Anti-Allergy Formula (ascorbate calcium/calcium pantothenate/quercetin)

Each 10 mg of calcium pantothenate is equivalent to 9.2 mg of pantothenic acid.

Ascorbic acid is usually administered orally. When oral administration is not feasible or when malabsorption is suspected, the drug may be administered IM, IV, or subcutaneously. When given parenterally, utilization of the vitamin reportedly is best after IM administration and that is the preferred parenteral route.

Calcium pantothenate and pantothenic acid are usually administered orally; dexpanthenol is usually administered by IM injection, but may be given slowly by IV infusion. Dexpanthenol may also be administered topically in the form of a cream.

For IV infusion in adults, dexpanthenol injection has been added to a large volume parenteral solution of 5% dextrose or lactated Ringer's injection and infused slowly.

No dosing information is available for this tab.

No dosing information is available for this tab.

Concurrent administration of more than 200 mg of ascorbic acid per 30 mg of elemental iron increases absorption of iron from the GI tract; however, most individuals are able to absorb orally ingested iron adequately without concurrent administration of ascorbic acid.

Increased urinary excretion of ascorbic acid and decreased excretion of aspirin occur when the drugs are administered concurrently.

Salicylates inhibit uptake of ascorbic acid by leukocytes and platelets. As a result, leukocyte and plasma concentrations of ascorbic acid are decreased to concentrations slightly higher than those associated with tissue depletion of the vitamin; however, there is no evidence to date that salicylate therapy precipitates ascorbic acid deficiency. Although concomitant administration of ascorbic acid supplements in patients receiving salicylates increases plasma ascorbic acid concentrations, leukocyte ascorbic acid concentrations are not increased and tissue stores of the vitamin may not be increased. Therefore, routine administration of ascorbic acid supplements to patients receiving salicylates is not warranted; however, patients receiving high dosages of salicylates who exhibit any signs or symptoms of ascorbic acid deficiency should be evaluated for such a deficiency.

Ascorbic acid has reportedly decreased the anticoagulant effect of warfarin; however, other investigators have failed to show this effect. Concurrent administration of ascorbic acid and fluphenazine reportedly resulted in decreased fluphenazine plasma concentration. Acidification of the urine following administration of ascorbic acid may result in altered excretion of other drugs.

On theoretical grounds, the manufacturers of dexpanthenol recommend that the drug not be given with or within 12 hours after administration of neostigmine or other parasympathomimetic drugs. Although the clinical importance has not been established, the miotic effects of anticholinesterase ophthalmic preparations (e.g., echothiophate iodide (no longer commercially available in the US), isoflurophate) reportedly may be potentiated by pantothenic acid. It has been reported that dexpanthenol prolonged the muscle relaxant effects of succinylcholine; however, a controlled trial failed to show this effect. The manufacturers recommend that dexpanthenol not be administered within 1 hour of succinylcholine. The manufacturers also warn that rare cases of allergic reactions of unknown cause have occurred during concomitant use of dexpanthenol injection and antibiotics, opiates, and barbiturates.

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

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)

P-Glycoprotein (P-Gp) Inducers; Phenobarbital/Ravidasvir

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 P-glycoprotein (P-gp) may decrease the absorption of ravidasvir.(1)

CLINICAL EFFECTS: Concurrent or recent use of a P-gp inducer may result in decreased levels and effectiveness of ravidasvir.(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 ravidasvir states concurrent use with P-gp inducers is contraindicated.(1)

DISCUSSION: Interaction studies with P-gp inducers have not been performed. Co-administration with potent inducers of P-gp are expected to decrease ravidasvir plasma concentrations and result in therapeutic failure.(1) Agents linked to this monograph include apalutamide, carbamazepine, fosphenytoin, green tea, lorlatinib, phenobarbital, phenytoin, primidone, quercetin, rifabutin, rifampin, and St. John's wort.(1-3)

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)

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

Aluminum & Magnesium Antacids;Polyvalent Cations/Raltegravir

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

MECHANISM OF ACTION: Aluminum and/or magnesium containing antacids may alter raltegravir absorption by altering gastric pH. Magnesium antacids and supplements containing polyvalent cations may bind to raltegravir in the GI tract, preventing its absorption.(1)

CLINICAL EFFECTS: Aluminum and/or magnesium containing antacids and supplements containing polyvalent cations may reduce levels and clinical effectiveness of raltegravir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of any formulation of raltegravir and aluminum and/or magnesium antacids is not recommended. Instruct patients not to use aluminum and/or magnesium containing antacids. Calcium carbonate may be used in place of aluminum and/or magnesium containing antacids in patients receiving raltegravir twice daily. Calcium carbonate is not recommended for patients receiving once daily raltegravir (1,200 mg daily).(1,2) The US HIV treatment guidelines state that if coadministration of other medications that contain polyvalent cations (e.g., Mg, Al, Fe, Ca, Zn, sucralfate) is necessary, administer raltegravir at least 2 hours before or at least 6 hours after polyvalent cations. Monitor for virologic response.(2)

DISCUSSION: Simultaneous administration of aluminum and magnesium hydroxide (20 ml) with raltegravir (400 mg BID) decreased raltegravir maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) by 44%, 49%, and 63%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 2 hours before raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 51%, 51%, and 56%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 2 hours after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 22%, 30%, and 57%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 4 hours before after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 22%, 19%, and 60%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 4 hours after after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 30%, 32%, and 62%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 6 hours before after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 10%, 13%, and 50%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 6 hours after after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 10%, 11%, and 49%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 12 hours after after raltegravir (1200 mg single dose) decreased raltegravir Cmax, AUC, and Cmin by 14%, 14%, and 58%, respectively.(1,3) Data from in vitro(3) and in vivo simulations(5) suggest that magnesium's effect on raltegravir may involve chelation as well as changes in pH.

Ascorbic Acid (Vitamin C)/Bortezomib

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

MECHANISM OF ACTION: Vitamin C can form a complex with the boronic acid moiety of the bortezomib molecule, preventing its absorption into cells.(1-4) This may protect normal tissue in the body, which may have higher levels of Vitamin C.(5)

CLINICAL EFFECTS: Concurrent administration of Vitamin C may result in decreased bortezomib activity.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Instruct patients receiving bortezomib therapy not to begin taking vitamin C supplements without consulting their oncologist first. Patients who are instructed to take vitamin C should follow their oncologist's instructions on how to separate dosages and should be carefully monitored for bortezomib efficacy.

DISCUSSION: An in vitro study with human plasma and multiple myeloma cells found that high levels of vitamin C (following 1 gram/day of ascorbic acid for 4 days) decreased bortezomib effectiveness by 26%. An in vivo study in mice found that vitamin C administration with bortezomib completely blocked the response of bortezomib.(6) An in vitro study in rat Schwann cells and myeloma cells(4) and an in vivo study in mice(7) found that delayed administration of vitamin C had no effect on bortezomib effects. In an in vivo study in multiple myeloma patients, concurrent ascorbic acid, arsenic trioxide, bortezomib, and high-dose melphalan in which ascorbic acid was administered close to bortezomib, the combination was safe and well tolerated, but produced no changes in response rates.(8) In another in vivo study in multiple myeloma patients, a regimen of ascorbic acid, bortezomib, and melphalan in which bortezomib was administered in the morning and ascorbic acid in the evening was found to be safe and efficacious, with 74% of patients responding to therapy.(9)

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/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)

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

Aluminum-Magnesium Hydroxide; Oral Calcium/Phenytoin

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

MECHANISM OF ACTION: Aluminum hydroxide; magnesium hydroxide, and oral calcium may bind to phenytoin, preventing its absorption.(1-4)

CLINICAL EFFECTS: Simultaneous ingestion of aluminum-magnesium hydroxide and/or calcium-containing products may result in decreased levels and effectiveness of phenytoin.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of phenytoin recommends that administration times of phenytoin and antacids being staggered.(1)

DISCUSSION: In a study in 8 healthy subjects, simultaneous administration of phenytoin (600 mg) with calcium carbonate significantly decreased the area-under-curve (AUC) of phenytoin.(2) In a study in 8 healthy subjects, simultaneous administration of aluminum-magnesium hydroxide or calcium carbonate significantly decreased the AUC of phenytoin.(3) In a study in 6 patients with epilepsy, concurrent administration of an aluminum-magnesium hydroxide antacid resulted in a small but statistically significant decrease in phenytoin AUC.(4)

Ascorbic Acid (Vitamin C)/Deferoxamine

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

MECHANISM OF ACTION: It is believed that ascorbic acid increases the iron available for chelation from an labile intracellular iron pool. Ascorbic acid may then facilitate iron-induced oxidative tissue damage.(1)

CLINICAL EFFECTS: Dietary ascorbic acid may increase the absorption of dietary iron. Supplemental ascorbic acid therapy given during chelation therapy may improve iron output;(1-9) however, excessive dosages may result in cardiac toxicity from iron-induced oxidative tissue damage.(1,2,11-13)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Ascorbic acid intake is often restricted in patients with iron overload; however, it has been used in conjunction with deferoxamine to increase iron excretion.(2) Supplemental ascorbic acid therapy should only be initiated after one month of deferoxamine therapy. Ascorbic acid therapy should only be given in patients receiving deferoxamine regularly and the dose should be given after the infusion has started. The dosage of ascorbic acid should be limited to 50 mg daily in children under 10 years of age; 100 mg daily in older children; and 200 mg daily, in divided doses, in adults.(2) Cardiac function should be monitored in patients receiving concurrent therapy. Discontinue ascorbic acid therapy in patients who develop cardiac dysfunction.(2)

DISCUSSION: Supplemental ascorbic acid therapy given during chelation therapy has been shown to improve iron output,(1-9) possibly by increasing iron available for chelation from an labile intracellular iron pool.(1) However, dosages in excess of 500 mg daily have been associated with cardiac dysfunction.(1,2,11-13)

Calcium & Iron Containing Supplements/Bictegravir

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

MECHANISM OF ACTION: Calcium or iron containing supplements may bind to bictegravir in the GI tract, preventing its absorption.(1)

CLINICAL EFFECTS: Calcium or iron containing supplements may reduce levels and clinical effectiveness of bictegravir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Bictegravir and calcium or iron containing supplements may be taken together with food. Routine administration of bictegravir under fasting conditions simultaneously with, or within 2 hours after, calcium or iron containing supplements is not recommended.(1) In pregnant patients, if bictegravir is taken on an empty stomach, take bictegravir at least 2 hours before or 6 hours after calcium or iron containing supplements.(1)

DISCUSSION: Simultaneous administration of aluminum and magnesium hydroxide (20 ml) in a fasted state with bictegravir (50 mg single dose) decreased bictegravir maximum concentration (Cmax) and area-under-curve (AUC) by 80% and 79%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 2 hours after bictegravir (50 mg single dose) in a fasted state decreased bictegravir Cmax and AUC by 7% and 13%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 2 hours before bictegravir (50 mg single dose) in a fasted state decreased bictegravir Cmax and AUC by 58% and 52%, respectively.(1) Simultaneous administration of aluminum and magnesium hydroxide (20 ml) in a fed state with bictegravir (50 mg single dose) decreased bictegravir Cmax and AUC by 49% and 47%, respectively.(1) Simultaneous administration of calcium carbonate (1200 mg single dose) in a fasted state with bictegravir (50 mg single dose) decreased bictegravir Cmax and AUC by 42% and 33%, respectively.(1) Simultaneous administration of calcium carbonate (1200 mg single dose) in a fed state with bictegravir (50 mg single dose) decreased bictegravir Cmax by 10% and increased AUC 3%, respectively.(1) Simultaneous administration of ferrous fumarate (324 mg single dose) in a fasted state with bictegravir (50 mg single dose) decreased bictegravir Cmax and AUC by 71% and 63%, respectively.(1) Simultaneous administration of ferrous fumarate (324 mg single dose) in a fed state with bictegravir (50 mg single dose) decreased bictegravir Cmax and AUC by 25% and 16%, respectively.(1)

Oral Calcium Products/Estramustine

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

MECHANISM OF ACTION: Calcium may bind to estramustine in the gastro-intestinal tract, preventing its absorption.(1-4)

CLINICAL EFFECTS: Simultaneous administration of oral calcium products may result in decreased levels and clinical effectiveness of estramustine.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK(1) and US(2) manufacturers of estramustine state that calcium containing products should not be taken simultaneously with estramustine. One Australian manufacturer of calcium carbonate recommends separating administration by at least 3 hours.(3)

DISCUSSION: In a randomized, cross-over study in 6 patients, simultaneous administration of estramustine (420 mg) with milk (200 ml containing 120 mg calcium) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of estromustine (a metabolite of estramustine) by 59% and 68%, respectively. The AUC of estrone (another estramustine metabolite) was decreased by 63%.(4)

Oral Calcium Products/Strontium

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

MECHANISM OF ACTION: Calcium may prevent the absorption of strontium.(1,2)

CLINICAL EFFECTS: Simultaneous administration of strontium with oral calcium products may result in decreased levels and effectiveness of strontium.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The administration of strontium and oral calcium products should be separated by at least 2 hours.(1,2)

DISCUSSION: Simultaneous administration of strontium with calcium or food decreased the bioavailability of strontium by 60-70% when compared to administration 3 hours after a meal.(1,2)

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)

Polyvalent Cations And Phosphate Binders/Vadadustat

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

MECHANISM OF ACTION: Vadadustat may form a chelate with iron supplements, phosphate binders, and other medicinal products whose primary component consists of polyvalent cations such as aluminum, calcium, magnesium, selenium, and zinc.(1)

CLINICAL EFFECTS: Simultaneous administration of vadadustat and polyvalent cations and phosphate binders decreases the exposure and effectiveness of vadadustat.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of vadadustat states that it should be administered at least 1 hour before or 2 hours after any medications or products whose primary component consists of iron, phosphate binders and polyvalent cations.(1)

DISCUSSION: Two studies evaluating the pharmacokinetics, safety, and tolerability of a single oral dose of vadadustat coadministered with a phosphate binder or iron supplement were conducted in healthy adult participants. Vadadustat exposure was reduced by coadministration with sevelamer carbonate, calcium acetate, ferric citrate, and ferrous sulfate. Geometric least squares mean ratios for area under the concentration-time curve (AUC) were reduced 37% to 55% by phosphate binders and 46% by ferrous sulfate. However, when vadadustat was administered 1 hour before phosphate binders, 90% confidence intervals for vadadustat exposure were within the no-effect boundaries of +50% to -33%, indicating that drug-drug interactions can be reduced by administering vadadustat 1 hour before phosphate binders.(2)

Polyvalent Cations/Baloxavir

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

MECHANISM OF ACTION: Aluminum, calcium, iron, magnesium, selenium, and zinc may form chelation compounds with baloxavir.(1)

CLINICAL EFFECTS: Simultaneous administration of products containing aluminum, calcium, iron, magnesium, selenium, and zinc may result in decreased levels of and clinical effects from baloxavir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent administration of baloxavir with cation-containing products.(1)

DISCUSSION: A significant decrease in baloxavir exposure was observed when baloxavir was coadministered with calcium, aluminum, magnesium, or iron in monkeys. No studies have been conducted in humans.(1)

Polyvalent Cations/Cabotegravir

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

MECHANISM OF ACTION: Cabotegravir chelates polyvalent cations such as aluminum, calcium, iron, magnesium, selenium, and zinc.(1)

CLINICAL EFFECTS: Simultaneous administration of cabotegravir and polyvalent cations may decrease the absorption and clinical effects of cabotegravir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of cabotegravir states that it should be administered at least 4 hours before or 2 hours after any medications or products containing polyvalent cations such as antacids or mineral supplements.(1)

DISCUSSION: Clinical studies have not been conducted. Prescribing information states cabotegravir levels may be decreased when coadministered with antacids containing polyvalent cations (examples include aluminum or magnesium hydroxide, calcium carbonate) suggesting cabotegravir is susceptible to chelation.(1)

Polyvalent Cations/Eltrombopag

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

MECHANISM OF ACTION: Eltrombopag chelates polyvalent cations such as aluminum, calcium, iron, magnesium, selenium, and zinc.(1)

CLINICAL EFFECTS: Simultaneous administration of eltrombopag and polyvalent cations may decrease the absorption and clinical effects of eltrombopag.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of eltrombopag states that it should be administered at least 2 hours before or 4 hours after any medications or products containing polyvalent cations such as antacids or mineral supplements.(1)

DISCUSSION: In a crossover study in 25 healthy subjects, administration of eltrombopag with an antacid (1524 mg aluminum hydroxide/1425 mg magnesium carbonate/sodium alginate) decreased eltrombopag levels by 70%.(1,2)

Polyvalent Cations/Roxadustat

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

MECHANISM OF ACTION: Roxadustat chelates polyvalent cations such as aluminum, calcium, iron, magnesium, selenium, and zinc.(1)

CLINICAL EFFECTS: Simultaneous administration of roxadustat and polyvalent cations may decrease the absorption and clinical effects of roxadustat.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of roxadustat states that it should be administered at least 1 hour before or 1 hour after any medications or products containing polyvalent cations such as antacids or mineral supplements.(1)

DISCUSSION: Clinical studies with polyvalent cations have not been conducted. In a study in health subjects, concurrent use of roxadustat with sevelamer carbonate or calcium acetate decreased roxadustat area-under-curve (AUC) by 67% and 46% and concentration maximum (Cmax) by 66% and 52%, respectively.(1)

Sel Oral Cations; Antacids; H2 Antag/Dolutegravir-Rilpivirin

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

MECHANISM OF ACTION: Aluminum, calcium, iron, lanthanum, magnesium, sucralfate, and zinc may form chelation compounds with dolutegravir.(1) Rilpivirine requires an acidic medium for absorption. Antacid or H2 antagonist induced decrease in gastric pH may result in decrease in rilpivirine absorption.(1)

CLINICAL EFFECTS: Simultaneous administration or administration of products containing aluminum, calcium, iron, lanthanum, magnesium, and/or sucralfate close to the administration time of dolutegravir may result in decreased absorption and clinical effectiveness of dolutegravir.(1) Simultaneous administration of an antacid or a H2 antagonist may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid concurrent therapy with dolutegravir-rilpivirine and cation-containing products. If it is necessary to use these agents concurrently, dolutegravir-rilpivirine should be administered 4 hours before or 6 hours after taking these medications.(1) Alternatively, dolutegravir-rilpivirine and supplements containing calcium or iron can be taken together with food.(1) In patients maintained on dolutegravir-rilpivirine, administer dolutegravir-rilpivirine at least 4 hours before or 6 hours after antacids .(1) In patients maintained on dolutegravir-rilpivirine, administer dolutegravir-rilpivirine at least 4 hours before or 12 hours after H2 antagonists.(1) Concurrent use of proton pump inhibitors will dolutegravir-rilpivirine is contraindicated.(1)

DISCUSSION: In a study in 16 subjects, the administration of an antacid (Maalox - aluminum and magnesium hydroxide) simultaneously with dolutegravir (50 mg single dose) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of dolutegravir by 72%, 74%, and 74%, respectively.(1) In a study in 16 subjects, the administration of an antacid (Maalox - aluminum and magnesium hydroxide) 2 hours after dolutegravir (50 mg single dose) decreased dolutegravir Cmax, AUC, and Cmin by 18%, 26%, and 30%, respectively.(1) In a study in 16 subjects, the administration of a multiple vitamin (One-A-Day) simultaneously with dolutegravir (50 mg single dose) decreased dolutegravir Cmax, AUC, and Cmin by 35%, 33%, and 32%, respectively.(1) In a study in 16 subjects, omeprazole (20 mg daily) decreased the Cmax, AUC, and Cmin of rilpivirine (150 mg daily) by 40%, 40%, and 33%, respectively. The Cmax and AUC of omeprazole decreased by 14% and 14%, respectively.(1) In a study in 24 subjects, famotidine (40 mg single dose) administered 12 hours before a single dose of rilpivirine (150 mg) had no significant effect on rilpivirine Cmax or AUC.(1) In a study in 23 subjects, famotidine (40 mg single dose) administered 2 hours before a single dose of rilpivirine (150 mg) decreased the rilpivirine Cmax and AUC by 85% and 76%, respectively.(1) In a study in 24 subjects, famotidine (40 mg single dose) administered 4 hours before a single dose of rilpivirine (150 mg) increased the rilpivirine Cmax and AUC by 21% and 13%, respectively.(1)

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 Oral Cations/Dolutegravir

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

MECHANISM OF ACTION: Aluminum, calcium, iron, lanthanum, magnesium, sucralfate, and zinc may form chelation compounds with dolutegravir.(1)

CLINICAL EFFECTS: Simultaneous administration or administration of products containing aluminum, calcium, iron, lanthanum, magnesium, and/or sucralfate close to the administration time of dolutegravir may result in decreased absorption and clinical effectiveness of dolutegravir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid concurrent therapy with dolutegravir and cation-containing products. If it is necessary to use these agents concurrently, dolutegravir should be administered 2 hours before or 6 hours after taking these medications.(1) Alternatively, dolutegravir and supplements containing calcium or iron can be taken together with food.(1)

DISCUSSION: In a study in 16 subjects, the administration of an antacid (Maalox - aluminum and magnesium hydroxide) simultaneously with dolutegravir (50 mg single dose) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of dolutegravir by 72%, 74%, and 74%, respectively.(1) In a study in 16 subjects, the administration of an antacid (Maalox - aluminum and magnesium hydroxide) 2 hours after dolutegravir (50 mg single dose) decreased dolutegravir Cmax, AUC, and Cmin by 18%, 26%, and 30%, respectively.(1) In a study in 16 subjects, the administration of a multiple vitamin (One-A-Day) simultaneously with dolutegravir (50 mg single dose) decreased dolutegravir Cmax, AUC, and Cmin by 35%, 33%, and 32%, respectively.(1)

Selected Oral Cations/Elvitegravir

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

MECHANISM OF ACTION: The exact mechanism is unknown, but aluminum, calcium, iron, lanthanum, magnesium, sucralfate, and zinc may bind to elvitegravir in GI tract.

CLINICAL EFFECTS: Simultaneous administration or administration of products containing aluminum, calcium, iron, lanthanum, magnesium, and/or sucralfate may result in decreased levels and effectiveness of elvitegravir, as well as the development of resistance.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Separate the administration of elvitegravir and products containing aluminum, calcium, iron, lanthanum, magnesium, and/or sucralfate by at least 2 hours.(1) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: Administration of an antacid (exact formulation not stated) 2 hours before elvitegravir (50 mg) decreased the maximum concentration (Cmax), area-under-curve (AUC), or minimum concentration (Cmin) of elvitegravir by 18%, 15%, and 10%, respectively.(1) Administration of an antacid 2 hours after elvitegravir (50 mg) decreased the Cmax, AUC, or Cmin of elvitegravir by 21%, 20%, and 20%, respectively.(1) Administration of an antacid 4 hours before elvitegravir (50 mg) decreased the Cmax and AUC of elvitegravir by 5%, and 4%, respectively.(1) Administration of an antacid 4 hours before elvitegravir (50 mg) decreased both the Cmax and AUC of elvitegravir by 2%.(1)

Selected Oral Cations/Selected Oral Quinolones

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

MECHANISM OF ACTION: Aluminum, calcium, iron, lanthanum, magnesium, and zinc may form chelation compounds with the quinolones.(1-40)

CLINICAL EFFECTS: Simultaneous administration or administration of products containing aluminum, calcium, iron, lanthanum, magnesium, and/or zinc close to the administration time of an oral quinolone may result in decreased absorption and clinical effectiveness of the quinolone.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid concurrent therapy with quinolones and cation-containing products. If it is necessary to administer these agents concurrently, follow the manufacturers' recommendations regarding timing of administration of the quinolone and cation-containing products. Manufacturer recommendations regarding the separation of administration times of quinolones and products containing aluminum, calcium, iron, lanthanum, magnesium, and/or zinc vary: ---Do not give ciprofloxacin for at least 2 hours before or 6 hours after oral cations.(1) ---Do not give delafloxacin for at least 2 hours before or 6 hours after oral cations.(2) ---Do not give enoxacin for at least 2 hours before or 8 hours after oral cations.(3) ---Do not give levofloxacin for at least 2 hours before or 2 hours after oral cations.(4) ---Do not give nalidixic acid for at least 2 hours before or 2 hours after oral cations.(5) ---Do not give norfloxacin for at least 2 hours before or 2 hours after oral cations.(6) ---Do not give ofloxacin for at least 2 hours before or 2 hours after oral cations.(7) ---Do not give sparfloxacin for at least 4 hours before oral cations.(8) ---Do not give sitafloxacin for at least 2 hours before or 2 hours after oral cations.(9) The US manufacturer of lanthanum recommends that quinolones be taken at least 1 hour before or 4 hours after lanthanum;(10) however, it would be prudent to follow the specific quinolone manufacturers' recommendations regarding concurrent administration of cations. The US manufacturer of ferric maltose recommends separation of ferric maltose by at least 4 hours. For quinolones not listed above, separate their administration from oral cations by as much time as feasible.

DISCUSSION: Aluminum, calcium, iron, magnesium, and zinc products have been shown to form chelation compounds with quinolone antibiotics, resulting in decreased absorption of the quinolone.(1-40) Treatment failures have been reported.(11-12) In a study in 12 healthy subjects, simultaneous administration of didanosine chewable tablets, which contain aluminum and magnesium, decreased ciprofloxacin area-under-curve (AUC) and maximum concentration (Cmax) by 92% and 98%, respectively.(14) The administration of ciprofloxacin 2 hours prior to Videx chewable/dispersible tablets decreased ciprofloxacin concentrations by 26%.(15,16) In a study in healthy subjects, pretreatment with an antacid containing aluminum-magnesium hydroxide at 5-10 minutes, 2 hours, and 4 hours before a single dose of ciprofloxacin decreased ciprofloxacin AUC by 84.9%, 76.8%, and 30%, respectively. There was no effect when the antacid was administered 6 hours before or 2 hours after.(17) In a study in 12 healthy subjects, aluminum hydroxide decreased ciprofloxacin AUC by 85%.(18) In a study in patients on continuous ambulatory peritoneal dialysis, peak levels of ciprofloxacin were decreased by 67% to 92% in patients receiving aluminum-containing antacids.(19) In a study in 15 healthy subjects, simultaneous administration of calcium acetate decreased the bioavailability of ciprofloxacin by 51%.(20) In a study in 6 healthy males, simultaneous administration of calcium carbonate decreased ciprofloxacin Cmax and AUC by 40% and 43%, respectively.(21) In a study in 12 healthy subjects, calcium carbonate decreased ciprofloxacin AUC by 40%.(18) In a study in 13 healthy males, calcium carbonate had no effect on ciprofloxacin bioavailability when administered 2 hours prior to the antibiotic.(22,23) In a study in healthy males, simultaneous administration of calcium polycarbophil decreased ciprofloxacin AUC by 50%.(24) In a study in 8 healthy males, simultaneous administration of ferrous fumarate (200 mg) decreased ciprofloxacin AUC by 70%.(25) In a study in healthy subjects, ferrous gluconate decreased ciprofloxacin bioavailability by 50%; however, no significant effects were seen with iron-ovotransferrin.(26) In a study in 8 healthy subjects, ferrous sulfate decreased the Cmax and AUC of simultaneously administered ciprofloxacin by 54% and 57%, respectively.(27) In a study in 8 healthy subjects, administration of ferrous sulfate decreased the Cmax and AUC of ciprofloxacin by 33% and 46%, respectively. Administration of ferrous gluconate decreased the Cmax and AUC of ciprofloxacin by 57% and 67%, respectively. Administration of a multivitamin product containing calcium, copper, iron, magnesium, manganese, and zinc decreased the Cmax and AUC of ciprofloxacin by 53% and 56%, respectively.(28) In a study in 12 healthy males, ferrous sulfate decreased ciprofloxacin AUC by 63%.(29) In a study in 12 healthy subjects, lanthanum carbonate decreased the area-under-curve (AUC) and maximum concentration (Cmax) of concurrently administered ciprofloxacin by 54% and 56%, respectively.(30) In a study in 12 healthy males, a multivitamin containing zinc decreased ciprofloxacin AUC by 22%.(29) In a study in 12 healthy subjects, an antacid containing aluminum-magnesium hydroxide had no effect on the pharmacokinetics of intravenous enoxacin.(31) In a study in 10 healthy subjects, administration of an aluminum-magnesium hydroxide antacid 0.5 hours or 2 hours before oral enoxacin (400 mg single dose) decreased the AUC of enoxacin by 73% and 43%, respectively. There were no significant effects on enoxacin AUC when the antacid was administered 8 hours before or 2 hours after enoxacin.(32) In a study in 9 healthy subjects, colloidal aluminum phosphate had no effect on the amount of enoxacin absorbed; however, ferrous sulfate (1050 mg) decreased the amount of enoxacin absorption by 10%.(33) In a study in 5 healthy subjects and 5 patients with cystic fibrosis, separation of levofloxacin (750 mg) and calcium carbonate (500 mg 3 times daily with meals) by 2 hours resulted in no interaction in healthy subjects; however, levofloxacin levels were not bioequivalent in patients with cystic fibrosis.(34) Concurrent magnesium-aluminum hydroxide or calcium have been shown to decrease the bioavailability of norfloxacin by 91.0% and 63.5%, respectively.(35) Concurrent zinc has been shown to decrease the bioavailability of norfloxacin.(36) In a study in 8 healthy subjects, ferrous sulfate decreased the Cmax and AUC of simultaneously administered norfloxacin by 75% and 73%, respectively.(27) Simultaneous aluminum phosphate was found to decrease the rate, but not the extent, of absorption of ofloxacin.(37) In a study in 8 healthy subjects, ferrous sulfate decreased the Cmax and AUC of simultaneously administered norfloxacin by 36% and 25%, respectively.(27) In an in vitro study, ferrous sulfate, aluminum hydroxide, and calcium carbonate decreased ofloxacin availability by 32.6%, 30.7%, and 26.2%, respectively. However, in vivo tests showed a significant effect with only aluminum hydroxide.(38) In a study in 9 healthy subjects, simultaneous administration colloidal aluminum phosphate had no effect on ofloxacin (200 mg) absorption; however, ferrous sulfate (1050 mg) decreased the ofloxacin fraction of dose absorbed by 10.85%.(33) In a study in 16 subjects, administration of either aluminum-magnesium hydroxide or calcium carbonate at least 2 hours before or after ofloxacin administration had no significant effects on ofloxacin levels.(39) The administration of an antacid containing aluminum hydroxide and magnesium hydroxide 2 hours before, 2 hours after, and 4 hours after sparfloxacin decreased sparfloxacin levels by 23%, 17%, and 5%, respectively.(40) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

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.

• No disease contraindications

There is no enhanced messaging for this drug.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

No enhanced messaging available.

No enhanced messaging available.

Animal reproduction studies have not been performed with dexpanthenol. It is not known whether dexpanthenol can cause fetal harm when administered to pregnant women. Dexpanthenol injection should be used during pregnancy only when clearly needed.

Since it is not known whether dexpanthenol is distributed into milk, dexpanthenol injection should be used with caution in nursing women.

No enhanced messaging available.