected dual CYP1A2 and CYP3A4 inhibitors linked include: enasidenib and fluvoxamine.(3,4)
Selected Inhibitors Of P-Gp Or Bcrp/Pazopanib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Inhibitors of P-glycoprotein (P-gp) or BCRP may increase the absorption of pazopanib.(1)
CLINICAL EFFECTS: The concurrent administration of pazopanib with an inhibitor of P-glycoprotein or BCRP may result in elevated levels of pazopanib and signs of toxicity.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of pazopanib states concurrent use of P-gp inhibitors or BCRP inhibitors should be avoided.(1) Monitor patients for increased side effects from pazopanib. The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(5) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Pazopanib is a substrate of P-gp and BCRP. Inhibitors of these transporters are expected to increase pazopanib levels.(1) BCRP inhibitors linked to this monograph include: asciminib, belumosudil, clopidogrel, cyclosporine, curcumin, darolutamide, eltrombopag, enasidenib, febuxostat, fostemsavir, grazoprevir, lazertinib, leflunomide, leniolisib, momelotinib, oteseconazole, pirtobrutinib, regorafenib, resmetirom, ritonavir, rolapitant, roxadustat, tafamidis, teriflunomide, tolvaptan, turmeric, vadadustat, and zongertinib.(1,3-5) P-glycoprotein inhibitors linked to this monograph include: asunaprevir, belumosudil, capmatinib, carvedilol, cyclosporine, danicopan, daraxonrasib, daridorexant, diltiazem, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, imlunestrant, isavuconazonium, ivacaftor, ledipasvir, neratinib, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, tezacaftor, ticagrelor, valbenazine, verapamil, vimseltinib, and voclosporin.(3,4)
Strong Cyp1a2 Inhibitors/Duloxetine
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of duloxetine.(1)
CLINICAL EFFECTS: Concurrent use of inhibitors of CYP1A2 may result in elevated levels of and toxicity from duloxetine.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of duloxetine states that concurrent use with strong inhibitors of CYP1A2 should be avoided.(1)
DISCUSSION: In a study in 14 male subjects, concurrent fluvoxamine increased duloxetine area-under-curve (AUC), maximum concentration (Cmax), and half-life by over 5-fold, about 2.5-fold, and approximately 3-fold, respectively.(1) In a study in 14 subjects who were poor metabolizers of CYP2D6, fluvoxamine (100 mg) increased the AUC and Cmax of duloxetine (40 mg BID) by 6-fold each.(1)
Strong Cyp1a2 Inhibitors/Tasimelteon
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Strong CYP1A2 inhibitors may inhibit the metabolism of tasimelteon.(1)
CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP1A2 may result in elevated levels of and toxicity from tasimelteon.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP1A2 inhibitors and tasimelteon.(1)
DISCUSSION: Fluvoxamine (50 mg daily for 6 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of tasimelteon by 2-fold and 7-fold, respectively.(1) Strong inhibitors of CYP1A2 include angelica root (angelica dahurica radix), ciprofloxacin, enasidenib, enoxacin, fluvoxamine, and rofecoxib.(2,3)
Strong Cyp1a2 Inhibitors/Tizanidine
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Strong CYP1A2 inhibitors may inhibit the metabolism of tizanidine.
CLINICAL EFFECTS: Concurrent use of strong CYP1A2 inhibitors may result in elevated levels of and effects from tizanidine, including hypotension (including decreases in both systolic and diastolic pressure), bradycardia, drowsiness, sedation, and decreased psychomotor function.(1-5)
PREDISPOSING FACTORS: The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(6)
PATIENT MANAGEMENT: The US manufacturer for tizanidine states concurrent use with strong CYP1A2 inhibitors is contraindicated.(1,3)
DISCUSSION: In a double-blind, randomized, cross-over study in 10 healthy subjects, pretreatment with ciprofloxacin (500 mg twice daily) for 3 days increased the tizanidine area-under-curve (AUC) and maximum concentration (Cmax) by 10-fold (range 6-fold to 24-fold) and 7-fold (range 4-fold to 21-fold), respectively, when compared to administration with placebo. During the ciprofloxacin phase, tizanidine pharmacodynamic effects were also increased; the mean decreases in systolic and diastolic blood pressure were 35 mmHg and 24 mmHg, respectively, and there were significant increases in sedation as shown by the Digit Symbol Substitution Test, subjective drug effect, and subjective drowsiness. During the placebo phase, the mean decreases in systolic and diastolic blood pressure were 15 mmHg and 11mm Hg, respectively.(7) In a case report, a 45 year old woman on maintenance tizanidine therapy was given ciprofloxacin which reduced her systolic and diastolic blood pressure 22 and 14 mmHg, respectively, on the day of ciprofloxacin administration. On day three the patient's blood pressure was reported low at 92/54 mmHg. On days 5 and 6, her body temperature and urine volume decreased 1.1 C and 496 mL/dL, respectively. The patient's symptoms improved immediately after ciprofloxacin was discontinued.(8) A retrospective study looked at adverse reaction case reports in the WHO pharmacovigilance database with concurrent tizanidine and ciprofloxacin administration and found that 57.1% of the adverse reactions were qualified as serious because of hospitalization. The most frequently observed reactions included hypotension, somnolence, fatigue, and asthenia.(9) A retrospective cohort study assessed the impact of concurrent administration of tizanidine and ciprofloxacin on outpatient physician visits and hospitalizations and found a significant association between exposure to tizanidine and ciprofloxacin and outpatient physician visits at 14 and 30 days (odds ratio (OR) = 1.61, (95% CI = 1.17-2.24)(p = 0.004); OR = 1.59 (95% CI = 1.1-2.34)(p = 0.016)) and a trend for increased risk of hospitalization for all evaluated time periods (OR = 1.68 (95% CI = 0.84-3.17), OR = 1.52 (95% CI = 0.63-3.33), OR = 2.19 (95% CI = 0.88-5.02).(10) Following multiple doses of enasidenib 100 mg, the AUC and Cmax of a single dose of caffeine 100 mg (a sensitive CYP1A2 substrate) increased by 655% and 18%, respectively.(3) In a study in 10 healthy subjects, pretreatment with fluvoxamine (100 mg daily for 4 days) increased the AUC and Cmax of a single dose of tizanidine (4 mg) by 33-fold (range: 14-fold to 103-fold) and by 12-fold (range 5-fold to 33-fold), respectively. Tizanidine half-life increased from 1.5 hours to 4.3 hours. The mean decrease in systolic blood pressure was 35 mmHg. The mean decrease in diastolic blood pressure was 20 mmHg. Heart rate decreased by 4 beats/minute. There were also significant effects on the Digit Substitution Test, subjective drug effects, and drowsiness.(1,11) There is one case report of an interaction between tizanidine and fluvoxamine.(12) In a study in human liver microsomes, fluvoxamine inhibited the metabolism of tizanidine.(13) Concomitant use of viloxazine significantly increases the total exposure, but not peak exposure, of sensitive CYP1A2 substrates, which may increase the risk of adverse reactions associated with these CYP1A2 substrates. In a study, viloxazine increased the AUC of caffeine by almost 6-fold.(5) Strong CYP1A2 inhibitors linked to this monograph include: angelica root (angelica dahurica radix), ciprofloxacin, enasidenib, enoxacin, fluvoxamine, rofecoxib, and viloxazine.(3) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Strong Cyp1a2 Inhibitors/Vorasidenib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Strong CYP1A2 inhibitors may inhibit the metabolism of vorasidenib.(1)
CLINICAL EFFECTS: Concurrent use of strong CYP1A2 inhibitors may result in elevated levels of and effects from vorasidenib, including hepatotoxicity.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer for vorasidenib states concurrent use with strong CYP1A2 inhibitors should be avoided.(1)
DISCUSSION: Vorasidenib is primarily metabolized by CYP1A2.(1) Concurrent use of vorasidenib and fluvoxamine (a strong CYP1A2 inhibitor) is predicted to increase vorasidenib maximum concentration (Cmax) and area-under-curve (AUC) by greater than 5-fold.(1) In a study, concurrent use of vorasidenib and ciprofloxacin (a moderate CYP1A2 inhibitor) increased vorasidenib Cmax 1.3-fold and AUC 2.5-fold.(1) Strong CYP1A2 inhibitors linked to this monograph include: angelica root (angelica dahurica radix), enasidenib, enoxacin, fluvoxamine, and rofecoxib.(2)
Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
Enasidenib/Hormonal Contraceptives
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Enasidenib may increase or decrease the metabolism of hormonal contraceptives.(1)
CLINICAL EFFECTS: Concurrent use of enasidenib may increase side effect from or reduce the effectiveness of hormonal contraceptives. Enasidenib may cause birth defects if used by pregnant women.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use a back-up method of birth control during enasidenib therapy. Women of reproductive potential should use effective non-hormonal methods of contraception during enasidenib therapy and for at least 2 months after the final dose.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2)
DISCUSSION: Enasidenib may increase or decrease metabolism of hormonal contraceptives. Enasidenib may increase or decrease the effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs. Women should use a back-up method of birth control during enasidenib therapy and for at least 1 month after the final dose.(1)
Enasidenib/Selected Azole Antifungal Cyp3a4 Substrates
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Enasidenib is a weak CYP3A4 inducer and may induce the metabolism of azole antifungal agents that are CYP3A4 substrates.(1-5)
CLINICAL EFFECTS: The concurrent use of enasidenib, a weak CYP3A4 inducer, with azole antifungal agents that are CYP3A4 substrates may result in reduced levels of the azole antifungal and therapeutic failure.
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Do not administer enasidenib with antifungal agents that are substrates of CYP3A4.(1) Concurrent therapy should only be undertaken if benefits are considered to outweigh risks. If concurrent therapy is necessary, observe the patient for a decrease in the therapeutic effect of the antifungal agent. It may be necessary to increase the dose of the antifungal agent.(2-5)
DISCUSSION: Intravenous midazolam (sensitive CYP3A4 substrate) area-under-curve (AUC) and maximum concentration (Cmax) decreased by 43% and 23%, respectively, following concomitant use of multiple doses of enasidenib 100 mg.(1) Selected azole antifungals include: isavuconazonium, itraconazole, ketoconazole, and voriconazole.
Enasidenib/Ubrogepant
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ubrogepant is a CYP3A4 and BCRP substrate.(1) Enasidenib is a weak CYP3A4 inducer and BCRP inhibitor.(2)
CLINICAL EFFECTS: Concurrent use of ubrogepant with enasidenib may lead to increased or decreased levels and effectiveness of ubrogepant.(1) The net effect of enasidenib on ubrogepant is unknown.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of ubrogepant does not have recommendations for concurrent use with agents that are both weak CYP3A4 inducers and BCRP inhibitors. Concurrent use should be avoided.(1) For concurrent use of ubrogepant with weak CYP3A4 inducers: The manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant. Initial dose of ubrogepant should be 100 mg. If a second dose is needed, the the dose of ubrogepant should be 100 mg.(1) For concurrent use of ubrogepant with BCRP inhibitors: The manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant. The dose of ubrogepant should not exceed 50 mg for initial dose. If a second dose of ubrogepant is needed, the dose should not exceed 50 mg.(1) For concurrent use of enasidenib with BCRP substrates: The manufacturer of enasidenib states that concurrent use of BCRP substrates should be avoided. If concurrent use cannot be avoided, monitor for adverse events more frequently and consider dose reduction of the BCRP substrate.(2)
DISCUSSION: Ubrogepant is a substrate of CYP3A4 and the BCRP transporter.(1) Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure. No dedicated drug interaction studies were conducted to assess concomitant use with moderate or weak CYP3A4 inducers. Dose adjustment for concomitant use of ubrogepant with moderate or weak CYP3A4 inducers is recommended based on a conservative prediction of 50% reduction in exposure of ubrogepant.(1) Use of P-gp or BCRP inhibitors may increase the exposure of ubrogepant. Clinical drug interaction studies with inhibitors of these transporters were not conducted. The US manufacturer of ubrogepant recommends dose adjustment if ubrogepant is coadministered with P-gp or BCRP inhibitors.(1)
Select Cyp2c19 Inhibitors/Citalopram (>20 Mg)
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Citalopram is primarily metabolized by the CYP2C19 isoenzyme.(1)
CLINICAL EFFECTS: Concurrent use of an agent that inhibits CYP2C19 may result in elevated levels of and toxicity from citalopram, including including risks for serotonin syndrome or prolongation of the QTc interval.(1-5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(5)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age, poor metabolizer status at CYP2C19, or higher blood concentrations of citalopram.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,5) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
PATIENT MANAGEMENT: The dose of citalopram should be limited to 20 mg in patients receiving concurrent therapy with an inhibitor of CYP2C19.(1,4) Evaluate the patient for other drugs, diseases and conditions which increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, discontinue other QT prolonging drugs) when possible.(1,2) Weigh the specific benefits versus risks for each patient. The US manufacturer recommends ECG monitoring for citalopram patients with congestive heart failure, bradyarrhythmias, taking concomitant QT prolonging medications or receiving concurrent therapy.(4) Citalopram should be discontinued in patients with persistent QTc measurements greater than 500 ms.(2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.
DISCUSSION: Concurrent use of citalopram (40 mg daily) and cimetidine (400 mg twice daily) for 8 days increased the maximum concentration (Cmax) and area-under-curve (AUC) of citalopram by 39% and 43%, respectively.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), armodafinil, asciminib, berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, elagolix, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, treosulfan, and vonoprazan.(7,8)
Selected Cyp2c19 Inhibitors/Clopidogrel
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) Inhibitors of CYP2C19 may decrease the conversion of clopidogrel to its active metabolite.(1)
CLINICAL EFFECTS: Concurrent use of CYP2C19 inhibitors may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Evaluate medication list or interaction alerts to determine if patient is receiving additional drugs which may also inhibit clopidogrel active metabolite formation. The US manufacturer of clopidogrel states that alternatives to clopidogrel should be considered in patients who are poor metabolizers of CYP2C19.(1) It would be prudent to assume that patients taking strong inhibitors of CYP2C19 are poor metabolizers of this isoenzyme. Moderate or weak inhibitors of CYP2C19 may have less of an effect on this interaction. Consider alternatives to CYP2C19 inhibitors in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on CYP2C19 inhibitors. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity.
DISCUSSION: Clopidogrel is a prodrug and requires conversion to the active metabolite by CYP2C19. Clopidogrel is not a sensitive substrate for CYP2C19 as CYP3A4, CYP2B6 and CYP1A2 also participate in active metabolite formation. Studies have not evaluated this specific drug combination; the actual magnitude of this interaction is not known. Given the possible consequences of clopidogrel treatment failure, it would be prudent to avoid concomitant use of clopidogrel and CYP2C19 inhibitors when possible. Selected CYP2C19 inhibitors include: armodafinil, berotralstat, cenobamate, elagolix, enasidenib, eslicarbazepine, fedratinib, fexinidazole, givosiran, lonafarnib, moclobemide, modafinil, obeticholic acid, osilodrostat, piperine, pirtobrutinib, rolapitant, rucaparib, tecovirimat, treosulfan, and triclabendazole.(4,5)
Selected Inhibitors Of Bcrp/Cladribine Oral
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Inhibitors of BCRP may increase the absorption of cladribine.(1-2)
CLINICAL EFFECTS: The concurrent administration of cladribine with an inhibitor of BCRP may result in elevated levels of cladribine and signs of toxicity.(1-2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of cladribine states concurrent use of BCRP inhibitors should be avoided during the 4- to 5-day cladribine treatment.(1-2) Selection of an alternative concurrent medication with no or minimal transporter inhibiting proprieties should be considered. If this is not possible, dose reduction to the minimum mandatory dose of the BCRP inhibitor, separation in timing of administration, and careful patient monitoring is recommended.(1-2) Monitor for signs of hematologic toxicity. Lymphocyte counts should be monitored.
DISCUSSION: Cladribine is a substrate of BCRP. Inhibitors of this transporter are expected to increase cladribine levels.(1-2) BCRP inhibitors linked to this monograph include: capmatinib, clopidogrel, curcumin, danicopan, darolutamide, dasabuvir, eltrombopag, enasidenib, ensitrelvir, febuxostat, fostamatinib, fostemsavir, glecaprevir/pibrentasvir, grazoprevir, lazertinib, oteseconazole, pacritinib, paritaprevir, regorafenib, resmetirom, ritonavir, rolapitant, roxadustat, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, tafamidis, ticagrelor, tolvaptan, turmeric, vadadustat, and zongertinib.(1-4)
Slt Strong Cyp1a2 Inhibitors/Olanzapine Extended Release Im
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of olanzapine by this pathway.(1-5)
CLINICAL EFFECTS: Concurrent use of CYP1A2 inhibitors may result in elevated levels of and toxicity from olanzapine. This may be particularly problematic in patients receiving the intramuscular (IM) extended release suspension as this dose form as been associated with post-injection delirium sedation syndrome. Patients with this syndrome have unexpectedly high olanzapine concentrations after a therapeutic dose. Symptoms usually begin within 3 hours of an injection and if not managed may be fatal. Although the cause has not been identified, very high olanzapine blood levels were also found in two patients who died 3-4 days after a therapeutic dose of extended release olanzapine injection.(8)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Whenever possible, it would be prudent to use an alternative agent that does not inhibit CYP1A2. If concurrent therapy cannot be avoided, the dose of olanzapine may need to be adjusted when a CYP1A2 inhibitor is initiated or discontinued. Concurrent therapy should be closely monitored for olanzapine side effects as described in the REMS for this product. Assure that patient has received, read and understood possible serious side effects described in the Medication Guide for olanzapine extended release injection.
DISCUSSION: In a study in 10 male smokers with schizophrenia, pretreatment with fluvoxamine (100 mg daily for 10 days) increased olanzapine area-under-curve (AUC), maximum concentration (Cmax), and half-life by 30-50%, 12-64%, and by 25-32%, respectively. Olanzapine volume of distribution and clearance were decreased by 4-26% and 26-38%, respectively.(1) In a study in 8 schizophrenic patients, the addition of fluvoxamine (100 mg daily) to olanzapine (10-20 mg daily) increased olanzapine levels from 12-112%. N-desmethylolanzapine levels were not significantly affected.(2) In a retrospective review, 10 patients receiving concurrent fluvoxamine and olanzapine were compared to 134 patients receiving olanzapine alone. The ratio of olanzapine concentration/daily dose was 2.3-fold higher in patients receiving concurrent fluvoxamine.(3) Fluvoxamine has been shown to increase olanzapine Cmax and AUC by 54% and by 52%, respectively, in female nonsmokers. Fluvoxamine has been shown to increase olanzapine Cmax and AUC by 77% and by 108%, respectively, in male smokers.(4,5) Selected Strong CYP1A2 inhibitors linked include: ciprofloxacin, enasidenib, enoxacin, fluvoxamine, and rofecoxib.(6,7)
Strong Cyp1a2 Inhibitors/Clozapine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: The metabolism of clozapine may be inhibited by CYP1A2 inhibitors.(1)
CLINICAL EFFECTS: The concurrent administration of clozapine with strong CYP1A2 inhibitors may result in elevated levels of clozapine and an increase in clozapine related side effects such as orthostatic hypotension, syncope, QT prolongation, profound sedation and seizures. This interaction may be noted with even low doses of CYP1A2 inhibitors and the onset of this interaction may be rapid.(1-7)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(8) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(8) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(9)
PATIENT MANAGEMENT: The manufacturer recommends reducing the clozapine dose to one-third the original dose with concurrent strong CYP1A2 inhibitors. Close monitoring is required to prevent clozapine toxicity. Clozapine levels should be monitored in patients receiving concurrent therapy with strong CYP1A2 inhibitors. Patients should be monitored for adverse clozapine effects and QT prolongation.(1) If concurrent therapy is warranted in patients receiving clozapine, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. When the strong CYP1A2 inhibitor is discontinued, the clozapine dose should be increased based on clinical response. Serum clozapine measurements may be useful.
DISCUSSION: Several case reports have documented increased levels of clozapine when fluvoxamine was added to therapy.(2-5) The increases in clozapine levels ranged from 231% to 780%. Several case reports describe increased clozapine-related side effects following the addition of fluvoxamine to clozapine therapy.(3,6-7) In a study in 16 subjects(1,10), the addition of fluvoxamine to patients receiving clozapine resulted in 3-fold increases in clozapine, N-desmethylclozapine, and clozapine N-oxide. The half-life of clozapine increased from 17 hours to 50 hours. Another study (11) compared patients receiving clozapine monotherapy to patients receiving concurrent therapy with clozapine and fluvoxamine and found that the dose-normalized clozapine concentration increased by a factor of 5-10 when fluvoxamine was added. Strong CYP1A2 inhibitors linked include: enasidenib and fluvoxamine.(13)
Strong Cyp1a2 Inhibitors/Melatonin
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong CYP1A2 inhibitors may significantly increase the area-under-curve (AUC) of melatonin by inhibiting CYP1A2.(1,2) Fluvoxamine, a strong CYP1A2 inhibitor, has also been shown to increase endogenous melatonin levels.
CLINICAL EFFECTS: The concurrent administration of melatonin and strong CYP1A2 inhibitors may result in significantly increased melatonin levels and subsequent side effects.(1-3)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The UK manufacturer of melatonin recommends against the concurrent use of melatonin and CYP1A2 inhibitors.(1) The Australian manufacturer of melatonin states concurrent use of melatonin and CYP1A2 inhibitors should be avoided.(2) Patients should be monitored for increased effects of melatonin when melatonin and CYP1A2 inhibitors are used concurrently.
DISCUSSION: In a study, fluvoxamine increased the area-under-curve (AUC) and concentration maximum (Cmax) of melatonin by 17-fold and 12-fold, respectively.(2) In a case report, a 51 year old female with chronic primary insomnia who received 5 mg melatonin at bedtime and 75 mg fluvoxamine in the afternoon experienced increased nocturnal sleep, from 2.5 hours (drug free) to 4.2 hours (melatonin alone) up to 5.5 hours per night (melatonin with fluvoxamine). Both melatonin and fluvoxamine alone increased melatonin levels; however administration of melatonin alone increased melatonin levels more than fluvoxamine alone. Concurrent use of melatonin and fluvoxamine increased melatonin levels 20-fold when compared to the administration of melatonin alone.(3) In a study involving five males, 5 mg of melatonin daily was given for one week, then 50 mg of fluvoxamine was added (administered three hours apart. The AUC of melatonin increased at least nine-fold (p<0.05). The Cmax increased at least six-fold in melatonin (p<0.01), versus the Cmax in patients who received melatonin alone.(4) Strong CYP1A2 inhibitors include: enasidenib, fluvoxamine, and viloxazine.(5)
Strong Cyp1a2 Inhibitors/Pirfenidone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Pirfenidone is primarily metabolized by CYP1A2 which is responsible for about 50% of its conversion to inactive drug. CYP2C9, 2C19, 2D6 and 2E1 are additional minor contributors to pirfenidone metabolism.(1,2) Strong inhibitors of CYP1A2 may inhibit the metabolism of pirfenidone.(1,2) Fluvoxamine is a strong inhibitor of CYP1A2 and CYP2C19, and a weak inhibitor of CYP2C9 and so inhibits both primary and secondary pirfenidone metabolic pathways.(3,4)
CLINICAL EFFECTS: Concurrent pirfenidone use with strong inhibitors of CYP1A2 may lead to increased systemic concentrations and toxicity from pirfenidone, including serious liver injury.(1,2)
PREDISPOSING FACTORS: A greater risk of adverse events may result from concomitant treatment with fluvoxamine, which also inhibits CYP2C19, or with strong or moderate inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), CYP2C19 (e.g. fluconazole, fluoxetine, ticlopidine) and CYP2D6 (e.g. fluoxetine, paroxetine). The magnitude of this interaction may be reduced in cigarette smokers. Cigarette smoking induces production of CYP1A2 and, in the absence of a CYP1A2 inhibitor, leads to decreased systemic concentrations of pirfenidone.(1)
PATIENT MANAGEMENT: The US manufacturer of pirfenidone states that concurrent use with strong inhibitors of CYP1A2 is not recommended. Use of strong CYP1A2 inhibitors should be discontinued prior to administration of pirfenidone and avoided during treatment with pirfenidone. Combinations of strong or moderate CYP1A2 inhibitors with strong or moderate CYP2C9, CYP2C19, and/or CYP2D6 inhibitors should also be discontinued prior to and avoided during pirfenidone treatment. If concurrent therapy of pirfenidone and strong CYP1A2 inhibitors cannot be avoided, reduce pirfenidone to one-267 mg capsule three times a day (total daily dose of 801 mg/day).(2) The Canadian(1) and Indian(5) manufacturers of pirfenidone states that fluvoxamine is contraindicated with pirfenidone and fluvoxamine should be discontinued prior to initiation of pirfenidone therapy. The concurrent use of pirfenidone and other strong or moderate CYP1A2 inhibitors should be used with caution.
DISCUSSION: Pirfenidone is converted to inactive metabolites prior to elimination. CYP1A2 is responsible for approximately half of this metabolism. In an interaction study conducted in non-smokers and smokers, coadministration of pirfenidone with fluvoxamine (a strong CYP1A2 inhibitor), an agent which inhibits multiple pirfenidone elimination pathways (CYP1A2, CYP2C9, CYP2C19), led to an approximately 4-fold and 7-fold, respectively, increase in pirfenidone exposure.(2) Strong CYP1A2 inhibitors include: angelica root (angelica dahurica radix), enasidenib, enoxacin, fluvoxamine, and rofecoxib.(4)
Strong Cyp1a2 Inhibitors/Pomalidomide
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Pomalidomide is primarily metabolized by CYP1A2, which accounts for approximately 50% of pomalidomide hepatic clearance respectively.(1)
CLINICAL EFFECTS: Concurrent use of strong CYP1A2 inhibitors may result in elevated levels of and toxicity from pomalidomide.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of pomalidomide states strong inhibitors of CYP1A2 should be avoided. Reduce the dose of pomalidomide to 2 mg if a strong CYP1A2 inhibitor must be administered concomitantly with pomalidomide. Closely monitor patients for hematologic and other toxicities and adjust pomalidomide dose accordingly.(2)
DISCUSSION: In a study in healthy volunteers, coadministration of fluvoxamine and pomalidomide resulted in an increase in pomalidomide's maximum concentration (Cmax) and area-under-the-curve (AUC) by 24% and 125% respectively.(2) In a study in healthy volunteers, coadministration of ketoconazole and fluvoxamine with pomalidomide resulted in an increase in pomalidomide's AUC by 146%.(2) Strong CYP1A2 inhibitors include angelica root, enasidenib, enoxacin, fluvoxamine, and rofecoxib.(3,4)
Weak Cyp2c19 Inhibitors/Mavacamten
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Weak CYP2C19 inhibitors may inhibit the metabolism of mavacamten.(1-3)
CLINICAL EFFECTS: Concurrent use of weak CYP2C19 inhibitors increases plasma exposure of mavacamten which may increase the incidence and severity of adverse reactions of mavacamten.(1-3)
PREDISPOSING FACTORS: CYP2C19 rapid and ultrarapid metabolizers may experience an increased incidence or severity of adverse effects.(1-3)
PATIENT MANAGEMENT: The US manufacturer of mavacamten recommends to initiate mavacamten at the recommended starting dosage in patients who are on stable therapy with a weak CYP2C19 inhibitor. Reduce dose by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients who are on mavacamten treatment and intend to initiate a weak CYP2C19 inhibitor. Schedule clinical and an echocardiographic assessment 4 weeks after inhibitor initiation, and do not up-titrate mavacamten until 12 weeks after inhibitor initiation.(1) Avoid initiation of concomitant weak CYP2C19 inhibitors in patients who are on stable treatment with the lowest recommended dose of mavacamten because a lower dose is not available.(1) For short-term use (e.g. 1 week), interrupt mavacamten therapy for the duration of the weak CYP2C19 inhibitor. After therapy with the weak CYP2C19 inhibitor is discontinued, mavacamten may be reinitiated at the previous dose immediately upon discontinuation.(1) The Canadian manufacturer of mavacamten recommends additional monitoring when concurrent use of weak CYP2C19 inhibitors is warranted. Adjust the dose of mavacamten based on clinical assessment.(2) The UK manufacturer of mavacamten states no dose adjustment is necessary with weak CYP2C19 inhibitors. Monitor left ventricular ejection fraction (LVEF) in 4 weeks then resume usual monitoring schedule.(3)
DISCUSSION: Concomitant use of mavacamten (15 mg) with omeprazole (20 mg), a weak CYP2C19 inhibitor, once daily increased mavacamten area-under-curve (AUC) by 48% with no effect on maximum concentration (Cmax) in healthy CYP2C19 normal metabolizers and rapid metabolizers.(1) Weak CYP2C19 inhibitors include: armodafinil, cimetidine, enasidenib, eslicarbazepine, felbamate, givosiran, isoniazid, obeticholic acid, osilodrostat, piperine, rucaparib, tecovirimat.(4,5)
Moderate Interaction: Assess the risk to the patient and take action as needed.
Enasidenib/Bcrp, Oatp1b1, And Oatp1b3 Substrates
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Enasidenib is an inhibitor of the BCRP, OATP1B1, and OATP1B3 transporters and may increase the absorption and/or decrease the elimination of drugs that are substrates of these transporters.(1)
CLINICAL EFFECTS: Concurrent use of enasidenib with drugs that are substrates of the BCRP, OATP1B1, and OATP1B3 transporters may result in increased frequency and severity of toxicity of the substrate.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The dose of the BCRP, OATP1B1, and OATP1B3 substrate should be reduced as recommended in the substrate prescribing information and as clinically indicated.(1)
DISCUSSION: In a study, enasidenib 100 mg daily increased the maximum concentration (Cmax) and area-under-curve (AUC) of rosuvastatin 10 mg by 366% and 244%, respectively.(1) Substrates of BCRP, OATP1B1, and OATP1B3 that are linked to this monograph include: atorvastatin, glecaprevir, pibrentasvir, simvastatin, velpatasvir, and voxilaprevir.(1,2)
Enasidenib/Rosuvastatin (<= 10 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Enasidenib is an inhibitor of the BCRP and OATP1B1 transporters and may increase the absorption and/or decrease the elimination of rosuvastatin.(1,3)
CLINICAL EFFECTS: Concurrent use of enasidenib may result in increased levels and side effects from rosuvastatin, including rhabdomyolysis.(1)
PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy.
PATIENT MANAGEMENT: The US manufacturer of rosuvastatin states that the dose of rosuvastatin should not exceed 10 mg daily when used concurrently with enasidenib. Monitor patients closely for signs and symptoms of toxicity from increased rosuvastatin concentrations.(1) The Australian manufacturer of rosuvastatin states that the starting dose of rosuvastatin should not exceed 5 mg daily when used with enasidenib.(2)
DISCUSSION: In a study, enasidenib 100 mg daily increased the maximum concentration (Cmax) and area-under-curve (AUC) of rosuvastatin 10 mg by 3.7-fold and 3.4-fold, respectively.(1-2)
Moderate And Weak Cyp3a4 Inducers/Tacrolimus
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate or weak CYP3A4 inducers may accelerate the metabolism of tacrolimus.(1)
CLINICAL EFFECTS: Concurrent use of a moderate or weak CYP3A4 inducer may result in decreased levels and effectiveness of tacrolimus.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of tacrolimus recommends monitoring tacrolimus whole blood trough concentrations and adjusting tacrolimus dose if needed. Monitor clinical response closely.(1)
DISCUSSION: A 13-year-old cystic fibrosis patient with a history of liver transplant on stable doses of tacrolimus underwent 2 separate courses of nafcillin therapy (a moderate CYP3A4 inducer). During the 1st course of nafcillin, his tacrolimus levels started to fall 3 days after starting nafcillin, became undetectable at day 8, and recovered to therapeutic levels without a change in tacrolimus dose 5 days after discontinuation of nafcillin. During the 2nd course of nafcillin, tacrolimus level became undetectable 4 days after starting nafcillin and recovered 3 days after stopping nafcillin.(2) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, modafinil, nafcillin, repotrectinib, telotristat, and tovorafenib.(3,4) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, meropenem-vaborbactam, nevirapine, oritavancin, omaveloxolone, oxcarbazepine, pioglitazone, relugolix, rufinamide, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vinblastine, and zanubrutinib.(3,4)
Oatp1b1-3 Inhibitors/Momelotinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: OATP1B1 and 1B3 inhibitors may decrease the hepatic uptake of momelotinib.(1)
CLINICAL EFFECTS: Concurrent use of OATP1B1 and 1B3 inhibitors may result in elevated levels of and side effects from momelotinib, including myelosuppression and hepatotoxicity.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Concurrent use of momelotinib with OATP1B1 and 1B3 inhibitors should be approached with caution. Monitor patients closely for adverse reactions and consider dose modifications per momelotinib prescribing recommendations.(1)
DISCUSSION: Concurrent administration of a single dose rifampin, an OATP1B1/1B3 inhibitor, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of momelotinib by 40% and 57%, respectively. The M21 metabolite Cmax increased 6% and AUC increased 12%.(1) OATP1B1 inhibitors include: atazanavir, belumosudil, boceprevir, cobicistat, cyclosporine, darolutamide, darunavir, eltrombopag, enasidenib, encorafenib, erythromycin, fostemsavir, gemfibrozil, glecaprevir-pibrentasvir, ledipasvir, letermovir, lopinavir, nirmatrelvir, paritaprevir, resmetirom, rifampin, roxadustat, saquinavir, simeprevir, telaprevir, tipranavir, vadadustat, velpatasvir, and voclosporin.(1,2)
Select Oatp1b1-3 Inhibitors/Letermovir
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: OATP1B1 and 1B3 inhibitors may decrease the hepatocyte uptake and increase the plasma concentration of letermovir.(1)
CLINICAL EFFECTS: Concurrent use of OATP1B1 and 1B3 inhibitors may result in elevated levels of and side effects from letermovir, including diarrhea, nausea, abdominal pain, and peripheral edema.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Concurrent use of letermovir with OATP1B1 and 1B3 inhibitors should be approached with caution. Monitor patients closely for adverse reactions and consider dose modifications per prescribing recommendations.(1)
DISCUSSION: Letermovir is a substrate of OATP1B1 and 1B3. Co-administration of letermovir with drugs that are inhibitors of OATP1B1 and 1B3 transporters may result in increases in letermovir plasma concentrations.(1) OAT1B1 and 1B3 inhibitors include: belumosudil, enasidenib, glecaprevir/pibrentasvir, paritaprevir, and vadadustat.(2-6)
Selected Cyp1a2 Inhibitors/Rasagiline (<= 0.5 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of rasagiline.(1)
CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from rasagiline.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of rasagiline states that patients receiving concurrent therapy with an inhibitor of CYP1A2 should receive no more than 0.5 mg of rasagiline daily.(1) Concurrent therapy with vemurafenib may require extended monitoring for interaction onset and severity because steady-state levels of vemurafenib are not attained for approximately 15 days.(2)
DISCUSSION: In a study in 12 healthy subjects, ciprofloxacin (500 mg twice daily) increased the area-under-curve (AUC) of rasagiline (2 mg twice daily) by 83%.(1) Strong CYP1A2 inhibitors linked to this monograph include: angelica root, ciprofloxacin, enasidenib, enoxacin, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include: capmatinib, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, and vemurafenib.(3-5)
Selected Cyp1a2 Inhibitors/Theophylline Derivatives
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: CYP1A2 inhibitors may reduce the elimination rate of theophylline derivatives.
CLINICAL EFFECTS: The concurrent administration of selected CYP1A2 inhibitors and theophylline or their derivatives may result in increased levels and toxicity of theophylline.(1-19)
PREDISPOSING FACTORS: Concomitant therapy with inhibitors of CYP3A4 (e.g. clarithromycin, itraconazole, ritonavir) which block a secondary metabolic pathway for theophylline, may increase the magnitude of this interaction.
PATIENT MANAGEMENT: Theophylline levels should be closely monitored in patients receiving concurrent therapy. The dosage of theophylline may need to be decreased after a CYP1A2 inhibitor is initiated. If the CYP1A2 inhibitor is discontinued in a patient stabilized on the combination, the theophylline level may fall. Monitor theophylline levels and adjust dose accordingly.
DISCUSSION: A study in 5 patients with active hepatitis B and 4 healthy subjects examined the effects of a single dose of interferon alpha (9 million units in 8 subjects, 18 million units in 1 subject). There was no effect on theophylline in 1 subject. In the other 8 subjects, interferon increased theophylline half-life by 70% and decreased theophylline clearance by 49% (range 33% to 81%).(1) A study in 11 healthy subjects examined the effects of interferon alpha (3 million International Units daily for 3 days) on a single aminophylline (4 mg/kg) infusion. Interferon increased the half-life, area-under-curve (AUC), and mean residence time by 13.7%, 17.9%, and 16.3%, respectively. Theophylline clearance decreased by 9.1%.(2) In a study in healthy males, peginterferon alfa-2a (180 mcg once weekly for 4 weeks) increased theophylline AUC by 25%.(3,4) Concurrent interferon alfa has been shown to increase theophylline levels by 100%.(5) A study in 7 patients with chronic hepatitis C examined the effects of interferon beta (3 million to 9 million International Units daily for 8 weeks) on theophylline ethylenediamine (single 250 mg infusion). Interferon decreased theophylline clearance by 26.3% and increased theophylline half-life by 39.3%. There was no correlation between interferon dose and effect. The greatest effect was seen in a patient who received 3 million International Units daily, while no effect was seen in a patient who received 9 million International Units daily.(6) Increased serum theophylline levels with signs and symptoms of theophylline toxicity have been reported in patients following the addition of mexiletine to their treatment.(7-15) In a study evaluated the combination of disulfiram and theophylline in 20 recovering alcoholics. Patients received a single IV dose of theophylline while being given either 250 mg or 500 mg of disulfiram daily. Both dosages of disulfiram decreased the clearance of theophylline. However, the effect was greatest in patients receiving disulfiram 500 mg daily.(16) Increases in serum theophylline concentration and half-life have been reported during concurrent administration of theophylline and ticlopidine.(17) In healthy subjects, rofecoxib (12.5 mg/day, 25 mg/day, or 50 mg/day for seven days) increased the area-under-curve (AUC) of a single dose of theophylline (300 mg) by 38% to 60%. Therefore, the manufacturer of rofecoxib recommends that theophylline levels be monitored if rofecoxib is initiated or changed in patients receiving theophylline.(18) Selected CYP1A2 inhibitors linked to this monograph include: acyclovir, Angelica dahurica, artemisinin, belumosudil, centanafadine, cannabidiol, curcumin, danshen, dipyrone, disulfiram, echinacea, enasidenib, fexinidazole, genistein, ginseng, interferons, methoxsalen, mexiletine, parsley, phenylpropanolamine, pipemidic acid, piperine, propafenone, ribociclib, rofecoxib, rucaparib, simeprevir, ticlopidine, triclabendazole, valacyclovir, and verapamil.(19)
Selected Cyp2c19 Inhibitors/Citalopram (<= 20 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Citalopram is primarily metabolized by the CYP2C19 isoenzyme.(1)
CLINICAL EFFECTS: Concurrent use of an agent that inhibits CYP2C19 may result in elevated levels of and toxicity from citalopram, including including risks for serotonin syndrome or prolongation of the QTc interval.(1-5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(5)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age, poor metabolizer status at CYP2C19, or higher blood concentrations of citalopram.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,5) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
PATIENT MANAGEMENT: The dose of citalopram should be limited to 20 mg in patients receiving concurrent therapy with an inhibitor of CYP2C19.(1,4) Evaluate the patient for other drugs, diseases and conditions which increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, hypocalcemia, hypomagnesemia, discontinue other QT prolonging drugs) when possible.(1,2) Weigh the specific benefits versus risks for each patient. The US manufacturer recommends ECG monitoring for citalopram patients with congestive heart failure, bradyarrhythmias, taking concomitant QT prolonging medications or receiving concurrent therapy.(4) Citalopram should be discontinued in patients with persistent QTc measurements greater than 500 ms.(2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.
DISCUSSION: Concurrent use of citalopram (40 mg daily) and cimetidine (400 mg twice daily) for 8 days increased the maximum concentration (Cmax) and area-under-curve (AUC) of citalopram by 39% and 43%, respectively.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), armodafinil, asciminib, berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, elagolix, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, treosulfan, and vonoprazan.(7,8)
Selected Cyp2c19 Inhibitors/Escitalopram (<= 15 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: At lower systemic concentrations, escitalopram is primarily metabolized by CYP2C19; at higher concentrations is also metabolized by CYP3A4.(1)
CLINICAL EFFECTS: Concurrent use of an agent which significantly inhibits CYP2C19, or which inhibits both CYP2C19 and CYP3A4 may result in elevated concentrations and toxicity from escitalopram, including risks for serotonin syndrome or prolongation of the QTc interval.(1,5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)
PREDISPOSING FACTORS: The risk of QT prolongation may be increased in patients with congenital long QT syndrome, cardiovascular disease (e.g. heart failure, myocardial infarction), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female sex, advanced age, poor metabolizer status at CYP2C19, concurrent use of more than one agent known to cause QT prolongation, or with higher blood concentrations of escitalopram.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,3) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
PATIENT MANAGEMENT: Evaluate patient for other drugs, diseases and conditions which may further increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, discontinue other QT prolonging drugs) when possible.(2,3) It would be prudent to limit the escitalopram dose to 10 mg daily in patients with QT prolonging risk factors who also receive concurrent therapy with selected CYP2C19 inhibitors.(5) Weigh the specific benefits versus risks for each patient. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.
DISCUSSION: A thorough QT study evaluating escitalopram 10 mg or 30 mg once daily was conducted; a change of 10 msec for upper bound of the 95% confidence level is the threshold for regulatory concern. In this study, changes to the upper bound of the 95% confidence interval were 6.4 msec and 12.6 msec for the 10 mg and supratherapeutic 30 mg dose respectively. The Cmax for 30 mg was 1.7-fold higher than the Cmax for the maximum recommended escitalopram dose of 20 mg. Systemic exposure at the 30 mg dose was similar to expected steady state concentrations in 2C19 poor metabolizers following a 20 mg escitalopram dose.(1) In an interaction study, 30 mg of omeprazole, an irreversible inhibitor of CYP2C19 was administered daily for 6 days. On day 5 a single dose of escitalopram 20 mg was also administered; the area-under-curve (AUC) of escitalopram was increased by 50%. Manufacturer prescribing information recommends a maximum citalopram dose of 20mg daily in patients receiving CYP2C19 inhibitors.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), armodafinil, asciminib, berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, elagolix, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, treosulfan, and vonoprazan.(4)
Selected Cyp2c19 Inhibitors/Escitalopram (> 15 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: At lower systemic concentrations, escitalopram is primarily metabolized by CYP2C19; at higher concentrations is also metabolized by CYP3A4.(1)
CLINICAL EFFECTS: Concurrent use of an agent which significantly inhibits CYP2C19, or which inhibits both CYP2C19 and CYP3A4 may result in elevated concentrations and toxicity from escitalopram, including risks for serotonin syndrome or prolongation of the QTc interval.(1,5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)
PREDISPOSING FACTORS: The risk of QT prolongation may be increased in patients with congenital long QT syndrome, cardiovascular disease (e.g. heart failure, myocardial infarction), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female sex, advanced age, poor metabolizer status at CYP2C19, concurrent use of more than one agent known to cause QT prolongation, or with higher blood concentrations of escitalopram.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,3) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
PATIENT MANAGEMENT: Evaluate patient for other drugs, diseases and conditions which may further increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, discontinue other QT prolonging drugs) when possible.(2,3) It would be prudent to limit the escitalopram dose to 10 mg daily in patients with QT prolonging risk factors who also receive concurrent therapy with selected CYP2C19 inhibitors.(5) Weigh the specific benefits versus risks for each patient. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.
DISCUSSION: A thorough QT study evaluating escitalopram 10 mg or 30 mg once daily was conducted; a change of 10 msec for upper bound of the 95% confidence level is the threshold for regulatory concern. In this study, changes to the upper bound of the 95% confidence interval were 6.4 msec and 12.6 msec for the 10 mg and supratherapeutic 30 mg dose respectively. The Cmax for 30 mg was 1.7-fold higher than the Cmax for the maximum recommended escitalopram dose of 20 mg. Systemic exposure at the 30 mg dose was similar to expected steady state concentrations in 2C19 poor metabolizers following a 20 mg escitalopram dose.(1) In an interaction study, 30 mg of omeprazole, an irreversible inhibitor of CYP2C19 was administered daily for 6 days. On day 5 a single dose of escitalopram 20 mg was also administered; the area-under-curve (AUC) of escitalopram was increased by 50%. Manufacturer prescribing information recommends a maximum citalopram dose of 20mg daily in patients receiving CYP2C19 inhibitors.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), armodafinil, asciminib, berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, elagolix, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, treosulfan, and vonoprazan.(4)
Selected Moderate-Weak Cyp3a4 Inducers/Exemestane
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: CYP3A4 inducers may induce the metabolism of exemestane.(1)
CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in decreased levels and effectiveness of exemestane.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US manufacturer of exemestane recommends that patients receiving concurrent therapy with a strong CYP3A4 inducer receive 50 mg of exemestane daily after a meal.(1) It may be prudent to consider a dosage increase for patients receiving weaker CYP3A4 inducers.
DISCUSSION: In a study in 10 healthy postmenopausal subjects, pretreatment with rifampin (a strong CYP3A4 inducer, 600 mg daily for 14 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of exemestane (25 mg) by 54% and 41%, respectively.(1) Strong inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 80% or more and include: carbamazepine, enzalutamide, mitotane, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort.(1-3) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine, floxacillin, garlic, gingko, ginseng, glycyrrhizin, lorlatinib, meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)
Selected Strong Cyp1a2 Inhibitors/Olanzapine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP1A2 inhibitors may inhibit the metabolism of olanzapine by CYP1A2.(1-5)
CLINICAL EFFECTS: Concurrent use of strong CYP1A2 inhibitors may result in elevated levels of and toxicity from olanzapine.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for olanzapine side effects. The dose of olanzapine may need to be adjusted if a strong CYP1A2 inhibitor is initiated or discontinued.
DISCUSSION: In a study in 10 male smokers with schizophrenia, pretreatment with fluvoxamine (100 mg daily for 10 days) increased olanzapine area-under-curve (AUC), maximum concentration (Cmax), and half-life by 30-50%, 12-64%, and by 25-32%, respectively. Olanzapine volume of distribution and clearance were decreased by 4-26% and 26-38%, respectively.(1) In a study in 8 schizophrenic patients, the addition of fluvoxamine (100 mg daily) to olanzapine (10-20 mg daily) increased olanzapine levels from 12-112%. N-desmethylolanzapine levels were not significantly affected.(2) In a retrospective review, 10 patients receiving concurrent fluvoxamine and olanzapine were compared to 134 patients receiving olanzapine alone. The ratio of olanzapine concentration/daily dose was 2.3-fold higher in patients receiving concurrent fluvoxamine.(3) Fluvoxamine has been shown to increase olanzapine Cmax and AUC by 54% and by 52%, respectively, in female nonsmokers. Fluvoxamine has been shown to increase olanzapine Cmax and AUC by 77% and by 108%, respectively, in male smokers.(4,5) Strong CYP1A2 inhibitors linked include: enasidenib, enoxacin, fluvoxamine, and rofecoxib.(6)
Selected Weak Cyp2d6 Inhibitors/Tamoxifen
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Inhibitors of CYP2D6 may inhibit the conversion of tamoxifen to endoxifen (an active metabolite of tamoxifen).(1-2) The role of endoxifen in tamoxifen's efficacy has been debated and may involve a minimum concentration level.(3-5)
CLINICAL EFFECTS: Concurrent use of inhibitors of CYP2D6 may decrease the effectiveness of tamoxifen in preventing breast cancer recurrence.
PREDISPOSING FACTORS: Concurrent use of weak CYP2D6 inhibitors in patients who are CYP2D6 intermediate metabolizers should be avoided. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.
PATIENT MANAGEMENT: Although data on this interaction are conflicting, it may be prudent to use alternatives to CYP2D6 inhibitors when possible in patients taking tamoxifen. The US manufacturer of tamoxifen states that the impact on the efficacy of tamoxifen by strong CYP2D6 inhibitors is uncertain and makes no recommendation regarding coadministration with inhibitors of CYP2D6.(12) The manufacturer of paroxetine (a strong CYP2D6 inhibitor) states that alternative agents with little or no CYP2D6 inhibition should be considered.(13) The National Comprehensive Cancer Network's breast cancer guidelines advises caution when coadministering strong CYP2D6 inhibitors with tamoxifen.(14) NCCN states when prescribing a selective serotonin reuptake inhibitor (SSRI), it is reasonable to avoid SSRIs that are strong and moderate CYP2D6 inhibitors, particularly fluoxetine and paroxetine, if an appropriate alternative exists.(14) Cancer Care Ontario breast cancer guidelines state concurrent use of weak CYP2D6 inhibitors should be closely monitored.(15) The European Society of Medical Oncology (ESMO) clinical practice guidelines for early breast cancer states patients on tamoxifen should be advised to avoid concurrent use of strong and moderate CYP2D6 inhibitors. Consider alternatives to tamoxifen if CYP2D6 inhibitors cannot be replaced with alternative agents.(16) If concurrent therapy is warranted, the risks versus benefits should be discussed with the patient.
DISCUSSION: Some studies have suggested that administration of fluoxetine, paroxetine, and quinidine with tamoxifen or a CYP2D6 poor metabolizer phenotype may result in a decrease in the formation of endoxifen (an active metabolite of tamoxifen) and a shorter time to breast cancer recurrence.(1-2,9) A retrospective study of 630 breast cancer patients found an increasing risk of breast cancer mortality with increasing durations of coadministration of tamoxifen and paroxetine. In the adjusted analysis, absolute increases of 25%, 50%, and 75% in the proportion of time of overlapping use of tamoxifen with paroxetine was associated with 24%, 54%, and 91% increase in the risk of death from breast cancer, respectively.(18) The CYP2D6 genotype of the patient may have a role in the effects of this interaction. Patients with wild-type CYP2D6 genotype may be affected to a greater extent by this interaction. Patients with a variant CYP2D6 genotype may have lower baseline levels of endoxifen and may be affected to a lesser extent by this interaction.(6-10) In a retrospective review, 1,325 patients treated with tamoxifen for breast cancer were classified as being poor 2D6 metabolizers (lacking functional CYP2D6 enzymes), intermediate metabolizers (heterozygous alleles), or extensive metabolizers (possessing 2 functional alleles). After a mean follow-up period of 6.3 years, the recurrence rates were 14.9%, 20.9%, and 29.0%, in extensive metabolizers, intermediate metabolizers, and poor metabolizers, respectively.(11) In October of 2006, the Advisory Committee Pharmaceutical Science, Clinical Pharmacology Subcommittee of the US Food and Drug Administration recommended that the US tamoxifen labeling be updated to include information about the increased risk of breast cancer recurrence in poor CYP2D6 metabolizers (either by genotype or drug interaction).(19-20) The labeling changes were never made due to ongoing uncertainty about the effects of CYP2D6 genotypes on tamoxifen efficacy. In contrast to the above information, two studies have shown no relationship between CYP2D6 genotype and breast cancer outcome.(21-23) As well, a number of studies found no association between use of CYP2D6 inhibitors and/or antidepressants in patients on tamoxifen and breast cancer recurrence,(24-28) though the studies were limited by problematic selection of CYP2D6 inhibitors and short follow-up. Weak inhibitors of CYP2D6 include: alogliptin, artesunate, celecoxib, chloroquine, cimetidine, clobazam, clomipramine, cobicistat, delavirdine, diltiazem, dimenhydrinate, diphenhydramine, dronabinol, dupilumab, echinacea, enasidenib, fedratinib, felodipine, fluvoxamine, gefitinib, hydralazine, imatinib, labetalol, lorcaserin, nicardipine, osilodrostat, ranitidine, ritonavir, sarpogrelate, sertraline, verapamil and viloxazine.(29)
Strong And Moderate Cyp1a2 Inhibitors/Ropinirole
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Ropinirole is a CYP1A2 substrate. Strong and moderate CYP1A2 inhibitors may decrease the metabolism of ropinirole.(1-3)
CLINICAL EFFECTS: The concurrent administration of strong or moderate CYP1A2 inhibitors and ropinirole may result in elevated levels of ropinirole, increased clinical effects, and signs of toxicity.(1-3)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: In patients receiving strong or moderate CYP1A2 inhibitors who are started on ropinirole, ropinirole may be titrated to effect according to the manufacturer's dosage instructions. If the strong or moderate CYP1A2 inhibitor is started or discontinued in a patient receiving ropinirole, the dosage of ropinirole may need to be adjusted.(1-2)
DISCUSSION: In a study in 12 subjects, the concurrent administration of ropinirole with ciprofloxacin resulted in increases in the maximum concentration (Cmax) and area-under-curve (AUC) of ropinirole by 84% and 60%, respectively. The major pathway for ropinirole metabolism has been shown to be CYP1A2.(1-3) Strong CYP1A2 inhibitors linked to this monograph include: Angelica dahurica, enasidenib, enoxacin, and fluvoxamine. Moderate CYP1A2 inhibitors linked to this monograph include: capmatinib, centanafadine, ciprofloxacin, dipyrone, fexinidazole, genistein, estrogen-containing contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine.(4)
Strong Cyp1a2 Inhibitors/Bromazepam
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP1A2 inhibitors may decrease the metabolism of bromazepam.(1)
CLINICAL EFFECTS: The concurrent administration of bromazepam with strong CYP1A2 inhibitors may result in elevated levels of bromazepam, which may result in increased adverse effects including profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Patients receiving concurrent therapy with bromazepam and strong CYP1A2 inhibitors should be monitored for increased benzodiazepine effects. If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. The dosage of the bromazepam may need to be decreased. Bromazepam may need to be discontinued.(2) Counsel patient to report excess drowsiness, confusion, memory problems including sleep-driving behaviors, loss of coordination, unusual dizziness of lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Benzodiazepines that do not undergo extensive Phase I metabolism (lorazepam, oxazepam) may be an alternative in patients receiving a strong CYP1A2 inhibitor.
DISCUSSION: Fluvoxamine, a strong CYP1A2 inhibitor, increased bromazepam area-under-curve (AUC) by 2.4-fold and half life by 1.9-fold.(1-3) Strong CYP1A2 inhibitors linked to this monograph include: angelica root, enasidenib, enoxacin, fluvoxamine, and rofecoxib. (4)
Strong Cyp1a2 Inhibitors/Diazoxide
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of diazoxide.(1)
CLINICAL EFFECTS: Concurrent use of inhibitors of CYP1A2 may result in elevated levels of and toxicity from diazoxide including hyperglycemia and fluid retention.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer recommends a dose reduction of diazoxide when use concomitantly with strong CYP1A2 inhibitors.(1) -For patients weighing 20 kg to < 30 kg: Give 25 mg for four weeks, then increase by 25 mg every two weeks for a target maintenance dose of 75 mg -For patients weighing 30 kg to <40 kg: Give 50 mg for two weeks, then increase to a target maintenance dose of 100 mg -For patients weighing 40 kg to <65 kg: Give 50 mg for two weeks, then increase by 50 mg every two weeks for a target maintenance dose of 150 mg -For patients weighing 65 kg to <100 kg: Give 100 mg for two weeks, then increase by 50 mg every two weeks for a target maintenance dose of 250 mg -For patients weighing 100 kg to <135 kg: Give 100 mg for weeks 1 and 2, increase to 200 mg for weeks 3 and 4, increase to 300 mg for weeks 5 and 6, then increase to a target maintenance dose of 325 mg
DISCUSSION: In a clinical study with fluvoxamine (a strong CYP1A2 inhibitor), fluvoxamine increased single dose diazoxide maximum concentration (Cmax) by 17.5% and area-under-curve (AUC) by 60% compared to the same parameter measured on single dose in the absence of fluvoxamine co-administration.(1) Strong CYP1A2 inhibitors linked to this monograph include: angelica root, enasidenib, enoxacin, fluvoxamine, and rofecoxib.(2,3)
Strong Cyp1a2 Inhibitors/Lidocaine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP1A2 inhibitors may inhibit the metabolism of lidocaine by CYP1A2.(1-4)
CLINICAL EFFECTS: Concurrent or recent use of strong CYP1A2 inhibitors may result in increased effects of lidocaine.(1-4)
PREDISPOSING FACTORS: This interaction may be more severe in patients taking strong CYP3A4 inhibitors.(2,3) The interaction may be less clinically significant in patients with severe liver impairment.(4)
PATIENT MANAGEMENT: Patients receiving this combination should be closely monitored for signs of lidocaine toxicity. The dosage of lidocaine should be adjusted based on serum lidocaine levels and patient response.
DISCUSSION: In a study in 8 subjects, pretreatment with fluvoxamine (100 mg daily) for 6 days increased the peak concentration (Cmax) and area-under-curve (AUC) of oral lidocaine (1 mg/kg) by 220% and 305%, respectively. Pretreatment with fluvoxamine (100 mg daily) and erythromycin (1500 mg daily) for 6 days increased lidocaine Cmax and AUC by 250% and 360%, respectively.(2) In a study in 9 subjects, pretreatment with fluvoxamine (100 mg daily) for 6 days decreased the clearance of intravenous lidocaine by 41%. Pretreatment with fluvoxamine (100 mg daily) and erythromycin (1500 mg daily) for 6 days decreased the clearance of intravenous lidocaine by 53%.(3) In a study in 10 healths subjects, 10 patients with mild (Child grade A) liver impairment, and 10 patients with severe (Child grade C) liver impairment, fluvoxamine decreased lidocaine clearance by 60% in healthy subjects and by 44% in patients with mild liver impairment. However, there was no significant effect in patients with severe liver impairment.(4) Strong CYP1A2 inhibitors linked include: angelica root, enasidenib, enoxacin, fluvoxamine, and rofecoxib.(5,6)
Strong Cyp1a2 Inhibitors/Ropivacaine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP1A2 inhibitors may inhibit the metabolism of ropivacaine.
CLINICAL EFFECTS: Concurrent use of a strong CYP1A2 inhibitor may result in increased levels of and toxicity from ropivacaine.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: In patients receiving concurrent strong CYP1A2 inhibitors and ropivacaine, monitor patients closely for signs of toxicity.
DISCUSSION: In a double-blind, randomized, cross-over study in 9 healthy subjects, ciprofloxacin (500 mg twice daily) decreased the clearance of a single dose of ropivacaine (0.6 mg/kg) by 31%.(1) In a double-blind, randomized, cross-over study in 8 healthy subjects, fluvoxamine (100 mg daily) increased the area-under-curve (AUC) of a single dose of ropivacaine (0.6 mg/kg) by 3.7-fold.(2) In a randomized, cross-over study in 12 healthy subjects, fluvoxamine (25 mg daily) increased the clearance of a single dose of ropivacaine (40 mg) by 68%. Ropivacaine half-life almost doubled.(3) Strong inhibitors of CYP1A2 include angelica root (angelica dahurica radix), enasidenib, enoxacin, fluvoxamine, and rofecoxib.(4,5)
Strong Cyp1a2 Or Cyp2d6 Inhibitors/Fenfluramine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP1A2 or CYP2D6 inhibitors may decrease the metabolism of fenfluramine.(1) Over 75% of fenfluramine is metabolized to norfenfluramine prior to elimination, primarily by CYP1A2, CYP2B6, and CYP2D6.(1)
CLINICAL EFFECTS: Concurrent use of agents that are strong CYP1A2 or CYP2D6 inhibitors may result in elevated levels of and toxicity from fenfluramine.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of fenfluramine states that the maximum daily dosage of fenfluramine with a strong CYP1A2 or CYP2D6 inhibitor in patients not on stiripentol is 20 mg. In patients on concomitant stiripentol and clobazam, the maximum fenfluramine dosage with strong CYP1A2 or CYP2D6 inhibitors is 17 mg.(1) If the strong CYP1A2 or CYP2D6 inhibitors is discontinued, consider gradually increasing the fenfluramine dosage to the usual recommended dose without the inhibitor.(1)
DISCUSSION: In a study of healthy volunteers, fluvoxamine 50 mg daily (a strong CYP1A2 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose fenfluramine 0.4 mg/kg by 102% and 22%, respectively, and decreased the AUC and Cmax of norfenfluramine by 22% and 44%, respectively.(1) In a study of healthy volunteers, paroxetine 30 mg daily (a strong CYP2D6 inhibitor) increased the AUC and Cmax of single-dose fenfluramine 0.4 mg/kg by 81% and 13%, respectively, and decreased the AUC and Cmax of norfenfluramine by 13% and 29%, respectively.(1) Strong CYP1A2 inhibitors linked to this monograph include: Angelica root, ciprofloxacin, enasidenib, vemurafenib, and viloxazine. Strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, hydroquinidine, and quinidine.(1-4)
Weak Cyp2d6 Inhibitors/Eliglustat
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Weak inhibitors of CYP2D6 may inhibit the metabolism of eliglustat. If the patient is also taking an inhibitor of CYP3A4, eliglustat metabolism can be further inhibited.(1)
CLINICAL EFFECTS: Concurrent use of an agent that is a weak inhibitor of CYP2D6 may result in elevated levels of and clinical effects of eliglustat, including prolongation of the PR, QTc, and/or QRS intervals, which may result in life-threatening cardiac arrhythmias.(1)
PREDISPOSING FACTORS: If the patient is also taking an inhibitor of CYP3A4 and/or has hepatic impairment, eliglustat metabolism can be further inhibited.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The dosage of eliglustat with weak inhibitors of CYP2D6 in poor CYP2D6 metabolizers should be limited to 84 mg daily.(1) The dosage of eliglustat with weak inhibitors of CYP2D6 in extensive CYP2D6 metabolizers with mild (Child-Pugh Class A) hepatic impairment should be limited to 84 mg daily.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Paroxetine (30 mg daily), a strong inhibitor of CYP2D6, increased eliglustat (84 mg BID) maximum concentration (Cmax) and area-under-curve (AUC) by 7-fold and 8.4-fold, respectively, in extensive metabolizers. Physiologically-based pharmacokinetic (PKPB) models suggested paroxetine would increase eliglustat Cmax and AUC by 2.1-fold and 2.3-fold, respectively, in intermediate metabolizers. PKPB models suggested ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily) by 4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1) PKPB models suggested terbinafine, a moderate inhibitor of CYP2D6, would increase eliglustat Cmax and AUC by 3.8-fold and 4.5-fold, respectively, in extensive metabolizers and by 1.6-fold and 1.6-fold, respectively in intermediate metabolizers. PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 7.5-fold and 9.8-fold, respectively.(1) PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine (a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 4.2-fold and 5-fold, respectively.(1) A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(5) Weak inhibitors of CYP2D6 include: alogliptin, artesunate, celecoxib, chloroquine, chlorpromazine, clobazam, clomipramine, desvenlafaxine, dimenhydrinate, diphenhydramine, dronabinol, dupilumab, echinacea, enasidenib, felodipine, gefitinib, hydralazine, hydroxychloroquine, lorcaserin, methadone, panobinostat, propafenone, sarpogrelate, sertraline, vemurafenib, and venlafaxine.(3,4)
Contraindications
*None.
- Lactation
- Differentiation syndrome
- Hyperbilirubinemia
- Leukocytosis
- Pregnancy
There are no moderate contraindications for this drug.
Adverse reactions
Adverse effects reported in >=20% of patients receiving enasidenib in clinical studies include nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite.
More Frequent
- Hypokalemia
- Hypophosphatemia
- Leukocytosis
Less Frequent
- Acute respiratory distress syndrome
- Pulmonary edema
- Tumor lysis syndrome
Rare or Very Rare
- Acute renal failure
- Acute respiratory failure
- Anemia
- Differentiation syndrome
- Dyspnea
- Hypoxia
- Multiple organ failure
- Neutropenic disorder
- Prolonged QT interval
- Thrombocytopenic disorder
More Frequent
- Anorexia
- Diarrhea
- Hyperbilirubinemia
- Hypocalcemia
- Nausea
- Vomiting
Less Frequent
- Dysgeusia
Rare or Very Rare
- Fatigue
- Fever
- Stomatitis
Precautions
No enhanced messaging available.
Safety and efficacy of enasidenib have not been established in pediatric patients.
Enasidenib may cause fetal harm if administered to pregnant patients based on animal findings.
Pregnancy status should be confirmed prior to initiation of enasidenib therapy. If enasidenib is used during pregnancy or if the patient or their partner becomes pregnant during therapy, the patient should be informed of the potential fetal hazard.
It is not known whether enasidenib or its metabolites are distributed into humanmilk. Because of the potential for serious adverse reactions to enasidenib in nursing infants, women should be advised to discontinue nursing during enasidenib therapy. Women may begin nursing 2 months after discontinuance of therapy. The effects of the drug on nursing infants or on the production of milk are unknown.
No dosage adjustment is necessary in geriatric patients.
In the principal efficacy study, 61% of patients receiving enasidenib were >=65 years of age and 24% were >=75 years of age. No overall differences in safety and efficacy were observed between these geriatric patients and younger adults.
In a pharmacokinetic population analysis, age (range of 19-100 years) did not have a substantial effect on the pharmacokinetics of enasidenib.
ICD codes
| Code | Type | Description |
|---|---|---|
| Acute myeloid leukemia with isocitrate dehydrogenase-2 (IDh2) mutation | ||
| C92.0 | ICD10CM | Acute myeloblastic leukemia |
| C92.00 | ICD10CM | Acute myeloblastic leukemia, not having achieved remission |
| C92.02 | ICD10CM | Acute myeloblastic leukemia, in relapse |
ICD code information from First Databank (FDB).
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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