Tums Dual Action (FAMOTIDINE) (famotidine/calcium carbonate/magnesium hydroxide)

In patients with renal impairment, doses and/or frequency of administration of famotidine can be modified in response to the degree of renal impairment. Adverse CNS effects have been reported in patients with moderate or severe renal insufficiency receiving famotidine, and modification of dosage and/or dosing interval may be used to avoid excess accumulation of the drug in such patients. In adults with moderate (creatinine clearances less than 50 mL/minute) or severe (creatinine clearances less than 10 mL/minute) renal impairment, the manufacturer states that dosage of famotidine may be reduced to half the usual dosage or the dosing interval may be prolonged to 36-48 hours as necessary according to the patient's clinical response. Some clinicians have recommended that one-half the usual adult dosage be administered in adults with creatinine clearances of 30-60 mL/minute per 1.48 m2 and that one-fourth the usual adult dosage be administered in those with creatinine clearances less than 30 mL/minute per 1.48 m2.

Based on the comparison of pharmacokinetic parameters of famotidine in adults and children, dosage adjustment also should be considered in children with moderate or severe renal impairment.

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

Antacids/Olverembatinib

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 aqueous solubility of olverembatinib is pH dependent. Higher gastric pH leads to lower solubility which may reduce olverembatinib absorption.(1)

CLINICAL EFFECTS: Coadministration of antacids may reduce the bioavailability of olverembatinib leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of olverembatinib states that concurrent use with antacids should be avoided.(1)

DISCUSSION: Olverembatinib has pH-dependent solubility.(1)

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)

H2 Antagonists/Olverembatinib

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 aqueous solubility of olverembatinib is pH dependent. Higher gastric pH leads to lower solubility which may reduce olverembatinib absorption.(1)

CLINICAL EFFECTS: Coadministration of H2 receptor antagonists may reduce the bioavailability of olverembatinib leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of olverembatinib states that concurrent use with H2 receptor antagonists should be avoided.(1)

DISCUSSION: Olverembatinib has pH-dependent solubility.(1)

H2 Antagonists; Proton Pump Inhibit/Posaconazole Suspension

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: H2 antagonists and proton pump inhibitors (PPIs) increase the stomach pH, possibly reducing gastrointestinal absorption of posaconazole suspension.

CLINICAL EFFECTS: Concurrent use of H2 antagonists or proton pump inhibitors (PPIs) may result in decreased effectiveness of posaconazole suspension.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the concurrent use of posaconazole suspension with H2 antagonists or proton pump inhibitors (PPIs).(1) If H2 antagonists or PPI therapy is required, use the tablet formulation or powder mix formulation of posaconazole.

DISCUSSION: Concurrent cimetidine (400 mg twice daily) decreased both posaconazole (200 mg daily) maximum concentration (Cmax) and area-under-curve (AUC) levels by 39%.(1) No significant effects with other H2 blockers have been noted.(1) Esomeprazole (40 mg daily for 3 days) decreased the Cmax and AUC of a single dose of posaconazole suspension (400 mg) by 46% and 32%, respectively.(1) In a study of posaconazole levels in patients with acute myeloid leukemia or myelodysplastic syndrome, use of pantoprazole was associated with decreased posaconazole levels.(3) In a cross-over study in 5 healthy subjects, esomeprazole decreased the Cmax and AUC of posaconazole suspension by 37% and 84%, respectively. Simultaneous intake of Coca-Cola did not completely counteract the effects of esomeprazole.(4) In a study in healthy subjects, esomeprazole decreased the Cmax and AUC of posaconazole suspension by 55% and 49%, respectively. Simultaneous intake of Coca-Cola did not completely counteract the effects of esomeprazole.(5)

H2 Antagonists; Proton Pump Inhibitors/Defactinib

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 aqueous solubility of defactinib is pH dependent. Higher gastric pH leads to lower solubility which may reduce defactinib absorption.(1)

CLINICAL EFFECTS: Coadministration of H2 antagonists or proton pump inhibitors (PPIs) may reduce the bioavailability of defactinib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of defactinib states that concurrent use with H2 antagonists or proton pump inhibitors should be avoided.(1) If concurrent use with an acid-reducing agent cannot be avoided, administer defactinib 2 hours before or 2 hours after the administration of a locally acting antacid.(1)

DISCUSSION: In an interaction study, defactinib area-under-the-curve (AUC) decreased by 79% and maximum concentration (Cmax) decreased by 85% following concomitant use of multiple doses of omeprazole 40 mg daily. The AUC and Cmax of N-desmethyl amide (M4), a major metabolite of defactinib, decreased by 83% and 88%, respectively.(1)

H2 Antagonists; Proton Pump Inhibitors/Levoketoconazole

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 aqueous solubility of levoketoconazole is pH dependent. Higher gastric pH leads to lower solubility. H2-receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) increase gastric pH and may decrease the absorption of levoketoconazole.(1)

CLINICAL EFFECTS: Coadministration of H2RAs or PPIs may reduce the bioavailability of levoketoconazole, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of levoketoconazole with PPIs and H2RAs should be avoided.(1)

DISCUSSION: Levoketoconazole is very slightly soluble in water but soluble below pH 2. H2RAs and PPIs raise gastric pH and may impair dissolution and absorption of levoketoconazole.(1)

H2 Antagonists; Proton Pump Inhibitors/Nirogacestat

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 aqueous solubility of nirogacestat is pH dependent. Higher gastric pH leads to lower solubility which may reduce nirogacestat absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) or H2 antagonists may reduce the bioavailability of nirogacestat, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of nirogacestat with proton pump inhibitors, H2 antagonists, and antacids should be avoided. If coadministration with an acid-reducing agent is unavoidable, take nirogacestat 2 hours before or 2 hours after a locally acting antacid.(1)

DISCUSSION: The solubility of nirogacestat is poor at a pH >= 6.(1) Concomitant use of proton pump inhibitors, H2 antagonists, or antacids are expected to reduce concentrations of nirogacestat.(1)

H2 Antagonists; Proton Pump Inhibitors/Secretin

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: H2 antagonists and proton pump inhibitors (PPIs) may result in an incorrect secretin stimulation test result.(1)

CLINICAL EFFECTS: Concurrent use of H2 antagonists and proton pump inhibitors (PPIs) may impact the accuracy of the secretin stimulation test.(1)

PREDISPOSING FACTORS: Patients with alcoholic or other liver disease may be hyperresponsive to stimulation with a secretin stimulation test, masking the presence of coexisting pancreatic disease. Consider additional testing and clinical assessment for diagnosis.(1)

PATIENT MANAGEMENT: The US manufacturer of human secretin states concurrent use of H2 antagonists and proton pump inhibitors (PPIs) at the time of stimulation testing may cause the patient to be hyperresponsive to secretin stimulation and suggest false gastrinoma results. The manufacturer recommends discontinuing H2 antagonists at least 2 days prior to testing. The US manufacturer of vonoprazan recommends stopping vonoprazan at least 4 weeks prior to testing.(2-3) Consult prescribing information for PPIs before administering prior to a secretin stimulation test.(1)

DISCUSSION: Concurrent use of H2 antagonists and proton pump inhibitors (PPIs) may impact the accuracy of the secretin stimulation test.(1)

H2 Antagonists; Proton Pump Inhibitors/Sotorasib

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 aqueous solubility of sotorasib is pH dependent. Higher gastric pH leads to lower solubility which may reduce sotorasib absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) or H2 antagonists may reduce the bioavailability of sotorasib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of sotorasib with proton pump inhibitors, H2 antagonists, and antacids should be avoided. If coadministration with an acid-reducing agent is unavoidable, take sotorasib 4 hours before or 10 hours after a locally acting antacid.(1) The UK manufacturer of sotorasib states if co-administration with an acid-reducing agent (such as a PPI or an H2 antagonist) is required, sotorasib should be taken with an acidic beverage (such as cola). Alternatively, sotorasib should be taken 4 hours before or 10 hours after administration of a local antacid.(2)

DISCUSSION: The solubility of sotorasib in the aqueous media decreases over the range pH 1.2 to 6.8 from 1.3 mg/mL to 0.03 mg/mL. In an interaction study, coadministration of repeat doses of omeprazole with a single dose of sotorasib decreased sotorasib maximum concentration (Cmax) by 65% and area-under-curve (AUC) by 57% under fed conditions, and decreased sotorasib Cmax by 57% and AUC by 42% under fasted conditions. Under fasted conditions, co-administration of repeat doses of omeprazole with a single dose of sotorasib and 240ml of an acidic beverage (non-diet cola) decreased sotorasib Cmax by 32% and AUC by 23%. The UK manufacturer of sotorasib states the clinical relevance of the decreased sotorasib exposure when co-administered with omeprazole and cola is unclear and sotorasib efficacy might be reduced.(2) Coadministration of a single dose of famotidine given 10 hours prior to and 2 hours after a single dose of sotorasib under fed conditions decreased sotorasib Cmax by 35% and AUC by 38%.(1)

H2 Antagonists; Proton Pump Inhibitors/Taletrectinib

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 aqueous solubility of taletrectinib is pH dependent. Higher gastric pH leads to lower solubility which may reduce taletrectinib absorption.(1)

CLINICAL EFFECTS: Coadministration of H2 antagonists or proton pump inhibitors (PPIs) may reduce the bioavailability of taletrectinib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of taletrectinib states that concurrent use with H2 antagonists or proton pump inhibitors should be avoided.(1) If concurrent use with an acid-reducing agent cannot be avoided, administer taletrectinib 2 hours before or 2 hours after the administration of a locally acting antacid.(1)

DISCUSSION: In an interaction study, taletrectinib area-under-the-curve (AUC) decreased by 40% and maximum concentration (Cmax) decreased by 65% following concomitant use of omeprazole 40 mg daily.(1)

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

Alum;Ca;Mag/Oral Phosphate Supplements; Urinary Ph Modifiers

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

MECHANISM OF ACTION: Medications containing significant amounts of aluminum, calcium, or magnesium may bind to the phosphate and prevent its absorption.(1)

CLINICAL EFFECTS: Concurrent use of medications containing significant amounts of aluminum, calcium, or magnesium may result in decreased effectiveness of phosphate supplements and urinary pH modifiers high in phosphate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving phosphate supplements or urinary pH modifiers high in phosphate should be instructed to avoid medications containing aluminum, calcium, or magnesium.(1) If concurrent use cannot be avoided, separate the administration of phosphate containing products by as much time as possible from medications containing aluminum, calcium, or magnesium. Some phosphate laxative products used as phosphate supplements may contain sufficient quantities of phosphate to interact as well.

DISCUSSION: The manufacturer of K-Phos states that products containing aluminum, calcium, or magnesium may bind to the phosphate and prevent its absorption. Therefore, patients receiving phosphate supplements and urinary pH modifiers high in phosphate should be instructed to avoid products containing aluminum, calcium, or magnesium.(1)

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.

Antacids/Selected Mesalamine

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

MECHANISM OF ACTION: Certain mesalamine formulations (namely Apriso) contain granules with an enteric coating that dissolves at pH 6 and above. Antacids may raise the intragastric pH, resulting in premature release of the drug in the stomach.(1)

CLINICAL EFFECTS: Simultaneous administration of certain mesalamine formulations (namely Apriso) with an antacid may result in premature release of mesalamine in the stomach and decreased effectiveness in the intestines and colon.(1-2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of Apriso states that coadministration with antacids should be avoided.(1) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: Dissolution of the enteric coating of mesalamine is pH-dependent. Coadministration of certain mesalamine formulations (namely Apriso) with antacids should be avoided.(1)

Antacids/Ziftomenib

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

MECHANISM OF ACTION: The aqueous solubility of ziftomenib is pH dependent. Higher gastric pH leads to lower solubility which may reduce ziftomenib absorption.(1)

CLINICAL EFFECTS: Coadministration with antacids may reduce the bioavailability of ziftomenib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of ziftomenib states that concurrent use with antacids should be avoided.(1) If concurrent use cannot be avoided, administer ziftomenib 2 hours before or 2 hours after the administration of an antacid.(1) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: The impact of antacids on the pharmacokinetics of ziftomenib has not been investigated in clinical studies. In an interaction study, coadministration of proton pump inhibitors (PPIs) decreased ziftomenib area-under-the-curve (AUC) by 53% and maximum concentration (Cmax) by 70%.(1)

Calcium Carbonate/Raltegravir (600 MG HD)

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

MECHANISM OF ACTION: Calcium carbonate may alter raltegravir absorption by altering gastric pH and binding to raltegravir in the GI tract, preventing its absorption.(1)

CLINICAL EFFECTS: Calcium carbonate may reduce levels and clinical effectiveness of raltegravir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Calcium carbonate is not recommended for patients receiving one daily raltegravir (600 mg HD tablets).(1)

DISCUSSION: Simultaneous administration of calcium carbonate (3000 mg) with raltegravir (1200 mg singe dose given as two 600 mg HD tablets) decreased raltegravir maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) by 74%, 72%, and 48%, respectively.(1,2) Administration of calcium carbonate (3000 mg) 12 hours after raltegravir (1200 mg singe dose given as two 600 mg HD tablets) decreased raltegravir Cmax, AUC, and Cmin by 2%, 10%, and 57%, respectively.(1,2) Data from in vitro(3) and in vivo simulations(4) suggest that magnesium's effect on raltegravir may involve chelation as well as changes in pH. Calcium may have a similar effect.

Cimetidine; Famotidine/Tizanidine

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

MECHANISM OF ACTION: Cimetidine and famotidine may inhibit the metabolism of tizanidine by CYP1A2.(1)

CLINICAL EFFECTS: Concurrent use of cimetidine or famotidine 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, such as cimetidine or famotidine, should be avoided. If concurrent use is warranted, tizanidine should be initiated with 2 mg dose and increased in 2-4 mg steps daily based on patient response to therapy.(1) If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy.(1)

DISCUSSION: In a study in 10 healthy subjects, concurrent fluvoxamine, another inhibitor of CYP1A2, increased tizanidine maximum concentration (Cmax), area-under-curve (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.(1) In a study in 10 healthy subjects, concurrent ciprofloxacin, another inhibitor of CYP1A2, increase tizanidine Cmax and AUC by 7-fold and 10-fold, respectively. Significant decreases in blood pressure and and increases in drowsiness and psychomotor impairment occurred.(1)

H2 Antagonists/Dasatinib; Pazopanib

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

MECHANISM OF ACTION: The solubility of dasatinib(1) and pazopanib(2) is pH dependent. Changes in gastric pH from H2 antagonists may decrease the absorption of dasatinib(1) and pazopanib.(2)

CLINICAL EFFECTS: Use of H2 antagonists may result in decreased levels and effectiveness of dasatinib(1) and pazopanib.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of H2-antagonists and proton pump inhibitors (PPIs) in patients receiving treatment with dasatinib(1) or pazopanib.(2) Consider the use of short-acting antacids in these patients.(1) If antacids are used, separate the administration times by at least two hours for dasatinib(1) and several hours for pazopanib.(2) The manufacturer of Phyrago states that it can be administered with gastric acid reducing agents. Administration times should be separated with antacids.(3)

DISCUSSION: In a study in 24 healthy subjects, administration of a single dose of dasatinib (50 mg) 10 hours after famotidine decreased dasatinib area-under-curve (AUC) and maximum concentration (Cmax) by 61% and 63%, respectively.(1) In a study in 14 healthy subjects, administration of a single dose of dasatinib (100 mg) 22 hours after omeprazole (40 mg at steady state) decreased dasatinib AUC and Cmax by 43% and 42%, respectively.(1) In a study in 24 healthy subjects, simultaneous administration of dasatinib (50 mg) with aluminum hydroxide/magnesium hydroxide (30 ml) decreased dasatinib AUC and Cmax by 55% and 58%, respectively. In the same subjects, administration of the antacid 2 hours before dasatinib decreased dasatinib Cmax by 26%, but had no effect on dasatinib AUC.(1) In a study in 13 patients, esomeprazole (40 mg daily for 5 days) decreased the Cmax and AUC of pazopanib (400 mg daily) by 42% and 40%, respectively, when compared to the administration of pazopanib alone.(2) Phyrago is not sensitive to increased gastric pH due to its polymer formulation. No clinically significant pharmacokinetic changes were seen with concurrent administration of Phyrago with omeprazole (proton pump inhibitor) or famotidine (H2 receptor antagonist).(3)

H2 Antagonists/Ziftomenib

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

MECHANISM OF ACTION: The aqueous solubility of ziftomenib is pH dependent. Higher gastric pH leads to lower solubility which may reduce ziftomenib absorption.(1)

CLINICAL EFFECTS: Coadministration of H2 receptor antagonists may reduce the bioavailability of ziftomenib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of ziftomenib states that concurrent use with H2 antagonists should be avoided.(1) If concurrent use cannot be avoided, administer ziftomenib 2 hours before or 10 hours after the administration of an H2 receptor antagonist.(1)

DISCUSSION: The impact of H2 receptor antagonists on the pharmacokinetics of ziftomenib has not been investigated in clinical studies. In an interaction study, coadministration of proton pump inhibitors (PPIs) decreased ziftomenib area-under-the-curve (AUC) by 53% and maximum concentration (Cmax) by 70%.(1)

H2 Antagonists;Proton Pump Inhibitors/Methylphenidate Xr-Odt

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

MECHANISM OF ACTION: The solubility of methylphenidate extended release orally disintegrating tablets (XR-ODT) is pH-dependent. At elevated pH, methylphenidate may be released from the tablets more quickly, resulting in increased absorption.(1)

CLINICAL EFFECTS: Coadministration of H2 antagonists or proton pump inhibitors (PPIs) may result in an altered pharmacokinetic profile of methylphenidate XR-ODT, which may change the effectiveness and/or adverse effects of methylphenidate XR-ODT.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of methylphenidate XR-ODT with H2 antagonists or PPIs is not recommended.(1,2)

DISCUSSION: In in vitro studies, when media pH was increased from 1.2 to 6.8, percentage release of methylphenidate from the XR-ODT tablet was increased by 67% at 0.5 hours, and by 93% at 2.5 hours. The increased dissolution of methylphenidate at higher pH may result in increased drug absorption and change the concentration-time profile of methylphenidate, which is correlated with pharmacological effect.(1)

Long Acting Antacids; H2s;Ppis/Selected Cephalosporins

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

MECHANISM OF ACTION: Absorption of oral cefpodoxime or cefuroxime may be reduced in patients receiving concomitant treatment with acid reducing agents.(1-5)

CLINICAL EFFECTS: Antibiotic efficacy against organisms with a high minimum inhibitory concentration (MIC) to cefpodoxime or cefuroxime could be decreased.

PREDISPOSING FACTORS: Taking cefpodoxime or cefuroxime on an empty stomach magnifies this effect.

PATIENT MANAGEMENT: If possible, avoid the use of H2 antagonists and proton pump inhibitors(PPIs) in patients taking cefpodoxime or cefuroxime. If concurrent therapy is needed with antacids, H2 antagonists, or PPIs, administer cefpodoxime or cefuroxime after eating to maximize oral absorption. Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: In a study of ten subjects, administration of cefpodoxime after single dose famotidine 40 mg decreased both maximum concentration (Cmax) and area-under-curve (AUC) by approximately 40 percent compared with administration of cefpodoxime on an empty stomach.(3) In a study of 17 subjects, administration of cefpodoxime after single dose ranitidine 150 mg decreased Cmax and AUC by approximately 40 percent compared with administration of cefpodoxime on an empty stomach.(4) In a study performed prior to the introduction of PPIs, administration of ranitidine 300 mg and sodium bicarbonate followed by cefuroxime taken on a empty stomach lowered both Cmax and AUC of cefuroxime by approximately 40 per cent compared with administration of cefuroxime alone on an empty stomach. Postprandial administration of cefuroxime in subjects taking ranitidine was similar to that of subjects taking cefuroxime on an empty stomach.(5)

Selected H2 Antagonists/Infigratinib; Selpercatinib

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

MECHANISM OF ACTION: The solubility of infigratinib and selpercatinib is pH dependent. Changes in gastric pH from H2 antagonists may decrease the absorption of infigratinib and selpercatinib.(1,2)

CLINICAL EFFECTS: Use of H2 antagonists may result in decreased levels and effectiveness of infigratinib and selpercatinib.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of H2 antagonists, proton pump inhibitors, and locally-acting antacids in patients receiving treatment with infigratinib or selpercatinib. If coadministration with H2 antagonists cannot be avoided, take infigratinib or selpercatinib at least 2 hours before or 10 hours after the H2 antagonist.(1,2) If the H2 antagonist is replaced with an antacid, take infigratinib or selpercatinib 2 hours before or 2 hours after the antacid.(1,2) If the H2 antagonist is replaced with a proton pump inhibitor, take selpercatinib with food.(2) Avoid taking proton pump inhibitors with infigratinib.(1)

DISCUSSION: Infigratinib is practically insoluble at pH 6.8.(1) In a study, ranitidine given 10 hours before and 2 hours after selpercatinib did not have a clinically significant effect on selpercatinib pharmacokinetics.(2)

Serum Phosphate Level-Altering Drugs/Erdafitinib

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

MECHANISM OF ACTION: Medications that alter serum phosphate may interfere with interpretation of phosphate levels that are needed to determine initial erdafitinib dose.(1)

CLINICAL EFFECTS: Serum phosphate levels that are elevated by concomitant medications may result in an inappropriately low dose and decreased effectiveness of erdafitinib. Serum phosphate levels that are decreased by concomitant medications may result in an inappropriately high dose and increased toxicity from erdafitinib.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of erdafitinib states that agents that alter serum phosphate levels should be avoided before the initial dose increase period for erdafitinib based on serum phosphate levels (days 14 to 21).(1)

DISCUSSION: Concomitant administration of serum phosphate level-altering agents during the initial dose increase period of erdafitinib based on serum phosphate levels (days 14 to 21) may interfere with serum phospate levels and lead to incorrect dosing of erdafitinib.(1) Agents that may alter serum phosphate levels linked to this monograph include: aluminum carbonate, aluminum hydroxide, calcium acetate, calcium carbonate, calcium citrate, cod liver oil, ferric citrate, lanthanum, magnesium carbonate, magnesium hydroxide, potassium phosphate, sevelamer, sodium phosphate, sucroferric oxyhydroxide, tenapanor, and vitamin D.(1)

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

Agents Affecting Gastric Ph/Itraconazole; Ketoconazole

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

MECHANISM OF ACTION: Antacids, buffers in didanosine products, H2 antagonists, and proton-pump inhibitors increase the stomach pH. Quinapril tablets may contain a high percentage of magnesium. Since some orally administered azole antifungal agents require an acidic medium for optimal absorption, agents may decrease the absorption of azole antifungal agents.

CLINICAL EFFECTS: Simultaneous administration of an antacid, buffered didanosine, a H2 antagonist, or a proton-pump inhibitor may result in decreased therapeutic effects of the azole antifungal.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If the concurrent administration of these two agents cannot be avoided, consider administering two capsules of glutamic acid hydrochloride 15 minutes before administering the antifungal and separate the administration times of the antifungal and the agent affecting gastric pH by at least two hours.

DISCUSSION: Itraconazole, ketoconazole, and posaconazole require an acidic medium for predictable dissolution and absorption decreases as pH increases and proton pump inhibitors are expected to decrease their absorption.(1-4) In a study in 11 healthy subjects, omeprazole (40 mg daily) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of itraconazole (200 mg single dose) by 66% and 64%, respectively.(5) In a study in 15 healthy subjects, omeprazole (40 mg daily) had no effect on the pharmacokinetics of itraconazole solution.(6) In a study in 9 healthy subjects, omeprazole (60 mg) decreased the AUC of ketoconazole (200 mg single dose) by 83.4% compared to control (ketoconazole alone). Administration of Coca-Cola (240 ml) with ketoconazole and omeprazole raised ketoconazole AUC to 65% of control values.(7) Omeprazole has been shown to have no significant effect on the absorption of fluconazole(8) or voriconazole.(9) Case reports and in-vivo studies have documented significant decreases in ketoconazole levels during concurrent therapy with H-2 antagonists, including cimetidine and ranitidine. Concurrent administration of itraconazole and famotidine resulted in a significant decrease in itraconazole levels, but no significant changes in famotidine levels. An interaction should be expected to occur between both ketoconazole or itraconazole and the other H-2 antagonists.(10-14) In randomized, open-labeled, cross-over study in 12 healthy subjects, simultaneous administration of an antacid decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of itraconazole (200 mg) by 66% and 70%, respectively. Time to Cmax (Tmax) increased by 70%.(15) This interaction has also been reported in a case report.(16) In a study in 3 subjects, simultaneous administration of a combination aluminum hydroxide/magnesium hydroxide (30 ml) decreased the AUC of a single dose of ketoconazole (200 mg) by 41%.(172) In a case report, a patient receiving concurrent ketoconazole with aluminum hydroxide, cimetidine, and sodium bicarbonate did not respond to therapy until cimetidine was discontinued and the administration time of aluminum hydroxide and cimetidine was changed to 2 hours after ketoconazole. In a follow-up study in 2 subjects, concurrent cimetidine and sodium hydroxide lowered ketoconazole levels.(18) In a study in 14 subjects, simultaneous administration of aluminum hydroxide/magnesium hydroxide (20 ml, 1800 mg/1200 mg) had no significant effects on fluconazole pharmacokinetics.(3) In a randomized, open-label, cross-over study in 6 subjects, simultaneous administration of itraconazole with buffered didanosine tablets resulted in undetectable levels of itraconazole.(19) In a randomized cross-over study in 12 HIV-positive subjects, administration of buffered didanosine tablets 2 hours after ketoconazole had no effects on ketoconazole levels.(20) In a randomized, cross-over, open-label study in 24 healthy subjects, simultaneous administration of enteric-coated didanosine had no effect on ketoconazole pharmacokinetics.(21) 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.

Aluminium And Magnesium Antacids/Sotalol

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

MECHANISM OF ACTION: Aluminum- and magnesium-containing antacids may reduce the absorption of sotalol.(1)

CLINICAL EFFECTS: Simultaneous administration of sotalol with antacids containing aluminum or magnesium may result in decreased levels and effectiveness of sotalol.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If coadministration with an aluminum- or magnesium-containing antacid agent is unavoidable, take the antacid 2 hours before or 2 hours after sotalol.(1)

DISCUSSION: In a study with 6 healthy volunteers, administration of oral sotalol simultaneously with antacids reduced the maximum concentration (Cmax) and area under the curve (AUC) of sotalol by 26% and 20%, respectively, compared to sotalol alone. There was a 25% reduction in the bradycardic effect at rest. Administration of the antacid two hours after oral sotalol had no effect on the pharmacokinetics or pharmacodynamics of sotalol.(1,2)

Aluminum & Mag Antacids; Lanthanum; Sevelamer/Mycophenolate

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

MECHANISM OF ACTION: Aluminum or magnesium antacids and non-calcium containing phosphate binders such as lanthanum and sevelamer decrease the absorption of mycophenolate.(1-3)

CLINICAL EFFECTS: The simultaneous administration of mycophenolate with aluminum or magnesium antacids and non-calcium containing phosphate binders such as lanthanum and sevelamer may decrease the levels of mycophenolate and its clinical effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of mycophenolate mofetil states that calcium free phosphate binders, such as sevelamer, should not be administered simultaneously with mycophenolate mofetil. Administer sevelamer at least 2 hours after administration of mycophenolate mofetil to decrease the extent of the interaction.(1) The US manufacturer of mycophenolate sodium states that mycophenolate sodium should not be administered simultaneously with antacids. Administer aluminum or magnesium containing antacids at least 2 hours after mycophenolate.(2) Close monitoring of mycophenolic acid levels may be warranted in patients on mycophenolate mofetil therapy that are initiating or discontinuing concurrent therapy with these agents. Patients on concurrent therapies may also require higher doses of mycophenolate mofetil in order to achieve desired blood levels.

DISCUSSION: In a study in 10 rheumatoid arthritis patients, the simultaneous administration of mycophenolate and Maalox TC (an antacid containing magnesium and aluminum hydroxide) resulted in decreases in the maximum concentration (Cmax) and area-under-curve (AUC) of mycophenolate by 33% and 17%, respectively.(1,2) In a study of 3 adult patients and 6 pediatric patients with stable renal graft function receiving mycophenolate mofetil, sevelamer (3-4 capsules of 403 mg twice daily) decreased the AUC and Cmax of mycophenolic acid by 26% and 36%, respectively.(1,3) In a study in 12 stable renal transplant patients, administration of magnesium-aluminum-containing antacids (30 ml) increased the Cmax and AUC of a single dose of mycophenolate sodium by 25% and 37%, respectively.(2)

Aluminum And Magnesium Antacids/Strontium

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

MECHANISM OF ACTION: Aluminum and magnesium containing antacids may reduce the absorption of strontium.(1,2)

CLINICAL EFFECTS: Simultaneous administration of strontium with antacids containing aluminum or magnesium may result in decreased levels and effectiveness of strontium.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK manufacturer of strontium states that administration of strontium and antacids containing aluminum or magnesium should be separated by at least 2 hours when practical.(1) The US manufacturer of strontium states that it is preferable to take antacids containing aluminum and magnesium at least 2 hours after strontium. However, when this dosing regimen is impractical due to the recommended administration of strontium at bedtime, concomitant intake remains acceptable.(2) Some vitamin preparations may contain sufficient quantities of magnesium salts with antacid properties to interact as well.

DISCUSSION: Simultaneous administration of strontium with aluminum and magnesium hydroxides 2 hours before or together with strontium decreased the area-under-curve (AUC) of strontium by 20%-25%. Absorption was almost unaffected when the antacid was given 2 hours after strontium.(1)

Aluminum And Magnesium Antacids; Lanthanum/Quinine

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

MECHANISM OF ACTION: Aluminum and magnesium antacids may delay or decrease the absorption of quinine.

CLINICAL EFFECTS: Concurrent use of antacids may result in decreased levels and effectiveness of quinine.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of quinine states that concurrent use with aluminum or magnesium containing antacids should be avoided. Some vitamin preparations may contain sufficient quantities of magnesium salts with antacid properties to interact as well.

DISCUSSION: Aluminum and magnesium antacids have been shown to decrease quinine absorption in rats.

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)

Aluminum; Magnesium Compounds/Selected Cephalosporins

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

MECHANISM OF ACTION: Aluminum and magnesium containing antacids may form chelation complexes with some cephalosporins, preventing their absorption.(1,2)

CLINICAL EFFECTS: Simultaneous administration of an aluminum and/or magnesium containing antacid with some cephalosporins may result in decreased levels and effectiveness of the cephalosporin.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of cefdinir recommends that cefdinir be taken at least 2 hours before or after an aluminum and/or magnesium containing antacid.(1) It would be prudent to separate the administration of cefaclor by at least this amount of time as well.(2)

DISCUSSION: Simultaneous administration of cefdinir (300 mg) with Maalox TC (30 ml) decreased cefdinir area-under-curve (AUC) and maximum concentration (Cmax) by 40%.(1) In a study in 15 healthy subjects, simultaneous administration of cefaclor advanced formulation (500 mg) with Maalox TC decreased the extent of cefaclor absorption.(2)

Aluminum; Magnesium-Containing Compounds/Gabapentin

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

MECHANISM OF ACTION: Aluminum or magnesium containing products may reduce the bioavailability of gabapentin.(1)

CLINICAL EFFECTS: Simultaneous administration of aluminum or magnesium containing products and gabapentin may result in decreased absorption of gabapentin by 20% and reduce its clinical effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If the use of both medications is unavoidable, it is recommended that gabapentin be taken at least 2 hours following the administration of aluminum or magnesium containing products.(1)

DISCUSSION: In 16 subjects, Maalox reduced the bioavailability of gabapentin by about 20%. The reduction was only 5% when gabapentin was administered 2 hours after the Maalox dose. It is for this reason that the manufacturer of gabapentin recommends that it be taken at least 2 hours after the administration of aluminum or magnesium containing products.(1)

Antacids And Selected Minerals/Oral Iron Supplements

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

MECHANISM OF ACTION: Some antacids may bind to iron, preventing its absorption. Alterations in gastric pH by antacids may also play a role. Iron may bind to other minerals such as calcium, manganese, tin, and zinc in the GI tract.

CLINICAL EFFECTS: Simultaneous administration of an antacid or minerals may decrease the absorption of orally administered iron.

PREDISPOSING FACTORS: The interaction with some combinations may be affected by the presence or absence of food.

PATIENT MANAGEMENT: Iron supplements should not be taken within 1 hour before or 2 hours after antacids, calcium, manganese, or zinc.(1) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: Magnesium hydroxide has been shown to inhibit the absorption of elemental iron,(2) although other studies have shown conflicting results.(3,4) Sodium bicarbonate has been shown to decrease the absorption of iron by 50%.(3) In a study in 61 healthy subjects, calcium citrate, calcium carbonate, and calcium phosphate inhibited iron absorption when taken with food. However, in the fasted state, calcium carbonate had no effect on iron absorption. In the fasted state, calcium citrate and calcium phosphate decreased iron absorption by 49% and 62%, respectively,(6) In a study in 23 healthy subjects, calcium acetate and calcium carbonate decreased the area-under-curve (AUC) of elemental iron (65 mg) by 27% and 19%, respectively.(7) In a study, manganese decreased iron absorption. A ratio of 5:1 of zinc:iron decreased iron absorption by 56%.(8) In a study, inorganic iron decreased zinc absorption.(9) In another study, ferrous sulfate decreased the absorption of zinc sulfate in a concentration dependent manner; however, heme chloride had no effect on zinc sulfate.(10) In a study in premature infants, administration of liquid zinc and iron supplements between feedings decreased iron uptake; however, no effect was seen when the supplements were mixed with feedings.(11) 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.

Antacids/Defactinib

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

MECHANISM OF ACTION: The aqueous solubility of defactinib is pH dependent. Higher gastric pH leads to lower solubility which may reduce defactinib absorption.(1)

CLINICAL EFFECTS: Coadministration with antacids may reduce the bioavailability of defactinib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of defactinib states that patients requiring acid-lowering therapy should separate defactinib from antacid administration by 2 hours.(1) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: The impact of antacids on the pharmacokinetics of defactinib has not been investigated in clinical studies. In an interaction study, defactinib area-under-the-curve (AUC) decreased by 79% and maximum concentration (Cmax) decreased by 85% following concomitant use of multiple doses of omeprazole 40 mg daily. The AUC and Cmax of N-desmethyl amide (M4), a major active metabolite of defactinib, decreased by 83% and 88%, respectively.(1)

Antacids/Delavirdine

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

MECHANISM OF ACTION: The exact mechanism is unknown. Antacids decrease the absorption of delavirdine.(1)

CLINICAL EFFECTS: The simultaneous administration of delavirdine with an antacid may decrease the absorption of delavirdine, which may result in subtherapeutic levels.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The administration of delavirdine and antacids should be separated by at least one hour.(1) Some vitamin preparations may contain sufficient quantities of magnesium salts with antacid properties to interact as well.

DISCUSSION: In a single dose study in 12 healthy subjects, the simultaneous administration of delavirdine with an alumina and magnesia oral suspension (20 ml) decreased the delavirdine area-under-curve (AUC) and maximum concentration (Cmax) by 44% and 52%, respectively.(1)

Antacids/Infigratinib; Selpercatinib

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

MECHANISM OF ACTION: The solubility of infigratinib and selpercatinib is pH dependent. Antacid-induced changes in gastric pH may decrease the absorption of infigratinib and selpercatinib.(1,2)

CLINICAL EFFECTS: Simultaneous administration of antacids may result in decreased levels and effectiveness of infigratinib and selpercatinib.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of antacids, proton pump inhibitors (PPIs), and H2 antagonists, in patients receiving treatment with infigratinib or selpercatinib. If coadministration with antacids cannot be avoided, take infigratinib or selpercatinib at least 2 hours before or 2 hours after the antacid.(1,2) If the antacid is replaced with a H2 antagonist, take infigratinib or selpercatinib 2 hours before or 10 hours after the H2 antagonist.(1,2) If the antacid is replaced with a PPI, take selpercatinib with food.(2)

DISCUSSION: Infigratinib is practically insoluble at pH 6.8.(1) Selpercatinib solubility is pH dependent.(2) Antacids may decrease the solubility and absorption of infigratinib and selpercatinib and decrease their effectiveness.

Antacids/Pritelivir

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

MECHANISM OF ACTION: The aqueous solubility of pritelivir is pH dependent. Higher gastric pH leads to lower solubility which may reduce pritelivir absorption.(1)

CLINICAL EFFECTS: Coadministration of antacids may reduce the bioavailability of pritelivir, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Take pritelivir at least 2 hours before or 2 hours after antacids.(1)

DISCUSSION: The combination of pritelivir with antacids has not been studied. Pritelivir absorption is pH-dependent.(1) Coadministration of a single oral dose of 100 mg pritelivir (on Day 1) with esomeprazole 40 mg once daily (from day -3 to Day 1; 4 days total) decreased pritelivir's maximum concentration (Cmax) by 76% and area-under-curve (AUC) by 59% compared to pritelivir administered alone.(1)

Antacids/Rilzabrutinib

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

MECHANISM OF ACTION: Rilzabrutinib solubility decreases with increasing pH. Antacid induced increase in gastric pH may result in a decrease in rilzabrutinib absorption.(1)

CLINICAL EFFECTS: Simultaneous administration of an antacid may result in decreased levels and effectiveness of rilzabrutinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Administer rilzabrutinib at least 2 hours before taking antacids.(1) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: The impact of antacids on the pharmacokinetics of rilzabrutinib has not been investigated in clinical studies. In an interaction study, administration of famotidine (H2 receptor antagonist) two hours after the evening dose of rilzabrutinib decreased the next morning dose of rilzabrutinib maximum concentration (Cmax) by 35% and area-under-curve (AUC) by 28%.(1) In another interaction study, coadministration of esomeprazole decreased rilzabrutinib Cmax by 55% and AUC by 51%.(1)

Antacids/Riociguat

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

MECHANISM OF ACTION: The mechanism of interaction is not clear. Increased gastric pH is thought to decrease riociguat solubility and absorption.(1)

CLINICAL EFFECTS: Simultaneous administration of riociguat with an antacid may result in decreased levels and effectiveness of riociguat.(1-2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Separate the administration of antacids and riociguat by at least 1 hour.(1) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: Administration of 10 mL of an aluminum hydroxide-magnesium hydroxide containing antacid decreased the area-under-curve (AUC)and maximum concentration (Cmax)of riociguat by 34% and 56% respectively.(1)

Antacids/Selected Kinase Inhibitors

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

MECHANISM OF ACTION: The solubility of bosutinib,(1) dasatinib,(2) erlotinib,(3) gefitinib,(4) neratinib,(5) nilotinib(6), pazopanib,(7) and pexidartinib(8) is pH dependent. Antacid-induced changes in gastric pH may decrease the absorption of these agents.(1-8)

CLINICAL EFFECTS: Simultaneous administration of antacids may result in decreased levels and effectiveness of bosutinib,(1) dasatinib,(2) erlotinib,(3) gefitinib,(4) neratinib,(5) nilotinib(6), pazopanib,(7) and pexidartinib.(8)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antacid use should be considered in place of H2 blockers or proton pump inhibitors in patients receiving bosutinib,(1) dasatinib,(2) erlotinib,(3) gefitinib,(4) neratinib,(5) nilotinib(6), pazopanib,(7) and pexidartinib;(8) however, separation of administration times is required. If antacids are used, separate the administration times by several hours(1-8) but at least 2 hours for bosutinib,(1) dasatinib,(2) nilotinib,(6) and pexidartinib(8), 6 hours for gefitinib,(4) and 3 hours for neratinib.(5) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: In a study in 24 healthy subjects, lansoprazole (60 mg) decreased bosutinib (400 mg single dose) area-under-curve (AUC) and maximum concentration (Cmax) by 26% and 46%, respectively.(1) In a study in 24 healthy subjects, simultaneous administration of dasatinib (50 mg) with aluminum hydroxide/magnesium hydroxide (30 ml) decreased dasatinib AUC and Cmax by 55% and 58%, respectively. In the same subjects, administration of the antacid 2 hours before dasatinib decreased dasatinib Cmax by 26%, but had no effect on dasatinib AUC.(2) In a study in 24 healthy subjects, administration of a single dose of dasatinib (50 mg) 10 hours after famotidine decreased dasatinib AUC and Cmax by 61% and 63%, respectively.(2) In a study, concurrent omeprazole decreased the AUC and Cmax of erlotinib by 46% and 61%, respectively.3) In a study, concurrent esomeprazole decreased the AUC of nilotinib by 34%.(6) In a study in 15 healthy subjects, lansoprazole (30 mg at steady state) decreased the Cmax and AUC of a single dose of neratinib (240 mg) by 71% and 65%, respectively.(5) There were no significant changes in nilotinib pharmacokinetics when famotidine was administered 10 hours before or 2 hours after nilotinib.(6) There were no significant changes in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered 2 hours before or after nilotinib.(6) Coadministration of esomeprazole decreased pexidartinib Cmax and AUC by 55% and 50%, respectively.(8)

Antacids/Sotorasib

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

MECHANISM OF ACTION: The aqueous solubility of sotorasib is pH dependent. Higher gastric pH leads to lower solubility which may reduce sotorasib absorption.(1)

CLINICAL EFFECTS: Coadministration of antacids may reduce the bioavailability of sotorasib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of sotorasib with proton pump inhibitors, H2 antagonists, and antacids should be avoided. If coadministration with an acid-reducing agent is unavoidable, take sotorasib 4 hours before or 10 hours after a locally acting antacid.(1)

DISCUSSION: The solubility of sotorasib in the aqueous media decreases over the range pH 1.2 to 6.8 from 1.3 mg/mL to 0.03 mg/mL. In an interaction study, coadministration of repeat doses of omeprazole with a single dose of sotorasib decreased sotorasib maximum concentration (Cmax) by 65% and area-under-curve (AUC) by 57% under fed conditions, and decreased sotorasib Cmax by 57% and AUC by 42% under fasted conditions. Coadministration of a single dose of famotidine given 10 hours prior to and 2 hours after a single dose of sotorasib under fed conditions decreased sotorasib Cmax by 35% and AUC by 38%.(1)

Antacids/Taletrectinib

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

MECHANISM OF ACTION: The aqueous solubility of taletrectinib is pH dependent. Higher gastric pH leads to lower solubility which may reduce taletrectinib absorption.(1)

CLINICAL EFFECTS: Coadministration with antacids may reduce the bioavailability of taletrectinib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of taletrectinib states that patients requiring acid-lowering therapy should separate taletrectinib from antacid administration by 2 hours.(1) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: The impact of antacids on the pharmacokinetics of taletrectinib has not been investigated in clinical studies. In an interaction study, taletrectinib area-under-the-curve (AUC) decreased by 40% and maximum concentration (Cmax) decreased by 65% following concomitant use of omeprazole 40 mg daily.(1)

Antacids; Buffered Formulations/Amprenavir; Atazanavir

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

MECHANISM OF ACTION: Antacids increase gastric pH. As gastric pH increases, the solubility of atazanavir decreases.(1,2) The exact mechanism behind the interaction between amprenavir and antacids is unknown.(3)

CLINICAL EFFECTS: Simultaneous administration of amprenavir or atazanavir with antacids or buffered formulations may result in decreased levels and effectiveness of amprenavir(3) and atazanavir.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of amprenavir states that amprenavir should be administered 1 hour before or after antacids or buffered formulations such as didanosine.(3) The manufacturer of atazanavir states that atazanavir should be administered 2 hours before or 1 hour after antacids or buffered formulations.(1,2) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: Simultaneous administration of atazanavir with didanosine buffered tablets decreased atazanavir area-under-curve (AUC), maximum concentration (Cmax) and minimum concentration (Cmin) by 87%, 89% and 84%, respectively. Administration of atazanavir 1 hour after didanosine buffered tablets had no significant effect on atazanavir pharmacokinetics.(1) Other buffered formulations and antacids are expected to substantially decrease atazanavir concentrations and therapeutic effectiveness as well.(1,2)

Antacids; H2 Antagonists/Ledipasvir; Velpatasvir

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

MECHANISM OF ACTION: The aqueous solubility of ledipasvir and velpatasvir is pH dependent. Higher gastric pH leads to lower solubility which may reduce ledipasvir and velpatasvir's absorption.(1-3)

CLINICAL EFFECTS: Administration of antacids and H2 antagonists may reduce the bioavailability of ledipasvir and velpatasvir, leading to decreased systemic levels and effectiveness.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: In order to assure systemic absorption and maximal effectiveness from use of this Hepatitis C treatment, counsel patient to separate products containing ledipasvir or velpatasvir from antacid administration by 4 hours.(1-3) H2 antagonists may be administered simultaneously or 12 hours apart from products containing ledipasvir or velpatasvir at a dose that does not exceed doses comparable to famotidine 40 mg twice daily (or a total daily dose comparable to famotidine 80 mg).(1-3) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: In an interaction study, famotidine 40 mg, given with or 12 hours after a ledipasvir-sofosbuvir dose did not have significant effects on ledipasvir-sofosbuvir exposure.(1) In an interaction study, famotidine 40 mg, given with or 12 hours prior to a velpatasvir-sofosbuvir dose did not have a significant effect on velpatasvir-sofosbuvir exposure.(2) In an interaction study, famotidine (dosage not stated) did not have a significant effect on the pharmacokinetic of sofosbuvir, velpatasvir, or voxilaprevir.(3)

Antacids; H2 Antagonists/Rilpivirine

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

MECHANISM OF ACTION: Rilpivirine requires an acidic medium for absorption. Antacid or H2 antagonist induced decrease in gastric pH may result in a decrease in rilpivirine absorption.(1)

CLINICAL EFFECTS: 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: In patients maintained on rilpivirine, administer antacids at least 2 hours before or 4 hours after rilpivirine.(1) In patients maintained on rilpivirine, administer H2 antagonists at least 12 hours before or 4 hours after rilpivirine.(1) Concurrent use of proton pump inhibitors with rilpivirine is contraindicated.(1) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: In a study in 16 subjects, omeprazole (20 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (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 after a single dose of rilpivirine (150 mg) increased the rilpivirine Cmax and AUC by 21% and 13%, respectively.(1)

Antacids; Selected H2 Antagonists/Acalabrutinib Capsules

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

MECHANISM OF ACTION: Acalabrutinib capsules solubility decreases with increasing pH. Antacid or H2 antagonist induced increase in gastric pH may result in a decrease in acalabrutinib capsules absorption.(1)

CLINICAL EFFECTS: Simultaneous administration of an antacid or a H2 antagonist may result in decreased levels and effectiveness of acalabrutinib capsules.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Separate administration of acalabrutinib capsules and antacids by at least 2 hours.(1) In patients on acalabrutinib capsules, administer acalabrutinib capsules at least 2 hours before taking H2 antagonists.(1) Concurrent use of proton pump inhibitors with acalabrutinib capsules is not recommended.(1) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well. Acalabrutinib tablets are not affected by coadministration with H2 antagonists or antacids, and may be used concurrently.(1)

DISCUSSION: In a study in healthy subjects, coadministration with an antacid (calcium carbonate 1 gram) decreased area-under-curve (AUC) of acalabrutinib capsules by 53%. Coadministration with a proton pump inhibitor (omeprazole 40 mg for 5 days) decreased AUC of acalabrutinib capsules by 43%.(1)

Calcium; Iron; Sucralfate/Thyroid Preparations

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

MECHANISM OF ACTION: The mechanism by which malabsorption of thyroid preparations occurs from calcium-containing products is presumed to be a binding of the medication to the thyroid hormone, forming an insoluble or nonabsorbable complex.(1-3) Iron may form a ferric-thyroxine complex with thyroid agents, preventing their absorption from the gastrointestinal tract.(1,4) Sucralfate binds to other agents in the gastrointestinal tract and alters absorption of other drugs, including thyroid agents.(1,5)

CLINICAL EFFECTS: The simultaneous administration of thyroid preparations with calcium, iron, or sucralfate may result in decreased levels and clinical effects of thyroid preparations.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Instruct patients to separate the administration time of thyroid preparations from calcium or iron by as much time as possible, preferably by at least four hours.(1) Administer thyroid preparations at least 2 hours before sucralfate.(5) Patients taking thyroid preparations and calcium- or iron-containing products or sucralfate should be monitored for changes in thyroid function. The dosage of the thyroid preparation may need to be increased. Separating the administration times of the thyroid preparation and the calcium- or iron-containing products or sucralfate may decrease the effects of the interaction.(1-5)

DISCUSSION: In a pharmacokinetic study 8 healthy, euthyroid adults were given levothyroxine alone and levothyroxine coadministered with calcium carbonate, calcium citrate, or calcium acetate in doses containing 500 mg elemental calcium. The coadministration of each of the three calcium preparations significantly reduced levothyroxine absorption by about 20%-25% compared with levothyroxine given alone.(3) In a study in 14 subjects, the simultaneous administration of thyroxine with ferrous sulfate for 12 weeks resulted in an increase in the mean level of thyroid stimulating hormone (TSH) from 1.6+/-0.4 mU/L to 5.4+/-2.8 mU/L. Mixing thyroxine with ferrous sulfate in vitro resulted in a poorly soluble complex.(4) In a study in 20 hypothyroid patients, the simultaneous administration of levothyroxine and calcium carbonate (1200 mg) daily for three months resulted in reductions in the mean free T4 and total T4 levels. These values increased in most patients following the discontinuation of calcium carbonate. A concurrent in-vitro study found that calcium carbonate adsorbed levothyroxine in solution at a pH of 2, gastric pH, but not at a pH of 7.4.(6) One author reported three cases of decreased levothyroxine efficacy following the addition of calcium carbonate to therapy.(7) In a study in 5 healthy subjects, levothyroxine (five 200 mcg tablets) was administered in 3 different dosing regimens: after an overnight fast, with the fifth and final dose of sucralfate (1 gram every 6 hours) and 8 hours after the second and final dose of sucralfate (2 grams every 12 hours). When administered alone, 80% of levothyroxine was absorbed within 6 hours of administration, compared to 23% when administered concurrently with sucralfate. There was no difference in levothyroxine absorption when administered alone or 8 hours after sucralfate.(8) There are several case reports documenting decreased effects of thyroid supplementation as the result of simultaneous administration of sucralfate.(9,10) 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.

Calcium; Iron; Sucralfate/Tiratricol

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

MECHANISM OF ACTION: The mechanism by which malabsorption of thyroid preparations such as tiratricol occurs from calcium-containing products is presumed to be a binding of the medication to the thyroid hormone, forming an insoluble or nonabsorbable complex.(1,2) Iron may form a ferric-thyroxine complex with thyroid agents such as tiratricol, preventing their absorption from the gastrointestinal tract.(1,2) Sucralfate binds to other agents in the gastrointestinal tract and alters absorption of other drugs, including thyroid agents such as tiratricol.(1-3)

CLINICAL EFFECTS: The simultaneous administration of thyroid preparations with calcium, iron, or sucralfate may result in decreased levels and clinical effects of thyroid preparations.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Instruct patients to take iron and calcium supplements at the same time every day relative to tiratricol dosing.(6,7) Patients taking thyroid preparations and calcium- or iron-containing products or sucralfate should be monitored for changes in thyroid function. The dosage of the thyroid preparation may need to be increased. Separating the administration times of the thyroid preparation and the calcium- or iron-containing products or sucralfate may decrease the effects of the interaction.(1-3)

DISCUSSION: Iron and calcium may interfere with the absorption of tiratricol.(1,2)

Di-; Trivalent Cations/Chloroquine; Hydroxychloroquine

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

MECHANISM OF ACTION: Di- and trivalent cations such as aluminum, calcium, lanthanum, and magnesium may adsorb chloroquine and hydroxychloroquine; preventing their absorption.(1-5) The adsorption may also limit the effectiveness of the di- or trivalent cation.(1)

CLINICAL EFFECTS: Simultaneous administration of di- or trivalent cations may result in decreased levels and effectiveness of chloroquine and hydroxychloroquine(2-5) and decreased effectiveness of the di- or trivalent cation.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Instruct patients to separate the administration times of these medicines by 2 to 4 hours.(2,3)

DISCUSSION: Adsorption of chloroquine by magnesium trisilicate was found to decrease hydrochloric acid uptake and decrease the amount of magnesium released in an acidic environment.(1) In a study, calcium carbonate, kaolin, and magnesium trisilicate were found to decrease the absorption of chloroquine by 52.8%, 46.5%, and 31.3%, respectively.(3) Magnesium trisilicate and magnesium oxide have been shown to decrease the release of chloroquine from tablets and to adsorb chloroquine after its release.(4) In a study in 6 subjects, magnesium trisilicate and kaolin decreased the area-under-curve (AUC) of chloroquine by 18.2% and 28.6%, respectively.(5)

Divalent & Trivalent Cations/Tetracyclines

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

MECHANISM OF ACTION: Di- and trivalent cations may form chelation complexes with tetracyclines, preventing their absorption.(1,2)

CLINICAL EFFECTS: Simultaneous administration of di- or trivalent cations may result in decreased levels of and therapeutics effects from tetracyclines.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Administer tetracyclines at least two hours before or after the di- or trivalent cations. When used for the treatment of H. pylori infection, tetracyclines and bismuth should be given simultaneously. The US manufacturer of omadacycline states to fast for at least four hours, administer omadacycline, and then wait four hours before taking di- or trivalent cations.(21) The US manufacturer of ferric maltose recommends separation of ferric maltose by at least 4 hours.(22)

DISCUSSION: Concurrent administration of aluminum hydroxide or divalent cations (such as calcium, magnesium, or zinc) has been shown to significantly decrease the gastrointestinal absorption of tetracycline.(3-5) Concurrent administration of tetracycline and magnesium-aluminum hydroxide gel has been shown to decrease the tetracycline area-under-curve (AUC) by 90%.(6) Magnesium-aluminum silicate has been shown to decrease the AUC of tetracycline by 27%.(7) Demeclocycline(8,9) methacycline,(10) chlortetracycline,(11) and oxytetracycline(10,12) have been shown to interact with aluminum hydroxide and/or dairy products. Doxycycline has been reported to interact with aluminum hydroxide gel.(13) Aluminum magnesium hydroxide has been shown to decrease doxycycline absorption by 84%.(14) Minocycline absorption has been shown to be impaired by aluminum, calcium, and magnesium.(15) Bismuth subsalicylate has been shown to decrease absorption of doxycycline and tetracycline by 37%(16) and 34%,(17) respectively. Since sucralfate is an aluminum salt of a sulfated disaccharide, it may also prevent absorption of tetracyclines. This complex has been used to provide site-specific delivery of tetracycline to gastric ulcers in the treatment of Helicobacter pylori gastric ulcer disease and may be useful in some indications.(18) Quinapril tablets contain a high percentage of magnesium and have been shown to decrease the absorption of tetracycline by 28-37%.(19) Lanthanum is expected to interact with tetracyclines as well.(20)

H2 Antagonists/Atazanavir

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

MECHANISM OF ACTION: H-2 antagonists increase gastric pH. As gastric pH increases, the solubility of atazanavir decreases.(1,2)

CLINICAL EFFECTS: Concurrent use of atazanavir and a H-2 antagonist may result in decreased levels and effectiveness of atazanavir.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Australian and US manufacturers of atazanavir(1,2) and cobicistat(3,4) state that patients who require H-2 antagonist therapy should receive atazanavir 300 mg daily with ritonavir 100 mg daily or cobicistat 150 mg daily, taken with and/or at least 10 hours after the H-2 antagonist dose. Patients who are also on tenofovir in addition to atazanavir and a H-2 antagonist should receive atazanavir 400 mg daily with ritonavir 100 mg daily or cobicistat 150 mg daily.(2,3,5) The dose of the H-2 antagonist should not exceed the equivalent of famotidine 40 mg twice daily in treatment-naive patients, and 20 mg twice daily in treatment-experienced patients.(2-5) Treatment-experienced pregnant patients in the second or third trimester on concurrent tenofovir disoproxil should have their atazanavir dose increased to 400 mg with ritonavir 100 mg daily. The use of atazanavir with both a H2-antagonist and tenofovir in treatment-experienced pregnant women is not recommended.(2) The Australian manufacturer of atazanavir states that atazanavir without ritonavir is not recommended when co-administered with H-2 antagonists.(1) The US manufacturer of atazanavir states that treatment-naive patients who are unable to tolerate ritonavir or cobicistat should receive atazanavir 400 mg daily with food at least 2 hours before and at least 10 hours after the H-2 antagonist. The H-2 antagonist dose should not exceed the equivalent of a 20 mg single dose of famotidine and the total daily dose should not exceed a 40 mg equivalent dose of famotidine. Treatment-experienced patients should not use unboosted atazanavir with a H-2 antagonist.(2) The US manufacturer of atazanavir states that atazanavir should not be administered without ritonavir in pediatric patients at least 13 years of age who weigh at least 40 kg who are receiving a H2 antagonist. Data are not sufficient to recommend a dose of atazanavir in patients weighing less than 40 kg.(2)

DISCUSSION: In a study in 15 subjects, simultaneous administration of atazanavir (400 mg daily) with famotidine (40 mg twice daily) decreased the atazanavir maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) by 47%, 41%, and 42%, respectively.(2) In a study in 14 subjects, atazanavir (400 mg daily) was administered 2 hours before and 10 hours after famotidine (40 mg twice daily). Atazanavir Cmax increased 8%. Atazanavir AUC and Cmin decreased by 5% and 21%, respectively.(2) In a study in 14 subjects, atazanavir (300 mg daily) and ritonavir (100 mg daily) were administered simultaneously with famotidine (40 mg twice daily). Atazanavir Cmax, AUC, and Cmin decreased by 14%, 18%, and 28%, respectively, compared to the same regimen alone. However, atazanavir Cmax was similar to levels seen with atazanavir 400 mg alone. Atazanavir AUC and Cmin were 1.79-fold and 4.46-fold higher than levels seen with atazanavir 400 mg alone.(2) In a study in 18 subjects, simultaneous administration of famotidine (20 mg twice daily) and atazanavir/ritonavir (300/100 mg daily) decreased the Cmax, AUC, and Cmin of atazanavir by 9%, 10%, and 19%, respectively.(2) In a study in 20 subjects, administration of atazanavir/ritonavir/tenofovir (300/100/300 mg daily) 12 hours after famotidine (40 mg daily) decreased the Cmax, AUC, and Cmin of atazanavir by 11%, 12%, and 23%, respectively.(2) In a study in 18 subjects, administration of atazanavir/ritonavir/tenofovir (300/100/300 mg daily) 12 hours after the evening dose and two hours before the morning dose of famotidine (40 mg twice daily) decreased the Cmax, AUC, and Cmin of atazanavir by 26%, 21%, and 28%, respectively.(2) In a study in 15 subjects, administration of atazanavir/ritonavir (400/100 mg) with famotidine (40 mg twice daily) decreased atazanavir Cmin by 14%. There were no significant effects on atazanavir Cmax or AUC.(2)

H2 Antagonists/Pritelivir

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

MECHANISM OF ACTION: The aqueous solubility of pritelivir is pH dependent. Higher gastric pH leads to lower solubility which may reduce pritelivir absorption.(1)

CLINICAL EFFECTS: Coadministration of H2 receptor antagonists may reduce the bioavailability of pritelivir leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Take pritelivir at least 2 hours before or 12 hours after H2 receptor antagonists.(1)

DISCUSSION: The combination of pritelivir with H2 receptor antagonists has not been studied. Pritelivir absorption is pH-dependent. Coadministration of a single oral dose of 100 mg pritelivir (on Day 1) with esomeprazole 40 mg once daily (from day -3 to Day 1; 4 days total) decreased maximum concentration (Cmax) by 76% and area-under-curve (AUC) by 59% compared to pritelivir administered alone.(1)

H2 Antagonists/Ravidasvir

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

MECHANISM OF ACTION: Absorption of ravidasvir may be reduced in patients receiving concomitant treatment with acid reducing agents.(1)

CLINICAL EFFECTS: Administration of H2 antagonists may reduce the bioavailability of ravidasvir, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: In order to assure systemic absorption and maximal effectiveness from use of this Hepatitis C treatment, counsel patients to administer H2 antagonists 4 hours after ravidasvir.(1)

DISCUSSION: Interaction studies with antacids have not been performed. Co-administration with H2 antagonists are expected to decrease ravidasvir plasma concentrations and potentially result in Hepatitis C treatment failure.(1)

H2 Antagonists/Rilzabrutinib

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

MECHANISM OF ACTION: Rilzabrutinib solubility decreases with increasing pH. H2 antagonist induced increase in gastric pH may result in a decrease in rilzabrutinib absorption.(1)

CLINICAL EFFECTS: Simultaneous administration of a H2 antagonist may result in decreased levels and effectiveness of rilzabrutinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Administer rilzabrutinib at least 2 hours before taking H2 antagonists.(1) Concurrent use of rilzabrutinib with proton pump inhibitors should be avoided.(1)

DISCUSSION: In an interaction study, administration of famotidine (H2 receptor antagonist) two hours after the evening dose of rilzabrutinib decreased the next morning dose of rilzabrutinib maximum concentration (Cmax) by 35% and area-under-curve (AUC) by 28%.(1)

H2 Antagonists/Selected Kinase Inhibitors

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

MECHANISM OF ACTION: The solubility of dacomitinib,(1) erlotinib,(2) gefitinib,(3) and nilotinib(4) is pH dependent. Changes in gastric pH from H2 antagonists may decrease the absorption of dacomitinib,(1) erlotinib,(2) gefitinib,(3) and nilotinib(4).

CLINICAL EFFECTS: Use of H2 antagonists may result in decreased levels and effectiveness of dacomitinib,(1) erlotinib,(2) gefitinib,(3) and nilotinib(4).

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Consider the use of short-acting antacids in patients taking dacomitinib,(1) erlotinib,(2) gefitinib,(3) and nilotinib(4). If antacids are used, separate the administration times by several hours(1-7) but at least 2 hours for bosutinib,(1) and nilotinib,(4) and 6 hours for gefitinib.(3) If H2 antagonist therapy is required with dacomitinib, dacomitinib must be given once daily 10 hours after the H2 blocker and 6 hours before the next dose of the H2 blocker.(1) If H2 antagonist therapy is required with erlotinib or nilotinib, the kinase inhibitor must be given 10 hours after the H2 blocker and at least 2 hours before the next dose of the H2 blocker.(2-4) If H2 antagonist therapy is required with gefitinib, gefitinib should be given at least 6 hours before or after the H2 antagonist.(3) Avoid the use of proton pump inhibitors (PPIs) in patients receiving treatment dacomitinib,(1) erlotinib,(2) gefitinib,(3) and nilotinib(4).

DISCUSSION: In a study, concurrent rabeprazole decreased the Cmax and AUC of dacomitinib by 51% and 39%, respectively.(1) In a study, concurrent omeprazole decreased the AUC and Cmax of erlotinib by 46% and 61%, respectively.(2) In a study, administration of erlotinib two hours after a dose of ranitidine (300 mg), erlotinib AUC and Cmax decreased by 33% and 54%, respectively. Administration of erlotinib 10 hours after and two hours before ranitidine (150 mg twice daily), erlotinib AUC and Cmax decreased by 15% and 17%, respectively.(2) In a case report, a patient that was given erlotinib (150 mg daily,) with algeldrate/magnesium hydroxide (800/400 mg four times daily 4 hours before or 2 hours after erlotinib) did not see a significant reduction in serum trough concentrations of erlotinib. When the patient was switched to intravenous pantoprazole via continuous infusion (8 mg per hour), serum erlotinib levels decreased significantly below minimal trough concentrations for effective tyrosine kinase inhibition. When the patient was switched to oral pantoprazole (40 mg twice daily), serum trough levels of erlotinib returned to therapeutic levels.(5) In a study in 22 healthy subjects, pretreatment with esomeprazole (40 mg daily), decreased the Cmax and AUC of a single dose of nilotinib (400 mg) by 27% and 34%, respectively.(4,7) Increasing the dosage of nilotinib or separating the administration time of nilotinib and the proton pump inhibitor is not expected to eliminate the interaction.(4) There were no significant changes in nilotinib pharmacokinetics when famotidine was administered 10 hours before or 2 hours after nilotinib.(4) There were no significant changes in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered 2 hours before or after nilotinib.(4)

H2 Antagonists; Proton Pump Inhibitors/Amphetamines

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

MECHANISM OF ACTION: H2 antagonists and proton pump inhibitors (PPIs) may alter the timing of absorption of amphetamines.

CLINICAL EFFECTS: Concurrent use of amphetamines and H2 antagonists or PPIs may result in an increased absorption rate and a change in timing of peak amphetamine levels.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer states that patients receiving concurrent amphetamines and H2 antagonists or PPIs should be monitored for changes in the timing and clinical effects of amphetamines.(1) Monitor patients receiving concurrent therapy for changes in amphetamine effectiveness and side effects. The Canadian manufacturer states that concurrent use of proton pump inhibitors and amphetamines should be avoided.(3)

DISCUSSION: During concurrent use of a proton pump inhibitor, the median time to maximum concentration (Tmax) of Adderall XR decreased from 5 hours to 2.75 hours.(3) In a 4-way crossover study in healthy subjects, omeprazole had no effect on the total exposure a single dose of mixed amphetamine salts (20 mg); however median Tmax decreased from 5 hours to 2.75 hours. Approximately 50% of subjects had a decrease in Tmax of equal to or greater than 1 hour.(4)

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)

Oral Multivalent Cations/Oral Bisphosphonates

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

MECHANISM OF ACTION: Multivalent cations may bind to and inhibit the absorption of oral bisphosphonates.(1-6)

CLINICAL EFFECTS: Simultaneous administration of products containing multivalent cations may result in decreased levels of and clinical effects from oral bisphosphonates.(1-6)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Instruct patients to separate the administration times of products containing multivalent cations and oral bisphosphonates. Manufacturer recommendations regarding the separation of administration times of oral bisphosphonates and multivalent cations vary. Do NOT give multivalent cation-containing products: - until at least 30 minutes after taking alendronate(1) - within 2 hours of etidronate(2) - until at least 1 hour after taking ibandronate(3) - until at least 30 minutes after taking risedronate(4) - within 2 hours of tiludronate(5)

DISCUSSION: Multivalent cations may bind to and inhibit the absorption of oral bisphosphonates, resulting in decreased levels of and clinical effects from these agents.(1-6) Administration of aluminum- or magnesium-containing antacids 1 hour before tiludronate decreased the bioavailability of tiludronate by 60%.(5)

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/Penicillamine, Oral

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

MECHANISM OF ACTION: Penicillamine chelates with polyvalent cations such as aluminum, calcium, iron, magnesium, and zinc in the GI tract reducing the absorption of the penicillamine.

CLINICAL EFFECTS: Reduced (to 30% of fasting) bioavailability of penicillamine with decreased pharmacologic response.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: In order to assure systemic absorption and maximal effectiveness from penicillamine, counsel patient to separate penicillamine by at least 1 hour before or 1 hours after any medications or products containing polyvalent cations such as antacids or mineral supplements. Monitor clinical status for decreased effectiveness and adjust the penicillamine dose if necessary.

DISCUSSION: Clinical studies with polyvalent cations have not been conducted. Multivitamins with low doses of cations including iron and zinc may decrease penicillamine absorption so insure patient is aware of the risks.

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)

Polyvalent Cations; Lanthanum; Sucralfate/Bictegravir

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

MECHANISM OF ACTION: Polyvalent cations, lanthanum, and sucralfate may bind to bictegravir in the GI tract, preventing its absorption.(1)

CLINICAL EFFECTS: Polyvalent cations, lanthanum and sucralfate may reduce levels and clinical effectiveness of bictegravir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Bictegravir must be taken 2 hours before or 6 hours after polyvalent cations, lanthanum or sucralfate. Medicines containing calcium can be taken together with bictegravir if taken with food.(1) Some vitamin preparations may contain sufficient quantities of polyvalent cations to interact as well.

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)

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 Antacids; Kaolin; Sucralfate/Digoxin

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

MECHANISM OF ACTION: The aluminum or magnesium salts may bind digoxin in the gastrointestinal tract, preventing the absorption of digoxin.

CLINICAL EFFECTS: Concurrent administration may result in decreased digoxin concentrations and possible decreased clinical effectiveness of digoxin.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with digoxin and aluminum and/or magnesium hydroxide, magnesium trisilicate, or sucralfate should be monitored for signs of decreased effects of digoxin. Digoxin concentrations should be monitored. The administration of digoxin and aluminum and/or magnesium hydroxide or magnesium trisilicate should be separated by at least one to two hours. The administration of digoxin and sucralfate should be separated by at least two hours. The separation of administration times may not be effective in all patients. The dosage of digoxin may need to be increased by 20% to 40% or the antacid or sucralfate may need to be discontinued. Some vitamin preparations may contain sufficient quantities of magnesium salts with antacid properties to interact as well.

DISCUSSION: Sucralfate was shown to decrease the mean digoxin area-under-curve (AUC) by 19% in a study in 12 healthy males. This difference was not seen when digoxin and sucralfate administration was separated by two hours.(1) In a case report, a patient developed intermittent pressure-like chest pain, shortness of breath, and a generalized feeling of fatigue during concurrent administration of digoxin and sucralfate, despite sucralfate administration being separated from digoxin administration by two hours.(2) The simultaneous administration of oral antacids containing magnesium trisilicate, magnesium hydroxide, and aluminum hydroxide or kaolin with digoxin tablets has been shown to decrease the gastrointestinal absorption of digoxin.(3-7) There is some evidence that digoxin capsules may not be affected;(5) however, additional information is needed.

Selected H2 Antagonists/Bosutinib; Neratinib

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

MECHANISM OF ACTION: The solubility of bosutinib(1) and neratinib(2) is pH dependent. Changes in gastric pH from H2 antagonists may decrease the absorption of bosutinib and neratinib.

CLINICAL EFFECTS: Use of H2 antagonists may result in decreased levels and effectiveness of bosutinib(1) and neratinib.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Consider the use of short-acting antacids in patients taking bosutinib(1) and neratinib.(2) If antacids are used, separate the administration times by at least 2 hours for bosutinib(1) and 3 hours for neratinib.(2) If H2 antagonist therapy is required with bosutinib, separate administration of the H2 blocker by at least 2 hours before or 2 hours after bosutinib.(1) If H2 antagonist therapy is required with neratinib, then neratinib must be given 10 hours after the H2 blocker and at least 2 hours before the next dose of the H2 blocker.(2) Avoid the use of proton pump inhibitors (PPIs) in patients receiving treatment with bosutinib(1) and neratinib.(2)

DISCUSSION: A single dose of bosutinib 400 mg was administered alone or following multiple doses of lansoprazole 60 mg without food. Lansoprazole decreased bosutinib maximum concentration (Cmax) and area-under-curve (AUC) by 46% and 26%, respectively.(1) In a study in 15 healthy subjects, lansoprazole 30 mg daily decreased the Cmax and AUC of a single dose of neratinib (240 mg) by 71% and 65%, respectively.(2)

Selected H2 Antagonists/Pexidartinib

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

MECHANISM OF ACTION: The solubility of pexidartinib is pH dependent. Changes in gastric pH from H2 antagonists may decrease the absorption of pexidartinib.(1)

CLINICAL EFFECTS: Use of H2 antagonists may result in decreased levels and effectiveness of pexidartinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Consider the use of short-acting antacids in patients taking pexidartinib. If antacids are used, separate the administration times by at least 2 hours. If H2 antagonist therapy is required, the pexidartinib must be given 10 hours after the H2 blocker and at least 2 hours before the next dose of the H2 blocker. Avoid the use of proton pump inhibitors (PPIs).(1)

DISCUSSION: Coadministration of esomeprazole decreased pexidartinib maximum concentration (Cmax) and area-under-curve (AUC) by 55% and 50%, respectively.(1)

Selected Minerals, Oral/Trientine

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

MECHANISM OF ACTION: Mineral supplements may bind to trientine and block its absorption.

CLINICAL EFFECTS: The levels and clinical effects of trientine may be decreased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of trientine states that mineral supplements should not be given with trientine. If concomitant therapy is necessary, take trientine on an empty stomach and separate administration at least one hour apart from any other drug. Monitor clinical status for decreased effectiveness and adjust the trientine dose if necessary.

DISCUSSION: Multivitamins with minerals may decrease trientine absorption so ensure patient is aware of the risks and counsel on instructions for concurrent use.

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. 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) MECHANISM OF ACTION: Aluminum, iron, lanthanum, magnesium, and zinc may form chelation compounds with the quinolones.(1-23)

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. CLINICAL EFFECTS: Simultaneous administration or administration of products containing aluminum, 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. 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. 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, iron, lanthanum, magnesium, and/or zinc vary: ---Do not give gatifloxacin for at least 4 hours before oral cations(1) ---Do not give gemifloxacin for at least 2 hours before or 3 hours after oral cations.(2) ---Do not give lomefloxacin for at least 2 hours before or 4 hours after oral cations.(3) ---Do not give moxifloxacin for at least 4 hours before or 8 hours after oral cations.(4) ---Do not give trovafloxacin for at least 2 hours before or after oral cations.(5) ---Do not give prulifloxacin for at least 2 hours before or 4 hours after oral cations.(23) The US manufacturer of lanthanum recommends that quinolones be taken at least 1 hour before or 4 hours after lanthanum;(6) 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. DISCUSSION: Magnesium and aluminum compounds have been shown to form chelation compounds with quinolone antibiotics, resulting in decreased absorption of the quinolone.(1-22) Treatment failures during concurrent use of cations and gatifloxacin(7) and pefloxacin(8) have been reported. In a study in 24 healthy subjects, administration of an aluminum-magnesium hydroxide antacid simultaneously, 2 hours before, or 2 hours after decreased the area-under-curve (AUC) of a single dose of gatifloxacin (400 mg) by 42%, 64%, or 18%, respectively. There were no affects on gatifloxacin AUC when the antacid was administered 4 hours after gatifloxacin.(9) In a study in 16 healthy males, administration of an aluminum-magnesium hydroxide antacid 10 minutes before or 3 hours after a single dose of gemifloxacin (320 mg) decreased the gemifloxacin AUC by 85% and 15%, respectively. There was no affect when the antacid was administered 2 hours after gemifloxacin.(10) In a study in 16 subjects, simultaneous administration of calcium carbonate decreased the maximum concentration (Cmax) and AUC of a single dose of gemifloxacin (320 mg) by 17% and 21%, respectively. There was no effect of calcium carbonate when administered either 2 hours before or after gemifloxacin.(11) In a study in 27 healthy males, the administration of ferrous sulfate (325 mg) 3 hours before a single dose of gemifloxacin (320 mg) decreased the Cmax and AUC of gemifloxacin by 20% and 11%, respectively. There were no effects when ferrous sulfate was administered 2 hours after gemifloxacin.(12) In a study in 8 healthy subjects, ferrous sulfate (100 mg elemental iron) decreased the Cmax and AUC of a single dose of lomefloxacin by 26% and 13%, respectively. There were no effects with concurrent calcium carbonate (500 mg calcium).(13) Magnesium- and aluminum-containing antacids have been shown to decrease the bioavailability of lomefloxacin by 40%.(14) Administration of moxifloxacin 2 hours before, simultaneously, or 4 hours after a magnesium- and aluminum-containing antacid decreased moxifloxacin AUC by 26%, 60%, and 23%, respectively.(15) Simultaneous administration of moxifloxacin and ferrous sulfate (100 mg) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of moxifloxacin by 39% and 59%, respectively.(16) Concurrent administration of calcium had no affect on moxifloxacin pharmacokinetics.(17) In a study in 10 healthy subjects, an aluminum-magnesium hydroxide antacid decreased the bioavailability of pefloxacin (400 mg) by 44.4%.(18) The administration of an antacid containing aluminum hydroxide and magnesium hydroxide 5 minutes before rufloxacin decreased rufloxacin levels by 36%. Administration of the antacid 4 hours after rufloxacin decreased rufloxacin levels by 13%.(19) Magnesium- and aluminum-containing antacids have been shown to decrease the bioavailability of temafloxacin by 40%.(20) Aluminum hydroxide has been shown to decrease the bioavailability of tosufloxacin by 31.6%.(21) Administration of an antacid containing aluminum hydroxide and magnesium hydroxide 30 minutes before trovafloxacin decreased trovafloxacin levels by 66%.(22) 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.

Slt Cation-Donating Antacids/Polystyrene Sulfonate

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

MECHANISM OF ACTION: Polystyrene sulfonate may bind the cation from the antacid, resulting in increased intestinal absorption of non-neutralized bicarbonate, which may result in systemic alkalosis and decreased potassium binding by polystyrene sulfonate. Intestinal obstruction has occurred with aluminum hydroxide because of concretion.

CLINICAL EFFECTS: Simultaneous oral use may result in metabolic alkalosis and a decrease in the potassium lowering effect of polystyrene sulfonate. Intestinal obstruction has been reported with aluminum hydroxide.

PREDISPOSING FACTORS: Patients with renal failure may be at a higher risk of systemic alkalosis.

PATIENT MANAGEMENT: Consider the use of alternative agents to cation-donating antacids in patients receiving oral polystyrene sulfonate when possible. If concurrent use is required, separate the dosing by several hours.(1) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: In a study in 11 patients with decreased renal function, the administration of magnesium hydroxide and sodium polystyrene sulfonate produced moderate to moderately severe metabolic alkalosis.(2) There are case reports documenting this affect as well.(3-7) Intestinal obstruction has been reported with aluminum hydroxide and sodium polystyrene sulfonate.(8) If the polystyrene sulfonate is administered rectally, a clinically significant interaction is not likely to occur.

There is no enhanced messaging for this drug.

There are no contraindication contraindications for this drug.

• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Constipation
• Dehydration
• Diarrhea
• Gastric cancer
• Hypercalcemia
• Kidney stone
• Sarcoidosis

• Hyperparathyroidism
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Kidney disease with reduction in glomerular filtration rate (GFr)

There is no enhanced messaging for this drug.

Rare or Very Rare

• Abnormal hepatic function tests
• Agranulocytosis
• Alkalosis
• Anaphylaxis
• Anemia
• Angioedema
• Atrioventricular block
• Bronchospastic pulmonary disease
• Cardiac arrhythmia
• Dyspnea
• Fecal impaction
• Hepatitis
• Hypercalcemia
• Hypotension
• Increased alanine transaminase
• Increased aspartate transaminase
• Interstitial pneumonitis
• Kidney stone
• Leukopenia
• Obstructive hyperbilirubinemia
• Pancytopenia
• Psychiatric disorder
• Rhabdomyolysis
• Seizure disorder
• Skin rash
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Toxic epidermal necrolysis
• Urticaria

More Frequent

• Constipation
• Diarrhea
• Dizziness
• Dysgeusia
• Headache disorder

Less Frequent

• Constipation
• Eructation
• Flatulence
• Musculoskeletal pain

Rare or Very Rare

• Acne vulgaris
• Acute abdominal pain
• Acute cognitive impairment
• Agitation
• Allergic conjunctivitis
• Alopecia
• Anorexia
• Anticholinergic toxicity
• Arthralgia
• Cramps
• Delirium
• Drowsy
• Dry skin
• Dysgeusia
• Facial edema
• Fatigue
• Fever
• Flushing
• General weakness
• Hallucinations
• Insomnia
• Lethargy
• Nausea
• Paresthesia
• Pruritus of skin
• Tinnitus
• Vomiting
• Xerostomia

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Reproduction studies in rats and rabbits using oral famotidine dosages up to 2 (approximately 2500 times the maximum human dosage) and 0.5 g/kg daily, respectively, or IV dosages up to 0.2 (approximately 250 times the maximum human dosage) and 0.1 g/kg daily, respectively, have not revealed evidence of harm to the fetus. Oral dosages of 2 g/kg daily inhibited weight gain in pregnant rats, and those of 0.5 and/or 2 g/kg daily on days 7-17 of gestation decreased fetal weight and delayed sternal ossification in the offspring. Decreased food intake and decreased weight gain also occurred in offspring of rats receiving these dosages from days 10-28 post partum. Death and locomotor dysfunction were observed in pregnant rats receiving IV famotidine dosages of 100 or 200 mg/kg daily. IV dosages of 100 or 200 mg/kg daily in rats have decreased pup body weight during the post-weaning period. Although no direct fetotoxic effects have been observed, sporadic abortions and decreases in fetal weight occurred secondary to substantial decreases in food intake in pregnant rabbits receiving oral dosages of 200 mg/kg (250 times the usual human dosage) or more daily. Decreased number of sacrocaudal vertebrae and delayed ossification have occurred in rabbits receiving oral famotidine dosages of 0.5 g/kg daily. There are no adequate and controlled studies to date using famotidine in pregnant women, and the drug should be used during pregnancy only when clearly needed. Women who are pregnant or nursing should seek the advice of a health professional before using famotidine for self-medication.

Famotidine is distributed into milk in humans and in animals. The drug has produced transient growth depression in the offspring of lactating rats receiving dosages at least 600 times the usual human dosage. Because of the potential for serious adverse reactions to famotidine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

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