Hypertensa (caffeine/choline bitartrate/AA no.11/herbal complex no.130)

Some clinicians suggest that when used as a mild CNS stimulant to overcome fatigue, oral doses of 100-200 mg of anhydrous caffeine are required. The manufacturers state that adults and children 12 years of age or older may receive a dosage of 100-200 mg no more frequently than every 3-4 hours.

For the treatment of apnea of prematurity, commercially available caffeine citrate injection in a loading dose of 20 mg/kg (10 mg/kg when expressed in terms of anhydrous caffeine) is administered by slow IV infusion (i.e., over 30 minutes) using a syringe infusion pump. Beginning 24 hours after the loading dose, maintenance doses of caffeine citrate of 5 mg/kg (2.5 mg/kg when expressed as anhydrous caffeine) may be administered every 24 hours, either orally or via slow IV infusion (i.e., over 10 minutes) using a syringe infusion pump. The manufacturer states that the safety and efficacy of dosing periods exceeding 10-12 days have not been established. Other dosing regimens+ for the treatment of apnea of prematurity have used caffeine doses (in terms of anhydrous caffeine) of 5-10 mg/kg, given IV, IM, or orally as a loading dose, and followed by 2.5-5 mg/kg, given IV, IM, or orally once daily. Maintenance dosage has been adjusted according to the patient's response and tolerance and plasma caffeine concentrations.

When caffeine citrate is used for the treatment of apnea of prematurity in infants with hepatic or renal impairment, serum concentrations of caffeine should be monitored and dosage adjusted to avoid toxicity.

Analeptic use of caffeine is strongly discouraged by most clinicians. However, the manufacturers of caffeine and sodium benzoate injection recommend IM, or in emergency respiratory failure, IV injection of 500 mg of the drug (about 250 mg of anhydrous caffeine) or a maximum single dose of 1 g (about 500 mg of anhydrous caffeine) for the treatment of respiratory depression associated with overdosage of CNS depressants, including opiate analgesics and alcohol, and with electric shock.

Some clinicians recommend that when caffeine and sodium benzoate injection is used in children for CNS stimulation+, an IM, IV, or subcutaneous dose of 8 mg/kg (about 4 mg of anhydrous caffeine per kg) (not to exceed 500 mg) or 250 mg/m2 (about 125 mg of anhydrous caffeine per m2) be given up to every 4 hours if necessary.

Caffeine may be administered orally. Caffeine citrate is administered orally or by slow IV infusion using a syringe infusion pump. Caffeine and sodium benzoate injection may be administered by IM or slow IV injection; the drug has also been administered subcutaneously.

The preservative-free commercially available injection is for single use only, and any unused portion should be discarded. It is important that such oral solution be measured accurately (e.g., using a 1-mL or other appropriate syringe).

No dosing information is available for this tab.

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

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)

Cyp3a4 Inducers/Lumateperone

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: Lumateperone is a substrate of CYP3A4. Inducers of CYP3A4 may induce the metabolism of lumateperone.(1)

CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inducer may decrease the exposure to lumateperone.(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 lumateperone states that concurrent use with CYP3A4 inducers should be avoided.(1)

DISCUSSION: Coadministration of lumateperone with rifampin, a strong CYP3A4 inducer, resulted in a 98% reduction in area-under-curve (AUC) and a 90% reduction in concentration maximum (Cmax).(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, repotrectinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 include: amprenavir, armodafinil, aumolertinib, bexarotene, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, garlic, genistein, gingko, ginseng, glycyrrhizin, nevirapine, omaveloxolone, oxcarbazepine, pioglitazone, quercetin, rufinamide, sotorasib, sulfinpyrazone, sunvozertinib, tecovirimat, terbinafine, ticlopidine, troglitazone, vemurafenib, and vinblastine.(2,3)

Cyp3a4 Inducers/Zuranolone

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: Inducers of CYP3A4 may induce the metabolism of zuranolone.(1)

CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in a loss of zuranolone efficacy.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid the concurrent use of zuranolone with CYP3A4 inducers.(1)

DISCUSSION: Coadministration of zuranolone with rifampin decreased the maximum concentration (Cmax) by 0.31-fold and area-under-curve (AUC) by 0.15-fold.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib. Weak CYP3A4 inducers linked to this monograph include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)

Disease Modifying Agents/Exagamglogene Autotemcel

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: The interaction potential of disease modifying agents with exagamglogene autotemcel is unknown.(1)

CLINICAL EFFECTS: Disease modifying agents may interfere with exagamglogene autotemcel therapy.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue disease modifying therapies for sickle cell disease (e.g. voxelotor, crizanlizumab) at least 8 weeks prior to the start of mobilization.(1) It is recommended that patients be transfused at least 8 weeks prior to the initiation of myeloablative conditioning. At initiation of red blood cell exchange or simple transfusions, discontinue disease modifying therapies for sickle cell disease (e.g. voxelotor, crizanlizumab).(1)

DISCUSSION: There is no experience with the use of disease modifying agents with exagamglogene autotemcel infusion.(1)

Disease Modifying Agents/Lovotibeglogene Autotemcel

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: The interaction potential of disease modifying agents with lovotibeglogene autotemcel is unknown.(1)

CLINICAL EFFECTS: Disease modifying agents may interfere with lovotibeglogene autotemcel therapy.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue disease modifying therapies (e.g. voxelotor, crizanlizumab) for sickle cell disease at least 8 weeks prior to start of mobilization and conditioning.(1)

DISCUSSION: There is no experience with the use of disease modifying agents with lovotibeglogene autotemcel infusion.(1)

P-Glycoprotein (P-Gp) Inhibitors/Doxorubicin

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: P-glycoprotein (P-gp) inhibition may increase doxorubicin cellular concentration, as well as decrease biliary or renal elimination.(1)

CLINICAL EFFECTS: Increased cellular or systemic levels of doxorubicin may result in doxorubicin toxicity, including cardiomyopathy, myelosuppression, or hepatic impairment.(1)

PREDISPOSING FACTORS: The interaction magnitude may be greater in patients with impaired renal or hepatic function.

PATIENT MANAGEMENT: Avoid the concurrent use of P-gp inhibitors in patients undergoing therapy with doxorubicin.(1) Consider alternatives with no or minimal inhibition. If concurrent therapy is warranted, monitor the patient closely for signs and symptoms of doxorubicin toxicity. For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(2)

DISCUSSION: Doxorubicin is a substrate of P-gp.(1) Clinical studies have identified and evaluated the concurrent use of doxorubicin and P-gp inhibitors as a target to overcome P-gp mediated multidrug resistance.(3,4) P-gp inhibitors linked to this monograph include: amiodarone, asciminib, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, cimetidine, cyclosporine, daclatasvir, danicopan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, eliglustat, erythromycin, flibanserin, fluvoxamine, fostamatinib, ginkgo, ginseng, glecaprevir/pibrentasvir, hydroquinidine, imlunestrant, istradefylline, ivacaftor, lapatinib, ledipasvir, mavorixafor, neratinib, osimertinib, paroxetine, pirtobrutinib, propafenone, quercetin, quinidine, quinine, ranolazine, sarecycline, schisandra, selpercatinib, simeprevir, sofosbuvir/velpatasvir/voxilaprevir, sotorasib, tepotinib, valbenazine, vemurafenib, vepdegestrant, verapamil, vimseltinib, and voclosporin.(5,6)

P-Glycoprotein (P-Gp) Inhibitors/Oral Lefamulin

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) may increase the absorption of lefamulin.(1) Oral lefamulin tablets may inhibit the metabolism of P-gp inhibitors that are also sensitive CYP3A4 substrates (i.e., asunaprevir, felodipine, ivacaftor, and neratinib).(1-3)

CLINICAL EFFECTS: The concurrent administration of lefamulin with an inhibitor of P-gp may result in elevated levels of lefamulin and signs of toxicity, such as QT prolongation. Coadministration of oral lefamulin with agents that are also sensitive CYP3A4 substrates (i.e., asunaprevir, felodipine, ivacaftor, and neratinib) may result in elevated levels and toxicities of the sensitive CYP3A4 substrate.

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.(4) 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, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)

PATIENT MANAGEMENT: The US manufacturer of lefamulin states that oral lefamulin tablet coadministration with P-gp inhibitors should be avoided.(1) If concomitant therapy with a P-gp inhibitor is necessary, monitor patients closely for prolongation of the QT interval. Obtain serum calcium, magnesium, and potassium levels and monitor ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. Concomitant use of asunaprevir, felodipine, ivacaftor, or neratinib requires close monitoring for adverse effects of these drugs.(1) The manufacturer of venetoclax states that if concurrent use with a P-gp substrate cannot be avoided, take lefamulin at least 6 hours before venetoclax.(5)

DISCUSSION: Coadministration of ketoconazole (a strong CYP3A4 and P-gp inhibitor) with lefamulin tablets increased lefamulin area-under-the-curve (AUC) and maximum concentration (Cmax) by 165% and 58%.(1) In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(1) P-gp inhibitors include: asunaprevir, belumosudil, capmatinib, carvedilol, cimetidine, danicopan, daridorexant, diosmin, flibanserin, fluvoxamine, fostamatinib, ginseng, glecaprevir/pibrentasvir, hydroquinidine, ivacaftor, ledipasvir, neratinib, pirtobrutinib, propafenone, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, valbenazine, vimseltinib, and voclosporin.(1-3)

P-Glycoprotein (P-Gp) 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 P-glycoprotein may increase the absorption of topotecan.(1)

CLINICAL EFFECTS: The concurrent administration of topotecan with an inhibitor of P-glycoprotein 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 P-glycoprotein inhibitors should be avoided. If concurrent use is warranted, carefully monitor patients for adverse effects.(1) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(2)

DISCUSSION: In clinical studies, the combined use of elacridar (100 mg to 1000 mg) increased the area-under-curve (AUC) of topotecan approximately 2.5-fold.(1) Oral cyclosporine (15 mg/kg) increased the AUC of topotecan lactone and total topotecan to 2-fold to 3-fold of the control group, respectively.(1) P-gp inhibitors linked to this monograph include: adagrasib, amiodarone, asciminib, asunaprevir, aumolertinib, azithromycin, belumosudil, bosutinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, erythromycin, flibanserin, ginseng, hydroquinidine, imlunestrant, isavuconazonium, itraconazole, ivacaftor, josamycin, ketoconazole, ledipasvir, lonafarnib, mavorixafor, neratinib, osimertinib, pibrentasvir/glecaprevir, posaconazole, propafenone, quinidine, ranolazine, selpercatinib, sotorasib, tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, vepdegestrant, verapamil, vimseltinib, and voclosporin.(3,4)

P-Gp Inhibitors/Daraxonrasib (>150 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: Daraxonrasib is a substrate of P-gp. P-gp inhibitors may inhibit the metabolism of daraxonrasib.(1)

CLINICAL EFFECTS: Concurrent use of P-gp inhibitors may increase the levels and toxicities of daraxonrasib, including dermatologic toxicity, stomatitis, GI perforation, and interstitial lung disease/pneumonitis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: For patients taking agents that are P-gp inhibitors, reduce the dose of daraxonrasib to 150 mg daily. After the P-gp inhibitor has been discontinued, resume the daraxonrasib dosage taken prior to initiating the inhibitor.(1)

DISCUSSION: In a pharmacokinetic model, quinidine 300 mg three times daily (a P-gp inhibitor) increased the area under curve (AUC) of daraxonrasib by 1.8-fold.(1) P-gp inhibitors include: abrocitinib, amiodarone, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, curcumin, danicopan, daridorexant, diosmin, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, imlunestrant, ivacaftor, lapatinib, neratinib, osimertinib, pirtobrutinib, propafenone, ranolazine, selpercatinib, tepotinib, tezacaftor, turmeric, valbenazine, velpatasvir, vemurafenib, vepdegestrant, vimseltinib, and voclosporin.(2-3)

Select P-Gp 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 P-glycoprotein (P-gp). Inhibitors of P-gp may increase intestinal absorption and decrease elimination of aumolertinib.(1)

CLINICAL EFFECTS: Concurrent use with selected P-gp 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 P-gp 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 P-gp.(1) P-gp inhibitors linked to this interaction are: abrocitinib, asunaprevir, belumosudil, capmatinib, carvedilol, cimetidine, cobicistat, conivaptan, curcumin, cyclosporine, danicopan, daridorexant, diltiazem, diosmin, flibanserin, fluvoxamine, fostamatinib, ginseng, glecaprevir/pibrentasvir, grapefruit, imlunestrant, indinavir, isavuconazole, itraconazole, ivacaftor, josamycin, ketoconazole, mifepristone, neratinib, nirmatrelvir, pirtobrutinib, ritonavir, telaprevir, tepotinib, tezacaftor, tipranavir, tucatinib, valbenazine, velpatasvir, verapamil, vimseltinib, voclosporin, and voxilaprevir.(3)

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)

Selected P-Glycoprotein (P-Gp) Inhibitors/Ensartinib

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: Ensartinib is a P-glycoprotein (P-gp) substrate. P-gp inhibitors may increase the levels of ensartinib.(1)

CLINICAL EFFECTS: The concurrent administration of a P-glycoprotein (P-gp) inhibitor may result in elevated levels of and toxicity from ensartinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of ensartinib states that concurrent use of P-glycoprotein (P-gp) inhibitors should be avoided.(1) The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(4)

DISCUSSION: Ensartinib is a substrate of P-gp. Inhibitors of P-gp may increase toxicity of ensartinib.(1) Inhibitors of P-gp linked to this monograph include: abrocitinib, amiodarone, Asian ginseng (Panax ginseng), asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, cyclosporine, danicopan, daraxonrasib, daridorexant, diosmin, eliglustat, flibanserin, fostamatinib, ginkgo biloba, glecaprevir and pibrentasvir, hydroquinidine, ivacaftor, lapatinib, mavorixafor, milk thistle (Silybum marianum), neratinib, osimertinib, propafenone, quercetin, quinidine, ranolazine, rolapitant, silibinin, silymarin, sotagliflozin, tepotinib, tezacaftor, valbenazine, velpatasvir, vemurafenib, venetoclax, vepdegestrant, vilazodone, vimseltinib, and voclosporin.(2,3)

Xanthine Derivatives/Adenosine; Hexobendine; Regadenoson

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: Xanthine derivatives may antagonize the effects of endogenous(1) and exogenous adenosine,(2,3) regadenoson,(4) and hexobendine.(5)

CLINICAL EFFECTS: Concurrent use of a xanthine derivative use may result in decreased effectiveness of adenosine, hexobendine and regadenoson. Aminophylline may increase the risk of adenosine-induced seizures.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with adenosine and a xanthine derivative should be monitored for decreased effectiveness of adenosine. The dosage of adenosine may need to be increased. Whenever possible, withhold xanthine derivatives for 5 half-lives prior to using adenosine in cardiac stress tests.(6) Methylxanthines should not be used to reverse the effects of adenosine in patients who experience adenosine-induced seizures.(3) Concurrent therapy with hexobendine and a xanthine oxidase derivative should also be monitored for decreased effectiveness of hexobendine.(5) The US manufacturer of regadenoson recommends that patients avoid methylxanthines (e.g. caffeine, pentoxifylline, and theophylline) for 12 hours prior to regadenoson administration. Aminophylline may be used to attenuate severe and/or persistent adverse reactions to regadenoson.(4)

DISCUSSION: In a study in six healthy subjects, theophylline significantly reduced the heart-rate response to adenosine. In addition, theophylline reduced the amount of abdominal and chest discomfort reported by subjects, allowing significantly higher infusion rates of adenosine.(7) Theophylline has also been reported to antagonize the vasorelaxant action of adenosine in human forearm arterioles.(8) In a study in five subjects, theophylline decreased the amounts of adenosine-induced side effects, including chest pain. There was no change in blood pressure or respiratory rate during concurrent adenosine and theophylline.(9) In a study in ten dog and twelve human subjects, the administration of adenosine after hexobendine increased coronary sinus blood flow. Aminophylline administration significantly decreased the coronary vasodilation response to adenosine and hexobendine.(5) In a study in ten healthy subjects, caffeine reduced the mean adenosine-induced increases in systolic blood pressure by 7.2 mmHg and heart rate by 8.4 beats/min when compared to placebo.(2) In another study in ten healthy subjects, caffeine was shown to lower the adenosine-induced response of blood pressure and heart rate.(3) Caffeine has also been reported to reduced adenosine-induced changes in minute ventilation and tidal volume.(3) Aminophylline has been shown to shorten the duration of coronary blood flow response to regadenoson.(3) Coronary flow reserve was 8% lower in patients who received caffeine (200 mg single dose) 2 hours prior to regadenoson administration when compared to subjects who received placebo instead of caffeine.(4)

Xanthine Derivatives/Dipyridamole Injectable

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: The xanthine derivatives are adenosine receptor antagonists. Concurrent administration may inhibit dipyridamole-induced increases in endogenous plasma adenosine levels, thus decreasing dipyridamole's vasodilator effects.(1)

CLINICAL EFFECTS: Concurrent administration may result in a decrease in dipyridamole's vasodilator effects. This may produce false-negative results during dipyridamole-thallium imaging tests.(1-3)

PREDISPOSING FACTORS: In patients with congestive heart failure and decreased hepatic function, the metabolism of xanthine derivatives may be decreased. These patients may need a longer xanthine-free period prior to dipyridamole-thallium imaging tests.(2)

PATIENT MANAGEMENT: Patients scheduled for dipyridamole-thallium imaging tests should have a xanthine-free period (including caffeine-containing products) for at least 24 hours prior to their exam.(3)

DISCUSSION: In a study in eight male subjects with documented coronary artery disease, intravenous dipyridamole administered during a dipyridamole-thallium 201 SPECT image test produced a significant increase in heart rate, a decrease in blood pressure, and angina in seven patients and ST segment depression in four patients. SPECT imaging showed reversible perfusion defects in myocardial segments supplied by stenotic coronary arteries. When the exam was repeated when the subjects were receiving therapeutic dosages of theophylline, there was no appearance of angina, ST depression, or hemodynamic changes and SPECT imaging shown total absence of reversible perfusion defects.(1) A study in eight patients with coronary artery disease evaluated the effects of caffeine on dipyridamole-201Tl myocardial imaging. The administration of dipyridamole alone resulted in chest pain and ST-segment depression in four patients. Concurrent caffeine infusion decreased the dipyridamole-induced decrease in blood pressure and heart rate. No patients experience chest pain or ST-segment depression. Six patients had false negative test results.(2) Another study found that the attenuation of the hemodynamic response to dipyridamole by caffeine was dose-dependent.(3)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Cyp3a4 Inducers/Erlotinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of erlotinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a CYP3A4 inducer may result in decreased levels and effectiveness of erlotinib.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid the concurrent use of CYP3A4 inducers in patients receiving therapy with erlotinib. Consider the use of alternative agents with less enzyme induction potential.(1) Consider increasing the dosage of erlotinib by 50 mg increments as tolerated at two week intervals (to a maximum of 450 mg) while closely monitoring the patient. The highest dosage studied with concurrent rifampin is 450 mg. If the dosage of erlotinib is increased, it will need to be decreased when the inducer is discontinued.(1)

DISCUSSION: Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(1) In a study, pretreatment with rifampin for 11 days decreased the AUC of a single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single 150 mg dose of erlotinib.(1) In a case report, coadministration of phenytoin (180mg daily) and erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from 1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold (from 3.53 L/h to 41.7 L/h).(2) In a study, concurrent use of sorafenib (400 mg twice daily) and erlotinib (150 mg daily) decreased the concentration minimum (Cmin), concentration maximum (Cmax), and AUC of erlotinib.(3) In an animal study, concurrent use of dexamethasone and erlotinib decreased the AUC of erlotinib by 0.6-fold.(4) Strong inducers of CYP3A4 include: barbiturates, encorafenib, enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(5,6) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine, and tovorafenib.(5,6) Weak inducers of CYP3A4 include: amprenavir, armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginkgo, ginseng, glycyrrhizin, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(5,6)

P-Glycoprotein (P-Gp) Inhibitors/Bilastine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibition may increase the absorption of bilastine.(1,2)

CLINICAL EFFECTS: Concurrent use of P-gp inhibitors may result in elevated levels and toxicities from bilastine, including headache and somnolence.(1,2)

PREDISPOSING FACTORS: The interaction magnitude may be greater in patients with moderate to severe renal impairment.

PATIENT MANAGEMENT: The Canadian manufacturer of bilastine states that concomitant use of P-gp inhibitors with bilastine is not recommended. Coadministration should be avoided in patients with moderate or severe renal impairment.(1) The UK manufacturer of bilastine states that coadministration of bilastine and P-gp inhibitors should be avoided in patients with moderate to severe renal impairment.(2) The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(5)

DISCUSSION: In a study, ketoconazole and erythromycin both increased bilastine area-under-curve (AUC) and maximum concentration (Cmax) by 2-fold and 2- to 3-fold, respectively.(1) The UK manufacturer of bilastine states that these changes do not appear to affect the safety of bilastine.(2) P-gp inhibitors linked to this monograph include: amiodarone, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, cyclosporine, daclatasvir, danicopan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, eliglustat, erythromycin, flibanserin, fluvoxamine, fostamatinib, ginkgo, ginseng, glecaprevir/pibrentasvir, hydroquinidine, imlunestrant, istradefylline, ivacaftor, lapatinib, ledipasvir, mavorixafor, neratinib, osimertinib, paroxetine, pirtobrutinib, posaconazole, propafenone, quercetin, quinidine, quinine, ranolazine, sarecycline, schisandra, selpercatinib, simeprevir, sofosbuvir/velpatasvir/voxilaprevir, sotorasib, tepotinib, valbenazine, vemurafenib, vepdegestrant, verapamil, vimseltinib, and voclosporin.(4,5)

P-Glycoprotein (P-Gp) Inhibitors/Pralsetinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibitors may inhibit cellular efflux of pralsetinib.(1)

CLINICAL EFFECTS: Concurrent administration of a P-gp inhibitor may result in elevated levels of and toxicity from pralsetinib, including hemorrhagic events, pneumonitis, hepatotoxicity, hypertension, and QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1-3)

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.(4) 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).(4)

PATIENT MANAGEMENT: Coadministration of pralsetinib with a P-gp inhibitor should be avoided.(1) If coadministration with a P-gp inhibitor cannot be avoided, use with caution and reduce the dose of pralsetinib as follows: -If the current dose is 400 mg once daily, decrease the dose to 300 mg daily. -If the current dose is 300 mg once daily, decrease the dose to 200 mg daily. -If the current dose is 200 mg once daily, decrease the dose to 100 mg daily. After the inhibitor is discontinued for three to five half-lives, resume the dose of pralsetinib at the dose taken prior to initiation of the inhibitor.(1) The manufacturer of venetoclax states that if concurrent use with a P-gp substrate cannot be avoided, take pralsetinib at least 6 hours before venetoclax.(5) The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(8) When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If the QTc interval exceeds 500 ms, interrupt pralsetinib therapy until QTc is <470 ms. Resume pralsetinib at the same dose if risk factors that cause QT prolongation an are identified and corrected. If risk factors that cause QT prolongation are not identified, resume pralsetinib at a reduced dose. Permanently discontinue pralsetinib if the patient develops life-threatening arrhythmia.(3)

DISCUSSION: Coadministration of a single dose of cyclosporine 600 mg (a P-gp inhibitor) with a single pralsetinib 200 mg dose increased pralsetinib concentration maximum (Cmax) by 48% and area-under-curve (AUC) by 81%.(1) P-glycoprotein inhibitors linked to this monograph include: asunaprevir, belumosudil, carvedilol, cyclosporine, danicopan, daraxonrasib, daridorexant, deutivacaftor, diosmin, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, ivacaftor, ledipasvir, neratinib, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, valbenazine, venetoclax, vimseltinib, and voclosporin.(6,7)

P-Glycoprotein (P-Gp) Inhibitors/Relugolix

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Relugolix is a substrate of the intestinal P-glycoprotein (P-gp) efflux transporter. Inhibitors of P-gp may increase the absorption of relugolix.(1)

CLINICAL EFFECTS: The concurrent administration of relugolix with an inhibitor of P-glycoprotein may result in elevated levels of relugolix and adverse effects, including hot flashes, skin flushing, musculoskeletal pain, hyperglycemia, acute renal injury, transaminitis, arrhythmias, and hemorrhage.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of relugolix states that the coadministration of relugolix with P-gp inhibitors should be avoided. If the P-gp inhibitor is to be used short-term, relugolix may be held for up to 2 weeks. If treatment with relugolix is interrupted for longer than 7 days, resume relugolix with a loading dose of 360 mg on the first day, followed by 120 mg once daily.(1) If coadministration with a P-gp inhibitor cannot be avoided, relugolix should be taken at least 6 hours before the P-gp inhibitor. Monitor the patient more frequently for adverse events.(1) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(2)

DISCUSSION: Coadministration of relugolix with erythromycin (a P-gp and moderate CYP3A4 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of relugolix by 6.2-fold. Voriconazole (a strong CYP3A4 inhibitor) did not have a clinically significant effect on the pharmacokinetics of relugolix.(1) P-gp inhibitors linked to this monograph include: amiodarone, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, curcumin, cyclosporine, daclatasvir, danicopan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, eliglustat, erythromycin, flibanserin, fluvoxamine, fostamatinib, ginkgo, ginseng, glecaprevir/pibrentasvir, indinavir, itraconazole, ivacaftor, josamycin, ketoconazole, lapatinib, lonafarnib, mavorixafor, mibefradil, mifepristone, neratinib, osimertinib, paroxetine, pirtobrutinib, posaconazole, propafenone, quinidine, quinine, ranolazine, ritonavir, sarecycline, schisandra, selpercatinib, simeprevir, sotorasib, telaprevir, telithromycin, tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, venetoclax, vepdegestrant, verapamil, vimseltinib, and voclosporin.(3,4)

P-Glycoprotein (P-Gp) Inhibitors/Vincristine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibitors may inhibit cellular efflux of vincristine.(1)

CLINICAL EFFECTS: Concurrent administration of a P-gp inhibitor may result in elevated levels of and toxicity from vincristine including myelosuppression, neurologic toxicity, tumor lysis syndrome, hepatotoxicity, constipation, or bowel obstruction.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of P-gp inhibitors in patients undergoing therapy with vincristine.(1) Consider alternatives with no or minimal P-gp inhibition. The manufacturer of vincristine states that concomitant use of P-gp inhibitors should be avoided.(1) The manufacturer of lopinavir/ritonavir states that patients who develop significant hematological or gastrointestinal toxicity on concomitant vincristine should temporarily hold lopinavir/ritonavir, or use alternative medications that do not inhibit CYP3A4 or P-gp.(2) The manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(3)

DISCUSSION: Vincristine is a substrate of P-gp. Inhibitors of P-gp may increase toxicity of vincristine.(1) There are several case reports of neurotoxicity with concurrent administration of vincristine and itraconazole.(4-6) There is a case report of neurotoxicity with concurrent administration of lopinavir-ritonavir with vincristine.(7) In a prospective study in 22 children receiving various chemotherapy with prophylactic itraconazole oral solution (0.5 ml/kg per day), two children receiving vincristine developed non-alcoholic steatohepatitis (NASH) and one child developed syndrome of inappropriate anti-diuretic hormone secretion (SIADH).(8) Inhibitors of P-gp linked to this monograph include: abrocitinib, amiodarone, Asian ginseng (Panax ginseng), asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, cyclosporine, danicopan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, elagolix, eliglustat, erythromycin, flibanserin, fluvoxamine, fostamatinib, ginkgo biloba, glecaprevir and pibrentasvir, imlunestrant, isavuconazonium, ivacaftor, lapatinib, mavorixafor, milk thistle (Silybum marianum), neratinib, osimertinib, pirtobrutinib, propafenone, quercetin, quinidine, ranolazine, rolapitant, Schisandra chinensis, selpercatinib, sofosbuvir, sotorasib, tepotinib, valbenazine, velpatasvir, vemurafenib, venetoclax, vepdegestrant, verapamil, vilazodone, vimseltinib, and voclosporin.(9-10)

Selected Cyp1a2 Substrates/Viloxazine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Viloxazine is a strong inhibitor of CYP1A2 and may increase the total exposure of sensitive CYP1A2 substrates.(1) The FDA defines strong inhibition as an increase in drug area-under-curve (AUC) greater than 5-fold.(2)

CLINICAL EFFECTS: Concurrent use of viloxazine with drugs primarily metabolized by CYP1A2 may lead to elevated drug levels and increase the risk of adverse reactions associated with the CYP1A2 substrate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Drugs linked to this monograph are moderately sensitive to CYP1A2 inhibition. Coadministration of viloxazine with moderately sensitive CYP1A2 substrates is not recommended. If coadministered, dose reduction of the CYP1A2 substrate may be warranted.(1)

DISCUSSION: 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.(1) Though not designed to evaluate drug interactions, the open-label portion of a pediatric randomized controlled trial looking at the association of riluzole concentrations with efficacy and adverse effects found that fluvoxamine (a strong CYP1A2 inhibitor) increased riluzole concentrations by about 2-fold.(3) CYP1A2 substrates linked to this monograph include: caffeine and riluzole.(2,4)

Selected Moderate And Weak Cyp1a2 Inhibitors/Tizanidine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Moderate and weak CYP1A2 inhibitors may inhibit the metabolism of tizanidine by CYP1A2.(1)

CLINICAL EFFECTS: Concurrent use of moderate and weak CYP1A2 inhibitors may result in elevated levels of and effects from tizanidine, including hypotension, bradycardia, drowsiness, sedation, and decreased psychomotor function.

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.(2)

PATIENT MANAGEMENT: The US manufacturer of tizanidine states that concurrent use of tizanidine with inhibitors of CYP1A2 should be avoided.(3) If adverse reactions such as hypotension, bradycardia or excessive drowsiness occur, reduce tizanidine dosage or discontinue tizanidine therapy.(3)

DISCUSSION: In a study, cannabidiol 750 mg twice daily (a weak CYP1A2 inhibitor) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a 200 mg single dose of caffeine (a sensitive CYP1A2 substrate) by 15% and 95%, respectively.(1) In a study in 10 healthy subjects, concurrent fluvoxamine, a strong inhibitor of CYP1A2, increased tizanidine Cmax, AUC, and half-life (T1/2) by 12-fold, 33-fold, and 3-fold, respectively. Significant decreases in blood pressure and increases in drowsiness and psychomotor impairment occurred.(3) In a study in 10 healthy subjects, concurrent ciprofloxacin, a strong inhibitor of CYP1A2, increased tizanidine Cmax and AUC by 7-fold and 10-fold, respectively. Significant decreases in blood pressure and increases in drowsiness and psychomotor impairment occurred.(3) Moderate CYP1A2 inhibitors linked to this monograph include: centanafadine, dipyrone, fexinidazole, genistein, methoxsalen, phenylpropanolamine, pipemidic acid, propranolol, rucaparib, and troleandomycin. Weak CYP1A2 inhibitors linked to this monograph include: allopurinol, artemisinin, belumosudil, caffeine, cannabidiol, curcumin, dan-shen, disulfiram, Echinacea, ginseng, parsley, piperine, ribociclib, simeprevir, thiabendazole, and triclabendazole.(4)

Selected P-Glycoprotein (P-Gp) Inhibitors/Dabigatran

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Dabigatran etexilate is a substrate for the P-glycoprotein (P-gp) system. Inhibition of intestinal P-gp leads to increased absorption of dabigatran.(1-3)

CLINICAL EFFECTS: The concurrent use dabigatran with P-gp inhibitors may lead to elevated plasma levels of dabigatran, increasing the risk for bleeding.

PREDISPOSING FACTORS: Factors associated with an increased risk for bleeding include renal impairment, concomitant use of P-gp inhibitors, patient age >74 years, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight < 50 kg.(1-4)

PATIENT MANAGEMENT: Assess renal function and evaluate patient for other pre-existing risk factors for bleeding prior to initiating concurrent therapy. The US manufacturer of dabigatran states that the concurrent use of dabigatran and P-gp inhibitors should be avoided in atrial fibrillation patients with severe renal impairment (CrCl less than 30 ml/min) and in patients with moderate renal impairment (CrCl less than 50 ml/min) being treated for or undergoing prophylaxis for deep vein thrombosis (DVT) or pulmonary embolism (PE). The interaction with P-gp inhibitors can be minimized by taking dabigatran several hours apart from the P-gp inhibitor dose.(1) The concomitant use of dabigatran with P-gp inhibitors has not been studied in pediatric patients but may increase exposure to dabigatran.(1) While the US manufacturer of dabigatran states that no dosage adjustment is necessary in other patients,(1) the Canadian manufacturer of dabigatran states that concomitant use of strong P-gp inhibitors (e.g., glecaprevir-pibrentasvir) is contraindicated. When dabigatran is used for the prevention of venous thromboembolism (VTE) after total hip or knee replacement concurrently with amiodarone, quinidine, or verapamil, the dose of dabigatran should be reduced from 110 mg twice daily to 150 mg once daily. For patients with CrCl less than 50 ml/min on verapamil, a further dabigatran dose reduction to 75 mg once daily should be considered. Verapamil should be given at least 2 hours after dabigatran to minimize the interaction.(2) The UK manufacturer of dabigatran also states the use of dabigatran with strong P-gp inhibitors (e.g., cyclosporine, glecaprevir-pibrentasvir or itraconazole) is contraindicated. Concurrent use of ritonavir is not recommended. When dabigatran is used in atrial fibrillation patients and for treatment of DVT and PE concurrently with verapamil, the UK manufacturer recommends reducing the dose of dabigatran from 150 mg twice daily to 110 mg twice daily, taken simultaneously with verapamil. When used for VTE prophylaxis after orthopedic surgery concurrently with amiodarone, quinidine, or verapamil, the dabigatran loading dose should be reduced from 110 mg to 75 mg, and the maintenance dose should be reduced from 220 mg daily to 150 mg daily, taken simultaneously with the P-gp inhibitor. For patients with CLcr 30-50 mL/min on concurrent verapamil, consider further lowering the dabigatran dose to 75 mg daily.(3) If concurrent therapy is warranted, monitor patients for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Consider regular monitoring of hemoglobin, platelet levels, and/or activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT). When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(10)

DISCUSSION: When dabigatran was co-administered with amiodarone, the extent and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The dabigatran area-under-curve (AUC) and maximum concentration (Cmax) were increased by about 60% and 50%, respectively;(1,2) however, dabigatran clearance was increased by 65%.(1) Pretreatment with quinidine (200 mg every 2 hours to a total dose of 1000 mg) increased the AUC and Cmax of dabigatran by 53% and 56%, respectively.(1,2) Chronic administration of immediate release verapamil one hour prior to dabigatran dose increased dabigatran AUC by 154%.(4) Administration of dabigatran two hours before verapamil results in a negligible increase in dabigatran AUC.(1) Administration of sofosbuvir-velpatasvir-voxilaprevir (400/100/200 mg daily) increased the Cmax and AUC of a single dose of dabigatran (75 mg) by 2.87-fold and 2.61-fold, respectively.(5) Simultaneous administration of glecaprevir-pibrentasvir (300/120 mg daily) with a single dose of dabigatran (150 mg) increased the Cmax and AUC by 2.05-fold and 2.38-fold, respectively.(6) A retrospective comparative effectiveness cohort study including data from 9,886 individuals evaluated adverse bleeding rates with standard doses of oral anticoagulants with concurrent verapamil or diltiazem in patients with nonvalvular atrial fibrillation and normal kidney function. The study compared rates of bleeding following co-administration of either dabigatran, rivaroxaban, or apixaban with verapamil or diltiazem, compared to co-administration with amlodipine or metoprolol. Results of the study found that concomitant dabigatran use with verapamil or diltiazem was associated with increased overall bleeding (hazard ratio (HR) 1.52; 95% confidence interval (CI), 1.05-2.20, p<0.05) and increased overall GI bleeding (HR 2.16; 95% CI, 1.30-3.60, p<0.05) when compared to amlodipine. When compared to metoprolol, concomitant dabigatran use with verapamil or diltiazem was also associated with increased overall bleeding (HR, 1.43; 95% CI, 1.02-2.00, p<0.05) and increased overall GI bleeding (HR, 2.32; 95% CI, 1.42-3.79, p<0.05). No association was found between increased bleeding of any kind and concurrent use of rivaroxaban or apixaban with verapamil or diltiazem.(7) A summary of pharmacokinetic interactions with dabigatran and amiodarone or verapamil concluded that concurrent use is considered safe if CrCl is greater than 50 ml/min but should be avoided if CrCl is less than 50 ml/min in VTE and less than 30 ml/min for NVAF. Concurrent use with diltiazem was considered safe.(9) P-gp inhibitors include amiodarone, asunaprevir, aumolertinib, belumosudil, capmatinib, carvedilol, cimetidine, conivaptan, cyclosporine, daclatasvir, danicopan, daraxonrasib, daridorexant, diosmin, erythromycin, flibanserin, fostamatinib, ginseng, glecaprevir, imlunestrant, indinavir, itraconazole, ivacaftor, josamycin, lapatinib, ledipasvir, lonafarnib, mavorixafor, neratinib, osimertinib, pibrentasvir, posaconazole, propafenone, quinidine, ranolazine, ritonavir, selpercatinib, sotorasib, telaprevir, telithromycin, tepotinib, tezacaftor, tucatinib, valbenazine, velpatasvir, vemurafenib, vepdegestrant, verapamil, vimseltinib, voclosporin, and voxilaprevir.(1-9)

Selected P-Glycoprotein (P-Gp) Inhibitors/Venetoclax

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Venetoclax is a substrate for the P-glycoprotein (P-gp) system. P-gp inhibitors may lead to increased levels of venetoclax.(1)

CLINICAL EFFECTS: Concurrent use of P-gp inhibitors may result in elevated levels of venetoclax, increasing the risk for tumor lysis syndrome and other toxicities.(1)

PREDISPOSING FACTORS: Risk factors for tumor lysis syndrome include (1): - the ramp-up phase of venetoclax therapy when tumor burden is highest - initial magnitude of tumor burden - renal impairment The risk of venetoclax toxicities may be increased in patients with severe hepatic impairment.(1)

PATIENT MANAGEMENT: Avoid P-gp inhibitors and consider alternative treatments when possible. If a P-gp inhibitor must be used, reduce venetoclax dose by at least 50%. Monitor more closely for signs of toxicity such as tumor lysis syndrome, hematologic and non-hematologic toxicities.(1) If the P-gp inhibitor is discontinued, the manufacturer of venetoclax recommends resuming the prior (i.e. pre-inhibitor) dose of venetoclax 2 to 3 days after discontinuation of the P-gp inhibitor.(1) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(2)

DISCUSSION: In 11 healthy subjects, a single dose of rifampin (a P-gp inhibitor) increased venetoclax maximum concentration (Cmax) and area-under-curve (AUC) by 106% and 78%, respectively.(1) In 11 previously treated NHL subjects, ketoconazole (a strong CYP3A4 inhibitor which also inhibits P-gp and BCRP) 400 mg daily for 7 days increased the Cmax and AUC of venetoclax 2.3-fold and 6.4-fold respectively.(1) In 12 healthy subjects, coadministration of azithromycin (500 mg Day 1, 250 mg for Days 2-5) decreased venetoclax Cmax and AUC by 25% and 35%. No dosage adjustment is needed when venetoclax is coadministered with azithromycin.(1) P-gp inhibitors include: amiodarone, asunaprevir, aumolertinib, belumosudil, capmatinib, carvedilol, cyclosporine, danicopan, daraxonrasib, daridorexant, diosmin, flibanserin, fostamatinib, ginseng, imlunestrant, ivacaftor, neratinib, osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, tezacaftor, tepotinib, valbenazine, vemurafenib, vepdegestrant, vimseltinib, and voclosporin.(3)

Theophylline Derivatives/Cimetidine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Cimetidine inhibits the metabolism of theophylline by CYP1A2.(1-10) The duration of cimetidine's inhibitory action is uncertain. Short-term cimetidine therapy appears to reverse rapidly(2) but may persist in prolonged therapy. Increased pentoxifylline serum levels may be the result of an increase in the oral bioavailability of pentoxifylline.(11)

CLINICAL EFFECTS: Concurrent cimetidine and theophylline derivative therapy may result in elevated theophylline derivative concentration levels, prolonged elimination half-life, and decreased clearance.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Theophylline derivative blood levels should be very closely monitored if cimetidine therapy is to be initiated, changed, or discontinued. Theophylline has a narrow therapeutic range; therefore, dosage reductions up to 30-50%(4) should be considered to prevent intoxication when cimetidine therapy is started. Antacids, famotidine, or possibly ranitidine might be more judicious choices than cimetidine in patients receiving theophylline derivatives.

DISCUSSION: It is well documented that cimetidine impairs the elimination of theophylline when the two agents are co-administered to patients.(1-10, 12-22) This interaction has been noted by a variety of routes including continuous intravenous infusion.(22) Reports indicate that with concurrent cimetidine, theophylline plasma concentrations increase, theophylline half-life is prolonged from 29% to 73%(1-3;9,12-14) and theophylline clearance is decreased by 18.5% to 46%.(1-3,9,13,23) Age and smoking do not appear to affect the magnitude of the interaction.(17,18,20) Significant changes can be seen within 24 hours(3,5) and may progress as co-therapy continues.(3) A study involving ten healthy patients demonstrated that concomitant administration of cimetidine significantly decreased the plasma clearance of oxtriphylline.(24) Aminophylline is involved in a similar interaction as theophylline as seen in one case report.(25) In one report cimetidine also decreased the clearance and prolonged the half-life of caffeine.(26,27) A study demonstrated that cimetidine caused a significant increase in plasma levels of pentoxifylline.(11) Information on ranitidine is conflicting. Several studies have shown that ranitidine does not influence theophylline.(9,15,16,19,28,29) One case report noted toxic theophylline levels after ranitidine;(30) however, this case report has been challenged.(31) In another case report, theophylline levels rose from 16.6 mcg/ml to 39.7 mcg/ml(32) when the patient was given ranitidine. Other reports have also noted a reduction in theophylline elimination by ranitidine.(33,34) Famotidine has shown to have no effect on theophylline metabolism in a clinical trial;(35) however, there is one case report of decreased theophylline clearance during famotidine therapy.(36) Dyphylline, a theophylline derivative that is not converted to theophylline in vivo, is not to be expected to interact with cimetidine. A study showed that cimetidine increased the average steady state plasma concentration of pentoxifylline and its metabolite by 25% and 30%, respectively.(37)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Caffeine-Containing Products/Migalastat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of this interaction is unknown.

CLINICAL EFFECTS: Concurrent use of a caffeine-containing product may result in decreased levels and effectiveness of migalastat.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid coadministration of migalastat with caffeine-containing products. Do not administer caffeine-containing products within 2 hours before and 2 hours after taking migalastat.(1)

DISCUSSION: Coadministration of migalastat with caffeine 190 mg decreased the migalastat maximum concentration (Cmax) by 60% and area-under-curve (AUC) by 55%.(1)

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)

Moderate And Weak Cyp3a4 Inducers/Ubrogepant

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 induce the metabolism of ubrogepant.(1)

CLINICAL EFFECTS: Concurrent use of a moderate or weak CYP3A4 inducer may result in decreased levels and effectiveness of ubrogepant.(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 recommends a dosage adjustment of ubrogepant when coadministered with moderate or weak CYP3A4 inducers. Initial dose of ubrogepant should be 100 mg. If a second dose is needed, the dose of ubrogepant should be 100 mg.(1)

DISCUSSION: 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) 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, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, rifabutin, telotristat, 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, bexarotene, brigatinib, brivaracetam, clobazam, danshen, dexamethasone, dicloxacillin, echinacea, elafibranor, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, relugolix, repotrectinib, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)

P-Glycoprotein (P-Gp) Inhibitors/Afatinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of P-glycoprotein (P-gp) may increase the absorption of afatinib.(1)

CLINICAL EFFECTS: The concurrent administration of afatinib with an inhibitor of P-glycoprotein may result in elevated levels of afatinib and signs of toxicity. These signs may include but are not limited to worsening diarrhea, stomatitis, skin rash/exfoliation/bullae or paronychia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of afatinib states the afatinib dose should be reduced by 10 mg if the addition of a P-glycoprotein inhibitor is not tolerated.(1) If afatinib dose was reduced due to addition of a P-gp inhibitor, resume the previous dose after the P-gp inhibitor is discontinued.(1) The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to afatinib.(2) The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(4)

DISCUSSION: A drug interaction study evaluated the effects of ritonavir 200 mg twice daily on afatinib exposure. Administration of ritonavir 1 hour before afatinib administration increased systemic exposure by 48%. Afatinib exposure was not changed when ritonavir was administered simultaneously with or 6 hours after afatinib dose.(1) P-glycoprotein inhibitors linked to this monograph are: amiodarone, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, cyclosporine, danicopan, daraxonrasib, daridorexant, deutivacaftor, diosmin, dronedarone, erythromycin, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, hydroquinidine, imlunestrant, isavuconazonium, itraconazole, ivacaftor, josamycin, ketoconazole, lapatinib, ledipasvir, lonafarnib, mavorixafor, neratinib, osimertinib, posaconazole, propafenone, quinidine, ranolazine, ritonavir, saquinavir, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, sotorasib, telaprevir, tepotinib, tucatinib, valbenazine, vemurafenib, vepdegestrant, verapamil, vimseltinib and voclosporin.(1-3)

P-Glycoprotein (P-Gp) Inhibitors/Mavorixafor

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Mavorixafor is a substrate of the P-glycoprotein (P-gp) transporter. P-gp inhibitors may significantly increase the absorption of mavorixafor.(1)

CLINICAL EFFECTS: Concurrent administration of mavorixafor with an inhibitor of P-glycoprotein may result in elevated levels of and effects from mavorixafor, including potentially life-threatening cardiac arrhythmias, torsades de pointes, and sudden death.(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, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: When used concomitantly with P-gp inhibitors, monitor more frequently for mavorixafor adverse effects and reduce the dose in 100 mg increments, if necessary, but not to a dose less than 200 mg.(1) The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to mavorixafor.(4) When concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study with healthy subjects, itraconazole 200 mg daily (a strong CYP3A4 and P-gp inhibitor) increased the exposure to single-dose mavorixafor 200 mg similar to that from single-dose mavorixafor 400 mg alone. This suggests that itraconazole increased mavorixafor exposure by about 2-fold.(1) A study in healthy volunteers found that ritonavir 100 mg twice daily (a strong CYP3A4 inhibitor and P-gp inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose mavorixafor 200 mg by 60% and 39%, respectively.(1) P-glycoprotein inhibitors linked to this monograph include: abrocitinib, Asian ginseng, asunaprevir, capmatinib, carvedilol, cyclosporine, danicopan, daridorexant, deutivacaftor, diosmin, elagolix, flibanserin, fostamatinib, ginkgo biloba, glecaprevir/pibrentasvir, ivacaftor, milk thistle, neratinib, pirtobrutinib, quercetin, rolapitant, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, velpatasvir, vilazodone, vimseltinib, and voclosporin.(1,4-6)

P-Gp Inhibitors/Daraxonrasib (<= 150 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Daraxonrasib is a substrate of P-gp. P-gp inhibitors may inhibit the metabolism of daraxonrasib.(1)

CLINICAL EFFECTS: Concurrent use of P-gp inhibitors may increase the levels and toxicities of daraxonrasib, including dermatologic toxicity, stomatitis, GI perforation, and interstitial lung disease/pneumonitis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: For patients taking agents that are P-gp inhibitors, reduce the dose of daraxonrasib from 300 mg to 150 mg daily. After the P-gp inhibitor has been discontinued, resume the daraxonrasib dosage taken prior to initiating the inhibitor.(1)

DISCUSSION: In a pharmacokinetic model, quinidine 300 mg three times daily (a P-gp inhibitor) increased the area under curve (AUC) of daraxonrasib by 1.8-fold.(1) P-gp inhibitors include: abrocitinib, amiodarone, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, curcumin, danicopan, daridorexant, diosmin, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, imlunestrant, ivacaftor, lapatinib, neratinib, osimertinib, pirtobrutinib, propafenone, ranolazine, selpercatinib, tepotinib, tezacaftor, turmeric, valbenazine, velpatasvir, vemurafenib, vepdegestrant, vimseltinib, and voclosporin.(2-3)

Select P-Gp Inhibitors/Edoxaban (<= 30 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Edoxaban is a substrate for P-glycoprotein (P-gp). Inhibitors of P-gp may increase intestinal absorption and decrease renal tubular elimination of edoxaban.(1,2)

CLINICAL EFFECTS: Concurrent use with selected P-gp inhibitors may result in higher systemic concentrations of edoxaban which may increase the risk for bleeding.(1,2)

PREDISPOSING FACTORS: Bleeding risk may be increased in patients with creatinine clearance below 50 mL per minute(1-4). Use of multiple agents which increase edoxaban exposure or affect hemostasis would be expected to increase the risk for bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Management recommendations between approving regulatory agencies (FDA or European Medicines Agency, EMA) are conflicting. EMA approved prescribing information specifically states that dosage adjustments are not required solely for concomitant use with amiodarone, quinidine, or verapamil regardless of indication.(3,4) Potential interactions with azithromycin, clarithromycin, or oral itraconazole are not described.(3) FDA approved prescribing recommendations for edoxaban are indication specific:(2) - For prevention of stroke or embolic events due to nonvalvular atrial fibrillation, no edoxaban dose adjustments are recommended during concomitant therapy with P-glycoprotein inhibitors. - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), the edoxaban dose should be reduced to 30 mg daily during concomitant use with azithromycin, clarithromycin, oral itraconazole, quinidine or verapamil. The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to edoxaban.(6) Monitor patients receiving anticoagulant therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. anti Factor Xa inhibition) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Discontinue edoxaban in patients with active bleeding. The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(9)

DISCUSSION: Edoxaban in vivo interaction studies have been performed for quinidine and verapamil. In vivo interaction studies have not been conducted for the remaining P-gp inhibitors linked to this monograph.(1,4) In an interaction study, the effect of repeat administration of quinidine (300 mg TID) on a single oral dose of edoxaban 60 mg was evaluated in healthy subjects. Both peak (Cmax) and total systemic exposure (AUC) to edoxaban and to the active M4 metabolite increased approximately 1.75-fold.(1) In an interaction study, the effect of repeat administration of verapamil (240 mg Verapamil SR Tablets (Calan SR) QD for 11 Days) on a single oral dose of edoxaban 60 mg on the morning of Day 10 was evaluated in healthy subjects. Total and peak systemic exposure to edoxaban increased 1.53-fold and 1.53-fold, respectively. Total and peak systemic exposure to the active M4 metabolite increased 1.31-fold and 1.28-fold, respectively.(1) Based upon the above results, patients in the DVT/PE trial had a 50% dose reduction (from 60 mg to 30 mg) during concomitant therapy with P-glycoprotein inhibitors. Approximately 0.5% of these patients required a dose reduction solely due to P-gp inhibitor use. This low rate of concurrent therapy was too small to allow for detailed statistical evaluation. Almost all of these patients were receiving quinidine or verapamil. In these patients, both trough edoxaban concentrations (Ctrough) used to evaluate bleeding risk, and total edoxaban exposure (AUC or area-under-curve) used to evaluate treatment efficacy, were lower than patients who did not require any edoxaban dose adjustment. In this DVT/PE comparator trial, subgroup analysis revealed that warfarin had numerically better efficacy than edoxaban in patients receiving P-gp inhibitors. Based upon the overall lower exposure to edoxaban in P-gp dose adjusted subjects, both EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the edoxaban 50% dose reduction overcorrected for the difference in exposure.(1,4) Consequently, EMA recommended no edoxaban dose adjustments for patients receiving concomitant therapy with quinidine or verapamil.(3,4) A summary of pharmacokinetic interactions with edoxaban and verapamil concluded that if concurrent use is considered safe.(7) P-gp inhibitors linked to this interaction are: amiodarone, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, daclatasvir, danicopan, daraxonrasib, daridorexant, diltiazem, diosmin, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, hydroquinidine, imlunestrant, indinavir, oral itraconazole, ivacaftor, josamycin, ledipasvir, lonafarnib, mavorixafor, neratinib, osimertinib, pirtobrutinib, posaconazole, propafenone, quinidine, ranolazine, selpercatinib, sotorasib, telaprevir, telithromycin, tezacaftor, tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, vepdegestrant, verapamil, vimseltinib, and voclosporin.(8)

Select P-Gp Inhibitors/Edoxaban (> 30 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Edoxaban is a substrate for P-glycoprotein (P-gp). Inhibitors of P-gp may increase intestinal absorption and decrease renal tubular elimination of edoxaban.(1,2)

CLINICAL EFFECTS: Concurrent use with selected P-gp inhibitors may result in higher systemic concentrations of edoxaban which may increase the risk for bleeding.(1,2)

PREDISPOSING FACTORS: Bleeding risk may be increased in patients with creatinine clearance below 50 mL per minute(1-4). Use of multiple agents which increase edoxaban exposure or affect hemostasis would be expected to increase the risk for bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Management recommendations between approving regulatory agencies (FDA or European Medicines Agency, EMA) are conflicting. EMA approved prescribing information specifically states that dosage adjustments are not required solely for concomitant use with amiodarone, quinidine, or verapamil regardless of indication.(3,4) Potential interactions with azithromycin, clarithromycin, or oral itraconazole are not described.(3) FDA approved prescribing recommendations for edoxaban are indication specific:(2) - For prevention of stroke or embolic events due to nonvalvular atrial fibrillation, no edoxaban dose adjustments are recommended during concomitant therapy with P-glycoprotein inhibitors. - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), the edoxaban dose should be reduced to 30 mg daily during concomitant use with azithromycin, clarithromycin, oral itraconazole, quinidine or verapamil. The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to edoxaban.(6) Monitor patients receiving anticoagulant therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. anti Factor Xa inhibition) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Discontinue edoxaban in patients with active bleeding. The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(9)

DISCUSSION: Edoxaban in vivo interaction studies have been performed for quinidine and verapamil. In vivo interaction studies have not been conducted for the remaining P-gp inhibitors linked to this monograph.(1,4) In an interaction study, the effect of repeat administration of quinidine (300 mg TID) on a single oral dose of edoxaban 60 mg was evaluated in healthy subjects. Both peak (Cmax) and total systemic exposure (AUC) to edoxaban and to the active M4 metabolite increased approximately 1.75-fold.(1) In an interaction study, the effect of repeat administration of verapamil (240 mg Verapamil SR Tablets (Calan SR) QD for 11 Days) on a single oral dose of edoxaban 60 mg on the morning of Day 10 was evaluated in healthy subjects. Total and peak systemic exposure to edoxaban increased 1.53-fold and 1.53-fold, respectively. Total and peak systemic exposure to the active M4 metabolite increased 1.31-fold and 1.28-fold, respectively.(1) Based upon the above results, patients in the DVT/PE trial had a 50% dose reduction (from 60 mg to 30 mg) during concomitant therapy with P-glycoprotein inhibitors. Approximately 0.5% of these patients required a dose reduction solely due to P-gp inhibitor use. This low rate of concurrent therapy was too small to allow for detailed statistical evaluation. Almost all of these patients were receiving quinidine or verapamil. In these patients, both trough edoxaban concentrations (Ctrough) used to evaluate bleeding risk, and total edoxaban exposure (AUC or area-under-curve) used to evaluate treatment efficacy, were lower than patients who did not require any edoxaban dose adjustment. In this DVT/PE comparator trial, subgroup analysis revealed that warfarin had numerically better efficacy than edoxaban in patients receiving P-gp inhibitors. Based upon the overall lower exposure to edoxaban in P-gp dose adjusted subjects, both EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the edoxaban 50% dose reduction overcorrected for the difference in exposure.(1,4) Consequently, EMA recommended no edoxaban dose adjustments for patients receiving concomitant therapy with quinidine or verapamil.(3,4) A summary of pharmacokinetic interactions with edoxaban and verapamil concluded that if concurrent use is considered safe.(7) P-gp inhibitors linked to this interaction are: amiodarone, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, daclatasvir, danicopan, daraxonrasib, daridorexant, diltiazem, diosmin, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, hydroquinidine, imlunestrant, indinavir, oral itraconazole, ivacaftor, josamycin, ledipasvir, lonafarnib, neratinib, osimertinib, pirtobrutinib, posaconazole, propafenone, quinidine, ranolazine, selpercatinib, sotorasib, telaprevir, telithromycin, tezacaftor, tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, vepdegestrant, verapamil, vimseltinib, and voclosporin.(8)

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 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 P-Glycoprotein (P-Gp) Inhibitors/Betrixaban

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Betrixaban is a substrate for the P-glycoprotein (P-gp) system. Inhibition of intestinal P-gp leads to increased absorption of betrixaban.(1)

CLINICAL EFFECTS: The concurrent use betrixaban with P-gp inhibitors may lead to elevated plasma levels of betrixaban, increasing the risk for bleeding.

PREDISPOSING FACTORS: Factors associated with an increased risk for bleeding include renal impairment, concomitant use of P-gp inhibitors, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight < 50 kg.(1)

PATIENT MANAGEMENT: Assess renal function and evaluate patient for other pre-existing risk factors for bleeding prior to initiating concurrent therapy. The concurrent use of betrixaban and P-gp inhibitors should be avoided in patients with severe renal impairment (CrCl less than 30 ml/min).(1) The recommended dose for patients receiving or starting concomitant P-gp inhibitors is an initial single dose of 80 mg followed by 40 mg once daily. The recommended duration of treatment is 35 to 42 days.(1) Note that if betrixaban is used with the combination of darunavir and cobicistat, dose adjustment of betrixaban is not necessary.(2) The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to betrixaban.(3) Careful monitoring for signs and symptoms of bleeding is warranted during concurrent therapy. Consider regular monitoring of hemoglobin, platelet levels, and/or activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT). Instruct patients to report any signs and symptoms of bleeding, such as bleeding from the eyes, gums or nose; unusual bruising; dark stools; red or dark brown urine; and/or abdominal pain or swelling.(1) The anticoagulant effect of betrixaban is expected to persist for at least 72 hours after the last dose. The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(8)

DISCUSSION: In the APEX randomized, double-blind study the incidence of major or clinically relevant non-major bleeds (CRNM) in the betrixaban 40mg and 80 mg group was higher in patients taking concomitant P-gp inhibitors (2.8% vs. 4.1% vs. 4.7%).(4) In a study in 12 subjects, concomitant administration of a single dose of betrixaban (40 mg) following a 5-day regimen of ketoconazole (200 mg twice daily) resulted in an increase in betrixaban's maximum concentration (Cmax) and area-under-the-curve (AUC) of 2.3-fold and 2.3-fold, respectively.(5) An open-label study looking at concomitant administration of a single dose of betrixaban with verapamil in 18 subjects found an increase in betrixaban's Cmax and AUC of approximately 4.7-fold and 3-fold, respectively.(5) In a study, concomitant administration of betrixaban (80 mg) with amiodarone resulted in an increase in betrixaban's Cmax by 143%.(5) A summary of pharmacokinetic interactions with betrixaban and amiodarone, diltiazem, or verapamil concluded that if concurrent use is warranted, the betrixaban dose should be reduced to 80 mg once then 40 mg daily. Use should be avoided if CrCl is less than 30 ml/min.(6) P-gp inhibitors include asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, cyclosporine, daclatasvir, danicopan, daraxonrasib, daridorexant, diltiazem, diosmin, dronedarone, erythromycin, flibanserin, fostamatinib, ginseng, glecaprevir, hydroquinidine, imlunestrant, indinavir, itraconazole, ivacaftor, josamycin, lapatinib, ledipasvir, lonafarnib, lopinavir, mavorixafor, neratinib, osimertinib, pibrentasvir, pirtobrutinib, posaconazole, propafenone, quinidine, ranolazine, ritonavir, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, sotorasib, telaprevir, telithromycin, tepotinib, tezacaftor, tucatinib, valbenazine, velpatasvir, vemurafenib, vepdegestrant, vimseltinib, voclosporin and voxilaprevir.(1,4-7)

Selected Xanthine Derivatives/Fluvoxamine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Fluvoxamine may inhibit the metabolism of the xanthine derivatives by CYP1A2.(1,2)

CLINICAL EFFECTS: Concurrent use of fluvoxamine and xanthine derivatives may result in elevated levels of the xanthine derivative and toxicity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of fluvoxamine recommends that the dose of theophylline be decreased to one-third of the usual daily dose in patients receiving concurrent therapy. Theophylline levels should be closely monitored and patients should be observed for signs of theophylline toxicity.(3) The dosage of theophylline may need to be adjusted if fluvoxamine is discontinued. Patients receiving fluvoxamine should be instructed to consume caffeine containing beverages and/or medications with caution.

DISCUSSION: In a study in 12 healthy subjects, the administration of a single dose of theophylline ethylenediamine (300 mg) on Day 4 of fluvoxamine (50 mg Day 1, 100 mg daily Days 2-6) decreased theophylline total clearance by 70%. The half-life of theophylline increased 2.3-fold (from 6.6 hours to 22 hours).(1) In a study in 12 healthy males, the administration of a single dose of theophylline (375 mg given as 442 mg aminophylline) with fluvoxamine (50 mg twice daily at steady state) decreased theophylline clearance by 3-fold.(3) Fluvoxamine has been shown to inhibit the metabolism of theophylline in vitro.(2) There are four case reports of theophylline toxicity during concurrent fluvoxamine therapy.(4-7) In a study in eight healthy subjects, the administration of a single dose of caffeine (200 mg) on Day 8 of fluvoxamine (50 mg daily Days 1-4, 100 mg daily Days 5-12) decreased caffeine clearance by 80%. The half-life of caffeine increased 5.2-fold (from 5 hours to 31 hours).(8) In a study, seven reports of impaired caffeine clearance were reported in patients whom received single 250mg doses of caffeine together with fluvoxamine (four doses of 100mg over two days). Fluvoxamine reduced the apparent oral clearance of caffeine by 91.3%, and prolonged its elimination half-life by 11.4-fold (from 4.9 hours to 56 hours). There were no changes in the pharmacodynamic effects of caffeine.(9)

Theophylline Derivatives/Lithium

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Theophylline derivatives increase the renal excretion of lithium.

CLINICAL EFFECTS: Decreased levels of lithium which may result in decreased clinical effectiveness.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lithium levels and response should be monitored in patients in whom theophylline therapy is initiated or withdrawn. Patients receiving concurrent therapy should be monitored for increased adverse effects.

DISCUSSION: In a study involving ten volunteers, the concurrent administration of lithium and theophylline resulted in a significant decrease in lithium serum levels. Upon discontinuation of theophylline, lithium levels and half-life increased, and the clearance of lithium decreased. Individual variability in these parameters was significant. The overall incidence of adverse effects was significantly greater with concurrent therapy including restlessness, tremor, and anorexia. In another study in ten normal subjects, lithium (1200 mg/day for seven days) was administered and it was reported that theophylline infusion (dosed to achieve a plasma level of 14 mcg/ml) increased lithium clearances by 51%. In a case report, reduced lithium levels as well as worsening of manic symptoms occurred after increasing doses of theophylline were administered. It has been shown that aminophylline increases the lithium/creatinine clearance ratio, which may result in decreased serum lithium below the therapeutic level. Caffeine withdrawal has been reported to increase lithium levels in several case reports. This interaction is most important to consider in patients who have been previously sensitive to relapse with decreased lithium levels and in whom levels are maintained at the therapeutic/prophylactic borderline.

Weak Cyp3a4 Inducers/Atogepant

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Weak CYP3A4 inducers may increase the metabolism of atogepant by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of weak CYP3A4 inducers with atogepant may result in decreased levels and clinical effectiveness of atogepant.(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 atogepant recommends that patients on concomitant weak CYP3A4 inducers receive atogepant 30 mg or 60 mg once daily for prevention of episodic migraines and receive atogepant 60 mg once daily for prevention of chronic migraines.(1) Patients receiving concurrent therapy with CYP3A4 inducers and atogepant should be observed for decreased clinical effectiveness.

DISCUSSION: In a study of healthy subjects, rifampin, a strong CYP3A4 inducer, decreased the area-under-curve (AUC) and maximum concentration (Cmax) of atogepant by 60% and 30%, respectively. Topiramate, a weak CYP3A4 inducer, decreased atogepant AUC and Cmax by 25% and 24%, respectively.(1) Weak CYP3A4 inducers linked to this monograph include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(1,2)

There is no enhanced messaging for this drug.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

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Rare or Very Rare

• Extrasystoles

More Frequent

• Gastrointestinal irritation
• Insomnia
• Nervousness

Less Frequent

• Excitement

Rare or Very Rare

• Agitation
• Hyperesthesia
• Hyperglycemia
• Irritability
• Nausea
• Scotomata
• Symptoms of anxiety
• Tachycardia
• Tinnitus
• Tremor
• Vomiting

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No enhanced messaging available.

There are no adequate and well-controlled studies in pregnant women. In studies performed in adult animals, caffeine (as caffeine base) administered to pregnant mice as sustained-release pellets at 50 mg/kg (less than the maximum IV loading dose for neonates on a mg/m2 basis) during the period of organogenesis caused a low incidence of cleft palate and exencephaly in fetuses. Based on data from a large retrospective epidemiologic study and from a large retrospective case-control study in humans, it appears that use of caffeine during pregnancy has little, if any, effect on the outcome of pregnancy. Although caffeine use during pregnancy does not appear to be associated with substantial risk, most clinicians recommend that pregnant women avoid or limit their consumption of foods, beverages, and drugs containing caffeine, since caffeine crosses the placenta.

Caffeine is distributed into the milk of nursing women. Milk-to-plasma ratios of 0.5-0.76 have been reported. The amount of caffeine ingested from usual quantities of caffeinated beverages is considered compatible with breast-feeding; however, caffeine may accumulate in nursing infants following moderate to heavy maternal consumption of caffeine, resulting in irritability and poor sleeping patterns.

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