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DRUG IMAGES
NEXIUM DR 20 MG CAPSULE
NEXIUM DR 40 MG CAPSULE
NEXIUM DR 10 MG PACKET
NEXIUM DR 20 MG PACKET
NEXIUM DR 5 MG PACKET
NEXIUM DR 2.5 MG PACKET
NEXIUM DR 40 MG PACKET
The following indications for NEXIUM (esomeprazole magnesium) have been approved by the FDA:
Indications:
Duodenal ulcer due to H. pylori
Erosive esophagitis
Gastric hypersecretion with systemic mastocytosis
Gastroesophageal reflux disease
Heartburn
Helicobacter pylori gastritis
Maintenance of healing erosive esophagitis
Pathological gastric acid hypersecretory condition
Prevention of NSAID-induced gastric ulcer
Zollinger-Ellison syndrome
Professional Synonyms:
Adenomatosis partial multiple endocrine
Brash
Campylobacter gastritis
DU due to H. pylori
Duodenal ulcer due to Campylobacter pylori
Duodenal ulcer due to Helicobacter pylori
Gastric acid hypersecretory conditions due to disease
Gastro-esophageal reflux
GE reflux disease
H. pylori gastritis
NSAID-induced gastric ulcer prophylaxis
Pancreatic ulcerogenic tumor syndrome
Pathological gastric acid hypersecretory states
Pathological hypersecretion state
Pathological hypersecretory condition
Pyrosis
Systemic mast cell disease with gastric hypersecretion
Z-E syndrome
Indications:
Duodenal ulcer due to H. pylori
Erosive esophagitis
Gastric hypersecretion with systemic mastocytosis
Gastroesophageal reflux disease
Heartburn
Helicobacter pylori gastritis
Maintenance of healing erosive esophagitis
Pathological gastric acid hypersecretory condition
Prevention of NSAID-induced gastric ulcer
Zollinger-Ellison syndrome
Professional Synonyms:
Adenomatosis partial multiple endocrine
Brash
Campylobacter gastritis
DU due to H. pylori
Duodenal ulcer due to Campylobacter pylori
Duodenal ulcer due to Helicobacter pylori
Gastric acid hypersecretory conditions due to disease
Gastro-esophageal reflux
GE reflux disease
H. pylori gastritis
NSAID-induced gastric ulcer prophylaxis
Pancreatic ulcerogenic tumor syndrome
Pathological gastric acid hypersecretory states
Pathological hypersecretion state
Pathological hypersecretory condition
Pyrosis
Systemic mast cell disease with gastric hypersecretion
Z-E syndrome
The following dosing information is available for NEXIUM (esomeprazole magnesium):
Dosage of esomeprazole magnesium or esomeprazole sodium is expressed in terms of esomeprazole.
Duration of therapy with a proton-pump inhibitor should be based on safety and efficacy data associated with a specific indication, dosing frequency as described by the manufacturer, and the needs of individual patients. The potential benefits versus possible risks of initiating or continuing proton-pump inhibitor therapy should be weighed carefully.
Oral dosage of esomeprazole for short-term (up to 6 weeks) treatment of erosive esophagitis due to acid-mediated GERD in infants 1 month to less than 1 year of age is based on weight. Infants weighing 3-5 kg may receive an oral esomeprazole dosage of 2.5 mg once daily, those weighing more than 5 kg but not more than 7.5
kg may receive 5 mg once daily, and those weighing more than 7.5 kg but not more than 12 kg may receive 10 mg once daily. The manufacturer states that dosages exceeding 1.33
mg/kg daily have not been studied in infants 1 month to less than 1 year of age.
The recommended oral dosage for the short-term treatment of symptomatic GERD in children 1-11 years of age without erosive esophagitis is 10 mg once daily for up to 8 weeks. The recommended oral dosage of esomeprazole for the short-term treatment of erosive esophagitis in children 1-11 years of age weighing less than 20 kg is 10 mg once daily for 8 weeks; 10 or 20 mg once daily for 8 weeks is recommended in children 1-11 years of age weighing 20 kg or more. The manufacturer states that dosages exceeding 1 mg/kg daily have not been studied in children 1-11 years of age.
The recommended oral dosage of esomeprazole for the short-term treatment of GERD in adolescents 12-17 years of age is 20 or 40 mg once daily for up to 8 weeks.
Pediatric patients who are unable to take esomeprazole orally for the treatment of GERD with erosive esophagitis may receive the drug IV. Infants 1 month to less than 1 year of age may receive an IV esomeprazole dosage of 0.5 mg/kg once daily; children and adolescents 1- 17 years of age may receive an IV dosage of 10 mg once daily if they weigh less than 55 kg or 20 mg once daily in they weigh 55 kg or more.
Esomeprazole should be administered by IV infusion (over 10-30 minutes) in infants, children, and adolescents. Treatment with IV esomeprazole should be discontinued as soon as the patient is able to take the drug orally.
Duration of therapy with a proton-pump inhibitor should be based on safety and efficacy data associated with a specific indication, dosing frequency as described by the manufacturer, and the needs of individual patients. The potential benefits versus possible risks of initiating or continuing proton-pump inhibitor therapy should be weighed carefully.
Oral dosage of esomeprazole for short-term (up to 6 weeks) treatment of erosive esophagitis due to acid-mediated GERD in infants 1 month to less than 1 year of age is based on weight. Infants weighing 3-5 kg may receive an oral esomeprazole dosage of 2.5 mg once daily, those weighing more than 5 kg but not more than 7.5
kg may receive 5 mg once daily, and those weighing more than 7.5 kg but not more than 12 kg may receive 10 mg once daily. The manufacturer states that dosages exceeding 1.33
mg/kg daily have not been studied in infants 1 month to less than 1 year of age.
The recommended oral dosage for the short-term treatment of symptomatic GERD in children 1-11 years of age without erosive esophagitis is 10 mg once daily for up to 8 weeks. The recommended oral dosage of esomeprazole for the short-term treatment of erosive esophagitis in children 1-11 years of age weighing less than 20 kg is 10 mg once daily for 8 weeks; 10 or 20 mg once daily for 8 weeks is recommended in children 1-11 years of age weighing 20 kg or more. The manufacturer states that dosages exceeding 1 mg/kg daily have not been studied in children 1-11 years of age.
The recommended oral dosage of esomeprazole for the short-term treatment of GERD in adolescents 12-17 years of age is 20 or 40 mg once daily for up to 8 weeks.
Pediatric patients who are unable to take esomeprazole orally for the treatment of GERD with erosive esophagitis may receive the drug IV. Infants 1 month to less than 1 year of age may receive an IV esomeprazole dosage of 0.5 mg/kg once daily; children and adolescents 1- 17 years of age may receive an IV dosage of 10 mg once daily if they weigh less than 55 kg or 20 mg once daily in they weigh 55 kg or more.
Esomeprazole should be administered by IV infusion (over 10-30 minutes) in infants, children, and adolescents. Treatment with IV esomeprazole should be discontinued as soon as the patient is able to take the drug orally.
No enhanced Administration information available for this drug.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| NEXIUM DR 20 MG PACKET | Maintenance | Adults take 1 packet (20 mg) by oral route once daily mixed with 15 ml water, let sit 2-3 minutes, stir and drink within 30 minutes |
| NEXIUM DR 40 MG PACKET | Maintenance | Adults take 1 packet (40 mg) by oral route 2 times per day mixed with 15 ml water, let sit 2-3 minutes, stir and drink within 30 minutes |
| NEXIUM DR 20 MG CAPSULE | Maintenance | Adults take 1 capsule (20 mg) by oral route once daily at least 1 hour before a meal swallowing whole. Do not crush or chew granules. |
| NEXIUM DR 40 MG CAPSULE | Maintenance | Adults take 1 capsule (40 mg) by oral route once daily |
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| GS ESOMEPRAZOLE MAG DR 20 MG | Maintenance | Adults take 1 capsule (20 mg) by oral route once daily at least 1 hour before a meal swallowing whole. Do not crush or chew granules. |
| ESOMEPRAZOLE MAG DR 20 MG CAP | Maintenance | Adults take 1 capsule (20 mg) by oral route once daily at least 1 hour before a meal swallowing whole. Do not crush or chew granules. |
| ESOMEPRAZOLE MAG DR 40 MG CAP | Maintenance | Adults take 1 capsule (40 mg) by oral route once daily |
| SM ESOMEPRAZOLE MAG DR 20 MG | Maintenance | Adults take 1 capsule (20 mg) by oral route once daily at least 1 hour before a meal swallowing whole. Do not crush or chew granules. |
| RA ESOMEPRAZOLE MAG DR 20 MG | Maintenance | Adults take 1 capsule (20 mg) by oral route once daily at least 1 hour before a meal swallowing whole. Do not crush or chew granules. |
| ESOMEPRAZOLE DR 20 MG PACKET | Maintenance | Adults take 1 packet (20 mg) by oral route once daily mixed with 15 ml water, let sit 2-3 minutes, stir and drink within 30 minutes |
| ESOMEPRAZOLE DR 40 MG PACKET | Maintenance | Adults take 1 packet (40 mg) by oral route 2 times per day mixed with 15 ml water, let sit 2-3 minutes, stir and drink within 30 minutes |
| QC ESOMEPRAZOLE MAG DR 20 MG | Maintenance | Adults take 1 capsule (20 mg) by oral route once daily at least 1 hour before a meal swallowing whole. Do not crush or chew granules. |
| EQL ESOMEPRAZOLE MAG DR 20 MG | Maintenance | Adults take 1 capsule (20 mg) by oral route once daily at least 1 hour before a meal swallowing whole. Do not crush or chew granules. |
| GNP ESOMEPRAZOLE MAG DR 20 MG | Maintenance | Adults take 1 capsule (20 mg) by oral route once daily at least 1 hour before a meal swallowing whole. Do not crush or chew granules. |
| CVS ESOMEPRAZOLE MAG 20 MG CAP | Maintenance | Adults take 1 capsule (20 mg) by oral route once daily at least 1 hour before a meal swallowing whole. Do not crush or chew granules. |
| HM ESOMEPRAZOLE MAG DR 20 MG | Maintenance | Adults take 1 capsule (20 mg) by oral route once daily at least 1 hour before a meal swallowing whole. Do not crush or chew granules. |
The following drug interaction information is available for NEXIUM (esomeprazole magnesium):
There are 3 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Atazanavir; Nelfinavir/Proton Pump Inhibitors 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: Proton pump inhibitors increase gastric pH. As gastric pH increases, the solubility of atazanavir and nelfinavir decreases.(1,2) Omeprazole has been shown to inhibit nelfinavir metabolism by CYP2C19.(3) CLINICAL EFFECTS: Concurrent use of atazanavir(1-2,4-8) or nelfinavir(3,8-9) and a proton pump inhibitor may result in decreased levels and effectiveness of atazanavir or nelfinavir. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US and Australian manufacturer of atazanavir states that treatment naive patients requiring a proton pump inhibitor should receive 300 mg atazanavir with 100 mg ritonavir. The proton pump inhibitor should not exceed a dose comparable to omeprazole 20 mg daily and should be administered 12 hours before atazanavir/ritonavir.(1,2) Atazanavir should not be administered with proton pump inhibitors without concurrent ritonavir in adults or pediatric patients of at least 13 years of age and weighing at least 40 kg.(1,2) The US and Australian manufacturer of atazanavir states that proton pump inhibitors should not be administered with atazanavir in treatment experienced patients.(1,2) Data are insufficient to recommend a dose of atazanavir in patients weighing less than 40 kg and receiving a proton pump inhibitor.(1) The Canadian and UK manufacturer of atazanavir states that the coadministration of atazanavir and proton pump inhibitors is not recommended. If coadministration is necessary, the dose of atazanavir should be increased to 400 mg daily taken with ritonavir 100 mg daily, and the dose of the proton pump inhibitor should not exceed the equivalent of omeprazole 20 mg.(10,11) The UK manufacturer of esomeprazole states that concurrent use with atazanavir is contraindicated.(9) The US manufacturer of esomeprazole(4) and omeprazole(5) states that concurrent use of atazanavir or nelfinavir is not recommended. The US manufacturers of dexlansoprazole (6), lansoprazole,(7) and pantoprazole(8) state that atazanavir and nelfinavir should not be coadministered with proton pump inhibitors. DISCUSSION: In a study of 16 subjects, atazanavir (400 mg daily) area-under-curve (AUC), maximum concentration (Cmax) and minimum concentration (Cmin) decreased 94%, 96% and 95% respectively, when given with omeprazole (40 mg daily). Omeprazole AUC and Cmax increased 145% and 124% respectively.(1) In a study of 15 subjects, atazanavir AUC, Cmax and Cmin decreased 76%, 72% and 78% respectively, when given with omeprazole (40 mg daily) and ritonavir (100 mg daily).(1) In a study in 13 subjects, administration of omeprazole (20 mg daily) 12 hours before atazanavir/ritonavir (300/100 mg daily) decreased atazanavir Cmax, AUC, and Cmin by 39%, 42%, and 46%, respectively; however, the atazanavir AUC and Cmin were 10% and 2.4-fold higher than average levels seen with atazanavir 400 mg alone.(1) In a study in 14 subjects, administration of omeprazole (20 mg daily) 1 hour before atazanavir/ritonavir (400/100 mg daily) decreased atazanavir Cmax, AUC, and Cmin by 31%, 30%, and 31%, respectively; however, the atazanavir AUC and Cmin were 32% and 3.3-fold higher than average levels seen with atazanavir 400 mg alone.(1) In a study in 10 healthy subjects, concurrent administration of lansoprazole (60 mg daily for 2 days) with atazanavir (400 mg) decreased atazanavir AUC by 94%.(14) In a case report, concurrent esomeprazole decreased atazanavir, but not fosamprenavir levels in a 65 year-old HIV-positive male.(15) In a study in 16 healthy, HIV-negative subjects, the concurrent administration of omeprazole or ranitidine with ritonavir-boosted darunavir had no effect on darunavir pharmacokinetics.(16) In a study in healthy subjects, the concurrent administration of esomeprazole (20 mg daily) with either fosamprenavir (1400 mg twice daily) or fosamprenavir (700 mg twice daily) and ritonavir (100 mg twice daily) for 14 days had no effect on amprenavir pharmacokinetics.(17) In a study in 19 subjects, concurrent omeprazole (40 mg daily) and nelfinavir (1250 mg twice daily) for 4 days decreased nelfinavir AUC, Cmax, and Cmin by 36%, 37%, and 39%.(7,17) The AUC, Cmax, and Cmin of the active M8 metabolite of nelfinavir decreased by 92%, 89%, and 75%, respectively.(4,17) A retrospective review of nelfinavir levels found concurrent use of omeprazole decreased the median M8/nelfinavir ratio.(12) In a case report a 56 year old HIV infected male received omeprazole (40mg daily) and atazanavir/ritonavir (300/100mg) for ten months. Investigators used Bayesian models to determine atazanavir exposure, and found atazanavir levels to be in the 25th percentile of boosted levels, but still above the 75th percentile for unboosted atazanavir.(20) A retrospective review of 76 patients taking proton pump inhibitors and 66 patients not using proton pump inhibitors found no association with a higher virologic failure rate in patients receiving proton pump inhibitors.(21) In a case report, a 50 year-old HIV-infected male with a CD4 count of 1095 cells/ml and an HIV load of 88 copies/ml on a nelfinavir based regimen was switched to an atazanavir/ritonavir (300/100mg daily) regimen. The patient was taking omeprazole (20mg daily) and admitted to taking the atazanavir at 150mg twice daily. The patients CD4 count dropped to 830 cells/ml, but his HIV load dropped to <75 copies/ml. The investigators summarized concurrent use of omeprazole did not adversely affect this patient's virologic load.(22) In a study in 18 healthy subjects, concurrent omeprazole (40 mg daily) with saquinavir/ritonavir (1000/100 mg twice daily) for 4 days increased saquinavir AUC by 83%. No toxicities were noted.(18) In a study in 12 healthy subjects, concurrent omeprazole (40 mg daily) with saquinavir/ritonavir (1000/100 mg twice daily) for 7 weeks increased saquinavir AUC, Cmin, and Cmax by 54%, 73%, 55% respectively. Omeprazole 2 hours prior to saquinavir/ritonavir increased saquinavir AUC, Cmin, and Cmax by 67%, 97%, and 65% respectively. No toxicities were noted.(23) In a study of 14 healthy subjects, concurrent omeprazole (20 mg daily and 40 mg daily) with indinavir (800mg daily) for 7 days decreased indinavir AUC by 34% and 47% respectively and no statistical changes were seen in the Cmax or Tmax of indinavir. When omeprazole (40mg daily) was given with indinavir/ritonavir (800mg/200mg daily) for 7 days indinavir AUC increased by 55% and no statistical changes were seen in indinavir Cmax or Tmax. Omeprazole (40mg daily) showed a Cmax increase of 50% and a half-life increase of 100% in the presence of ritonavir.(24) In a study of 19 healthy subjects, concurrent omeprazole (20 mg daily) with fosamprenavir/ritonavir (1400/200 mg daily) or atazanavir/ritonavir (300/100)for 3 weeks showed no effect on amprenavir pharmacokinetics, but decreased atazanavir AUC and Cmin by 27%.(25) In a retrospective review of 15 HIV-infected patients receiving indinavir (800mg three times daily), nine patients were also receiving omeprazole (20-40mg daily). Of these nine patients, four had plasma concentrations of indinavir below the 95% confidence interval of plasmas concentration in patients receiving indinavir alone, four were within the 95% confidence interval, and one was above the 95% confidence interval.(26) In a case report, a 40 year-old HIV-infected male with extensive antiretroviral history and virological failure began atazanavir/ritonavir (300/100mg daily). The patient was restarted on lansoprazole during atazanavir/ritonavir therapy, and despite lansoprazole and tenofovir therapy the patients plasma concentrations of atazanavir remained consistent with historical values, and the patients Cmin stayed well above the established values for the combination of atazanavir/ritonavir with tenofovir.(27) In a study of 68 healthy subjects, coadministration of omeprazole (40mg daily) with lopinavir/ritonavir (400/100mg twice daily or 800/200mg once daily) showed no statistical change in pharmacokinetics.(28,29) However, when given with atazanavir/ritonavir (300/100 daily) bioavailability of atazanavir decreased by 48-62%.(28) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
ATAZANAVIR SULFATE, EVOTAZ, REYATAZ, VIRACEPT |
| Rilpivirine/Proton Pump Inhibitors 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: Rilpivirine requires an acidic medium for absorption. The proton pump inhibitor induced decrease in gastric pH may result in a decrease in rilpivirine absorption.(1) CLINICAL EFFECTS: Concurrent use of a proton pump inhibitor may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of rilpivirine states that concurrent use of proton pump inhibitors is contraindicated.(1) When substituting antacids for proton pump inhibitors in patients maintained on rilpivirine, administer the antacid at least 2 hours before or 4 hours after rilpivirine.(1) When substituting H2 antagonists for proton pump inhibitors in patients maintained on rilpivirine, administer the H2 antagonist at least 12 hours before or 4 hours after rilpivirine.(1) 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) |
COMPLERA, EDURANT, JULUCA, ODEFSEY |
| Cilostazol (Greater Than 50 mg BID)/Selected Strong & Moderate CYP2C19 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong and moderate inhibitors of CYP2C19 may inhibit the metabolism of cilostazol.(1-4) CLINICAL EFFECTS: Concurrent use of strong or moderate inhibitors of CYP2C19 may result in elevated levels of 3,4-dehydro-cilostazol, a metabolite of cilostazol that is 4-7 times as active as cilostazol.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The dose of cilostazol should be limited to 50 mg twice daily in patients receiving concurrent therapy with strong and moderate inhibitors of CYP2C19.(1) The Australian manufacturer of esomeprazole states concomitant use with cilostazol is contraindicated.(5) DISCUSSION: In a study in 20 subjects examined the effects of omeprazole (40 mg daily) on a single dose of cilostazol (100 mg). Concurrent omeprazole increased the cilostazol maximum concentration (Cmax) and area-under-curve (AUC) by 18% and 26%, respectively. The Cmax and AUC of the 3,4-dehydro-cilostazol metabolite of cilostazol increased 29% and 69%, respectively. The Cmax and AUC of the OPC-13213 metabolite of cilostazol decreased by 22% and 31%, respectively.(4) |
CILOSTAZOL |
There are 20 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Hydantoins/Omeprazole; Esomeprazole SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Omeprazole and esomeprazole may inhibit the CYP2C19 metabolism of hydantoins.(1-3) Hydantoins may induce the CYP3A4 metabolism of omeprazole and esomeprazole.(1-3) CLINICAL EFFECTS: Concurrent administration of omeprazole or esomeprazole and hydantoins may result in elevated levels of the hydantoin. Phenytoin has a narrow therapeutic range. Early symptoms of phenytoin toxicity may include nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. Severe toxicity may produce organ dysfunction (e.g. coma, irreversible cerebellar dysfunction and atrophy, hypotension, bradycardia, seizures, and cardiac arrest) and may be fatal.(1) Concurrent use of omeprazole or esomeprazole with CYP3A4 inducers may result in decreased levels and effectiveness of omeprazole or esomeprazole.(1-3) PREDISPOSING FACTORS: Renal impairment, hepatic impairment, or hypoalbuminemia. PATIENT MANAGEMENT: Avoid concomitant use of CYP3A4 inducers with omeprazole or esomeprazole.(2,3) Patients should be monitored for changes in response to hydantoins when omeprazole or esomeprazole are added to or discontinued from hydantoin therapy. Serum hydantoin concentration should be monitored to assist in dosage adjustments.(1) Monitor the patient for signs of hydantoin toxicity (e.g. nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting). DISCUSSION: In a double-blind cross-over study in ten healthy subjects, concurrent phenytoin (300 mg single dose on day seven of omeprazole therapy) and omeprazole (40 mg daily for nine days) therapy resulted in area-under-curve (AUC) increasing 19% when compared to phenytoin and placebo. There were no significant changes in phenytoin peak concentration, (Cmax) time to Cmax, or half-life.(4) In another cross-over study on eight healthy subjects, concurrent phenytoin (250 mg single dose administered intravenously over 30 minutes on day seven of omeprazole therapy) and omeprazole (40 mg daily for eight days) resulted in plasma clearance decreasing 15% and half-life increasing 27% when compared to phenytoin and placebo. There was a small, but not significant, increase in phenytoin plasma concentrations during concurrent omeprazole therapy.(5) The results of these studies are disputed in a study of eight epileptic patients maintained on phenytoin (dosage range 200-450 mg daily). There were no significant changes in phenytoin levels or phenytoin urinary excretion after three weeks of concurrent omeprazole (20 mg daily) therapy when compared to previous steady-state values. The authors speculated that the low dose of omeprazole (20 mg daily) was not enough to produce the inhibition of phenytoin metabolism seen in other studies.(6) In an interaction study, rifampin 600 mg daily for 7 days decreased omeprazole AUC by 89.5%.(8,9) |
CEREBYX, DILANTIN, DILANTIN-125, FOSPHENYTOIN SODIUM, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED |
| Selected Kinase Inhibitors/Proton Pump Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The solubility of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) pazopanib(8), and pexidartinib (9) is pH dependent. Changes in gastric pH from proton pump inhibitors may decrease the absorption of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) pazopanib,(8) and pexidartinib.(9) CLINICAL EFFECTS: Use of proton pump inhibitors may result in decreased levels and effectiveness of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) pazopanib,(8) and pexidartinib.(9) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid the use of proton pump inhibitors (PPIs) in patients receiving treatment with bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) pazopanib,(8) and pexidartinib.(9) Consider the use of short-acting antacids in these patients.(1-9) If antacids are used, separate the administration times by several hours(1-9) but at least 2 hours for bosutinib,(1) dasatinib,(3) nilotinib,(7) and pexidartinib(9), 6 hours for gefitinib,(5) and 3 hours for neratinib.(6) If PPIs are required with gefitinib, administer gefitinib 12 hours after the last dose or 12 hours before the next dose of the PPI. Administer gefitinib 6 hours before or after H2-antagonists or antacids.(5) If H2 antagonist therapy is used with bosutinib, separate administration by at least 2 hours.(1) 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.(2) If H2 antagonist therapy is required with erlotinib, neratinib, nilotinib, or pexidartinib, 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.(4,6,7,9) If H2 antagonist therapy is required with gefitinib, gefitinib should be given at least 6 hours before or after the H2 antagonist.(5) The manufacturer of Phyrago states that it can be administered with gastric acid reducing agents. Administration times should be separated with antacids. DISCUSSION: In a study, concurrent rabeprazole decreased the Cmax and AUC of dacomitinib by 51% and 39%, respectively.(2) 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.(3) 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.(3) 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.(3) In a study, concurrent omeprazole decreased the AUC and Cmax of erlotinib by 46% and 61%, respectively.(4) 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.(4) 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.(9) In a study in healthy subjects, high dose ranitidine with sodium carbonate was administered to maintain gastric pH above 5.0 and gefitinib AUC decreased 47%.(5) 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.(6) 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.(7,10) Increasing the dosage of nilotinib or separating the administration time of nilotinib and the proton pump inhibitor is not expected to eliminate the interaction.(7) There were no significant changes in nilotinib pharmacokinetics when famotidine was administered 10 hours before or 2 hours after nilotinib.(7) There were no significant changes in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered 2 hours before or after nilotinib.(7) 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.(11) In an open-label, crossover study in 17 evaluable patients, omeprazole (40 mg daily) had no significant effects on the pharmacokinetics, pharmacodynamics, or safety of bortezomib (1.3 mg/m2).(12) Coadministration of esomeprazole decreased pexidartinib Cmax and AUC by 55% and 50%. (13) Phyrago is not sensitive to increased gastric pH due to its polymer formulation. No clinically significant dasatinib pharmacokinetic changes were seen with concurrent administration of Phyrago with omeprazole (proton pump inhibitor) or famotidine (H2 receptor antagonist).(14) |
BOSULIF, DANZITEN, DASATINIB, ERLOTINIB HCL, GEFITINIB, IRESSA, NERLYNX, NILOTINIB HCL, PAZOPANIB HCL, SPRYCEL, TARCEVA, TASIGNA, TURALIO, VIZIMPRO, VOTRIENT |
| Posaconazole Suspension/H2 Antagonists; Proton Pump Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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) |
NOXAFIL, POSACONAZOLE |
| Clopidogrel/Esomeprazole; Omeprazole; Cimetidine SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) Proton pump inhibitors (PPIs) may inhibit CYP2C19 mediated conversion to the active metabolite of clopidogrel. The magnitude and clinical significance of CYP2C19 inhibition is highly variable between agents.(1) CLINICAL EFFECTS: Concurrent use of esomeprazole, omeprazole, or cimetidine may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Evaluate patient risk for gastrointestinal(GI) bleeding. When PPIs are needed, use dexlansoprazole, lansoprazole, pantoprazole or rabeprazole as they have a lower interaction risk.(1,3) Consider the use of H2 blockers (such as famotidine, nizatidine, or ranitidine) in patients with a low bleeding risk and reserve the use of PPIs for patients at higher risk of GI bleeding. US manufacturers for clopidogrel and omeprazole state concurrent use of clopidogrel esomeprazole and omeprazole should be avoided.(1,4-5) As esomeprazole and omeprazole are irreversible inhibitors of CYP2C19, separating clopidogrel from esomeprazole or omeprazole administration times does not change the magnitude of this interaction.(1,4,6) The US manufacturer of clopidogrel states that alternatives to clopidogrel should be considered in patients who are poor metabolizers of CYP2C19.(1) It would be prudent to assume that patients taking strong inhibitors of CYP2C19 are poor metabolizers of this isoenzyme. Moderate CYP2C19 inhibitors, such as omeprazole, and weak CYP2C19 inhibitors, such as cimetidine, may also affect this interaction. Consider alternatives to esomeprazole, omeprazole, and cimetidine in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on esomeprazole, omeprazole, and cimetidine. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity. DISCUSSION: US manufacturer for clopidogrel states omeprazole and esomeprazole have been shown to reduce antiplatelet activity of clopidogrel and recommends against concomitant use. The antiplatelet effect of clopidogrel is reduced by approximately 40% in patients receiving 80 mg per day of omeprazole. Dexlansoprazole, lansoprazole and pantoprazole are described as having less effect on clopidogrel antiplatelet activity.(1,3) In the primary literature, documentation for this interaction is conflicting. However, both in-vitro and retrospective analyses indicate that omeprazole decreases the effectiveness of clopidogrel. Although the half-lives of esomeprazole and omeprazole (a racemic mixture of R- and esomeprazole) are short, the effect on CYP2C19 is long lasting because esomeprazole is an irreversible inhibitor of CYP2C19.(6) In two studies in healthy subjects, concurrent omeprazole decreased the effects of clopidogrel on platelets.(7-8) Several studies have found coadministration of clopidogrel with omeprazole resulted in increased platelet aggregation compared to clopidogrel with pantoprazole, or no PPI.(9-12) In a study, use of omeprazole was associated with a decreased risk of upper gastrointestinal bleeding in patients receiving dual antiplatelet therapy with clopidogrel and aspirin. There was no significant difference between the groups in rate of cardiovascular events.(12) Three studies found that simultaneous omeprazole with clopidogrel reduced clopidogrel concentrations and effects.(13-15) In a cross-over trial, healthy subjects received clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg oral once daily) co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 35% to 40% over this time period.(16) In a study in 39 healthy subjects, the effects of omeprazole and rabeprazole on clopidogrel in patients with different CYP2C19 genotypes was examined. In rapid 2C19 metabolizers, simultaneous omeprazole and rabeprazole significantly decreased clopidogrel response. In decreased 2C19 responders, there was wide variation in clopidogrel response and simultaneous omeprazole and rabeprazole had no significant effect on overall clopidogrel effects; however, some subjects became low responders to clopidogrel while on PPI therapy. Staggered dosing of omeprazole had no effect on clopidogrel response in rapid metabolizers, but decreased clopidogrel response in decreased metabolizers.(17) Several retrospective studies found that patients who took clopidogrel with a PPI had increased incidence of major cardiovascular events compared to patients who took clopidogrel without a PPI.(18-22) A retrospective cohort study of 20,596 patients in the Tennessee Medicaid program, evaluated both cardiovascular disease event and GI bleed risk in patients prescribed clopidogrel with or without concurrent PPI use. Pantoprazole was prescribed in 62% of PPI patients. Concomitant PPI and clopidogrel use decreased the risk of hospitalization from GI bleeding by 50%. There was no clear-cut increase risk for serious cardiovascular disease events; however, the 95% CI for this was wide.(23) A post-hoc analysis of the PRINCIPLE-TIMI 44 trial and the TRITON-TIMI trial examined the effects of PPI use on the pharmacodynamic effects and clinical efficacy of clopidogrel. The PRINCIPLE-TIMI 44 trial examined 201 patients undergoing cardiac catheterization with planned percutaneous coronary intervention, 53 of which were taking a PPI at randomization. Patients receiving a PPI had significantly lower rates of inhibition of platelet aggregation at 0.5 hours, 2 hours, 6 hours, and 18-24 hours post-loading dose of clopidogrel. After 15 days of maintenance therapy, there were significantly more non-responders in the group receiving PPI (50% versus 7.9%). The TRITON-TIMI trial examined 13,608 patients who underwent cardiac catheterization with planned percutaneous coronary intervention, 4529 of which were taking a PPI at randomization. Patients received clopidogrel treatment for 6-15 months. There were no significant differences in occurrence of cardiovascular death, non-fatal MI, or non-fatal stroke between patients taking PPIs at randomization and those not; however, use of PPIs was only assessed at randomization and not during the study.(24) |
CLOPIDOGREL, CLOPIDOGREL BISULFATE, PLAVIX |
| Citalopram (Greater Than 20 mg)/Select CYP2C19 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Citalopram is primarily metabolized by the CYP2C19 isoenzyme.(1) CLINICAL EFFECTS: Concurrent use of an agent that inhibits CYP2C19 may result in elevated levels of and toxicity from citalopram, including including risks for serotonin syndrome or prolongation of the QTc interval.(1-5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(5) PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age, poor metabolizer status at CYP2C19, or higher blood concentrations of citalopram.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,5) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. PATIENT MANAGEMENT: The dose of citalopram should be limited to 20 mg in patients receiving concurrent therapy with an inhibitor of CYP2C19.(1,4) Evaluate the patient for other drugs, diseases and conditions which increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, discontinue other QT prolonging drugs) when possible.(1,2) Weigh the specific benefits versus risks for each patient. The US manufacturer recommends ECG monitoring for citalopram patients with congestive heart failure, bradyarrhythmias, taking concomitant QT prolonging medications or receiving concurrent therapy.(4) Citalopram should be discontinued in patients with persistent QTc measurements greater than 500 ms.(2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. DISCUSSION: Concurrent use of citalopram (40 mg daily) and cimetidine (400 mg twice daily) for 8 days increased the maximum concentration (Cmax) and area-under-curve (AUC) of citalopram by 39% and 43%, respectively.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, and tecovirimat.(7,8) |
CELEXA, CITALOPRAM HBR |
| Methotrexate (Oncology-Injection )/Proton Pump Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Proton pump inhibitors may inhibit the active secretion of methotrexate from the kidney via inhibition of the hydrogen-potassium ATPase(1) and may reduce uptake of methotrexate into breast cancer resistance protein via competitive inhibition.(2,3) CLINICAL EFFECTS: The concurrent use of methotrexate and proton pump inhibitors may result in elevated levels of methotrexate and increased methotrexate-related adverse effects and toxicities, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia. PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Impaired renal function, ascites, or pleural effusions PATIENT MANAGEMENT: For patients receiving high dose methotrexate with leucovorin rescue, consider discontinuation of proton pump inhibitors for the duration of therapy. Patients receiving concurrent use of methotrexate and proton pump inhibitors should be monitored closely for elevated methotrexate levels and methotrexate toxicity. The US manufacturer of omeprazole states that secretory ability returns gradually over three to five days following discontinuation.(4) Therefore, it would seem prudent to discontinue proton pump inhibitors several days prior to methotrexate therapy. DISCUSSION: In a clinical trial in 74 patients on high dose (1-5 G/m2) methotrexate therapy, data was examined to determine if proton pump inhibitor (omeprazole, pantoprazole, rabeprazole) use affects methotrexate elimination. Delayed elimination was found to be more frequent in those with co-administration of a proton pump inhibitor (31.7% vs. 13.8%), resulting in higher plasma methotrexate concentrations at 24, 48, and 74 hours. The effect was seen with lansoprazole, omeprazole, pantoprazole, and rabeprazole.(2) There are three case reports(1,5,6) of elevated methotrexate levels or delayed methotrexate elimination resulting from concurrent administration of high dose methotrexate and omeprazole, including one patient(6) that developed severe mucositis. In each case, omeprazole was discontinued and normal methotrexate kinetics were observed on subsequent cycles with no further adverse effects noted. In a case report of a 59 year-old male on low dose (15 mg weekly) methotrexate, administration of pantoprazole (20 mg daily) was found to increase the AUC of the metabolite 7-hydroxymethotrexate by 70%.(7) In a clinical trial, 28 adults with rheumatoid arthritis on low dose (7.5-15 mg weekly) methotrexate were assigned to receive lansoprazole (30 mg daily) and naproxen (500 mg twice daily) on Days 1-7 of therapy. The half life of the metabolite 7-hydroxymethotrexate was prolonged with concurrent administration, but no other statistically significant differences were found in regards to the plasma concentration profiles of methotrexate or 7-hydroxymethotrexate.(8) |
METHOTREXATE, METHOTREXATE SODIUM |
| Clobazam/Strong; Selected Moderate CYP2C19 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Clobazam's active metabolite, N-desmethylclobazam, is metabolized by the CYP2C19 isoenzyme.(1) The FDA categorizes N-desmethylclobazam as a sensitive substrate for CYP2C19. Sensitive substrates are drugs whose plasma area-under-curve (AUC) have been shown to increase 5-fold or higher when co-administered with a strong inhibitor of the enzyme.(2) CLINICAL EFFECTS: Concurrent use of a strong or selected moderate inhibitor of CYP2C19 may result in elevated levels of and toxicity from the active metabolite of clobazam, including profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The dosage of clobazam may need to be adjusted when initiating or discontinuing a strong or selected moderate inhibitor of CYP2C19.(1) When initiating a strong or selected moderate inhibitor of CYP2C19 in a patient maintained on clobazam, monitor closely for increased effects from clobazam and adjust dose accordingly.(1) If possible, use an alternative treatment which does not inhibit CYP2C19. When initiating clobazam in a patient maintained on a strong or moderate inhibitor of CYP2C19, it would be prudent to follow the manufacturer's recommendations for dosage adjustments in patients who are CYP2C19 poor metabolizers. In these patients, consider a starting dose of 5 mg/day and reduce weekly dosage adjustments to half the normal increase. Based on clinical response, the dosage may be titrated to normal dosage levels based on weight group at Day 21.(1) DISCUSSION: The active metabolite of clobazam, N-desmethylclobazam, is metabolized by CYP2C19. Levels of N-desmethylclobazam are 3-5 times higher in poor metabolizers of CYP2C19 and 2 times higher in intermediate metabolizers of CYP2C19. Thus, strong and moderate inhibitors of CYP2C19 are expected to result in a 3 to 5-fold increase in levels of N-desmethylclobazam as well.(1) Strong and selected moderate inhibitors of CYP2C19 include: esomeprazole, fluconazole, fluvoxamine, omeprazole, and ticlopidine.(2) Esomeprazole and omeprazole are irreversible inhibitors of CYP2C19. Although intermittent use may lead to moderate CYP2C19 inhibition, routine use may lead to inactivation of all available CYP2C19, converting patient to the CYP2C19 poor metabolizer phenotype.(3) 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. |
CLOBAZAM, ONFI, SYMPAZAN |
| Ledipasvir; Velpatasvir/Proton Pump Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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 absorption.(1-3) CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of ledipasvir and velpatasvir, leading to decreased systemic levels and effectiveness.(1-3) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Omeprazole 20 mg daily, or comparable doses of other PPIs, may be administered simultaneously with ledipasvir-sofosbuvir under fasting conditions.(1) Coadministration of proton pump inhibitors is not recommended with sofosbuvir-velpatasvir. When concomitant proton pump inhibitor use is necessary in patients receiving sofosbuvir-velpatasvir, velpatasvir-sofosbuvir should be administered with food and taken 4 hours before omeprazole 20 mg. Use with other proton pump inhibitors has not been studied.(2) Omeprazole 20 mg daily may be administered with sofosbuvir-velpatasvir-voxilaprevir. Use with other proton pump inhibitors has not been studied.(3) When clinically appropriate, consider use of H2 blockers or antacids.(1-3) DISCUSSION: In an interaction study, omeprazole 20 mg given once daily simultaneously with ledipasvir-sofosbuvir, decreased ledipasvir exposure (AUC) by 4%. When omeprazole 20 mg once daily was given 2 hours prior to ledipasvir-sofosbuvir dose, ledipasvir exposure (AUC) decreased approximately 50%.(1) In an interaction study, omeprazole 20 mg given once daily simultaneously with sofosbuvir-velpatasvir decreased velpatasvir exposure (AUC) by 37%. When omeprazole 20 mg once daily was given 12 hours prior to sofosbuvir-velpatasvir dose, velpatasvir exposure (AUC) decreased 57%. When omeprazole 20 mg once daily was given 2 hours prior to sofosbuvir-velpatasvir dose, velpatasvir AUC decreased 48%. When omeprazole 20 mg once daily was given 4 hours after sofosbuvir-velpatasvir dose, velpatasvir AUC decreased 33%. When omeprazole 40 mg once daily was given 4 hours after sofosbuvir-velpatasvir dose, velpatasvir AUC decreased 56%.(2) In an interaction study, when omeprazole 20 mg once daily was given 2 hours prior to the sofosbuvir-velpatasvir-voxilaprevir dose, sofosbuvir AUC, velpatasvir AUC, and voxilaprevir AUC decreased 27%, 54%, and 20%, respectively. When omeprazole 20 mg once daily was given 4 hours after the sofosbuvir-velpatasvir-voxilaprevir dose, sofosbuvir AUC, velpatasvir AUC, and voxilaprevir AUC decreased 18%, 51%, and 5%, respectively %.(3) Proton pump inhibitors linked to this monograph are: dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole. |
EPCLUSA, HARVONI, LEDIPASVIR-SOFOSBUVIR, SOFOSBUVIR-VELPATASVIR, VOSEVI |
| Esomeprazole; Omeprazole/Select CYP2C19 and CYP3A4 Inducer SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Proton pump inhibitors are primarily metabolized by CYP2C19, while CYP3A4 also plays a role in metabolism.(1,2) Enzalutamide, rifampin, and St. John's wort are moderate inducers of CYP2C19 and strong inducers of CYP3A4.(3,4) Apalutamide is a strong inducer of CYP2C19 and CYP3A4.(5) Efavirenz and pacritinib are moderate inducers of CYP2C19 and CYP3A4.(3,6) CLINICAL EFFECTS: Concurrent use of agents which induce both CYP2C19 and CYP3A4 decrease systemic exposure and may result in decreased effectiveness of proton pump inhibitors.(1-7) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid concurrent use of esomeprazole or omeprazole with CYP2C19 or CYP3A4 inducers.(1,2) Monitor patients receiving concurrent therapy for reduced proton pump inhibitor (PPI) effectiveness. Although specific dosing recommendations are not available, a higher dose of the proton pump inhibitor may be considered to maintain PPI efficacy. DISCUSSION: In an interaction study, subjects with prostate cancer received omeprazole before and after enzalutamide 160 mg daily for at least 55 days. Enzalutamide decreased omeprazole area-under-curve (AUC) by 70.5%.(3,4) In an interaction study, rifampin 600 mg daily for 7 days decreased omeprazole AUC by 89.5%.(3,7) In an interaction study, pacritinib 200 mg twice daily at steady state decreased the maximum concentration (Cmax) and AUC of a single dose of omeprazole (20 mg) by 27% and 51%, respectively. In an interaction study, St. John's wort decreased the maximum concentration (Cmax) and AUC of omeprazole by 37.5% and 49.6%, respectively. The Cmax and AUC of omeprazole sulfone (via CYP2C19) increased by 160.3% and 136.6%, respectively. The Cmax and AUC of 5-hydroxyomeprazole (via CYP3A4) increased by 38.1% and 37.2%, respectively.(8,9) |
EFAVIRENZ, EFAVIRENZ-EMTRIC-TENOFOV DISOP, EFAVIRENZ-LAMIVU-TENOFOV DISOP, ERLEADA, RIFADIN, RIFAMPIN, SYMFI, SYMFI LO, VONJO, XTANDI |
| Capecitabine/Proton Pump Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The aqueous solubility of capecitabine is pH dependent. Higher gastric pH leads to lower solubility and altered tablet dissolution which may reduce capecitabine absorption.(1,2) CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of capecitabine, leading to decreased systemic levels and effectiveness.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Coadministration of proton pump inhibitors with capecitabine may decrease bioavailability. When clinically appropriate, consider using H2 blockers or antacids. DISCUSSION: A retrospective study in early stage colorectal cancer patients treated with adjuvant monotherapy capecitabine examined recurrence-free survival (RFS) and overall survival (OS) in 1335 patients with and without concurrent proton pump inhibitor (PPI) therapy. The PPI group was defined as a prescription for a PPI filled at any point in time during capecitabine treatment. Patients in the capecitabine with concurrent PPI group had a statistically significant decrease in 5-year RFS (74% v 83%; hazard ratio (HR) 1.89; 95% confidence interval (CI) 1.07-3.35; p=0.03) compared to capecitabine without PPI therapy. OS was not significantly different between groups (81% PPI v 78% non-PPI; HR 1.13; 95% CI 0.6-2.14; p=0.7). After adjusting for male gender, stage III colorectal cancer, advance age >68, poorer ECOG PS, there was a trend toward decreased RFS in PPI patients (HR 1.65; 95% CI 0.93-2.94; p=0.09).(1) An ad hoc analysis of the TRIO-013/LOCiC trial examined coadministration of PPI therapy, defined as 20% or more overlap between a PPI prescription and trial treatment duration with capecitabine and/or lapatinib, on progression-free survival (PFS) and overall survival (OS). The secondary analysis examined 545 patients in which 42% were on concurrent PPI therapy. Patients in the non-PPI group had an improved median PFS (5.7 v 4.2 months; HR 1.55; 95% CI 1.29-1.81; p<0.001) and median OS (11.3 v 9.2 months; HR 1.34; 95% CI 1.06-1.62; p=0.04) compared with PPI users. A multivariate analysis reviewed effects of PPIs on both PFS and OS with capecitabine alone and found effects of PPI use on both PFS and OS was still significant (HR 1.68; p<0.001 and HR 1.41; p=0.001, respectively).(2) In a study in 12 subjects, concomitant administration of capecitabine with aluminum-magnesium hydroxide containing antacid 20 mL increased area-under-curve (AUC) and concentration maximum (Cmax) by 16% and 35%, respectively.(3) Proton pump inhibitors linked to this monograph include: dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole. |
CAPECITABINE, XELODA |
| Secretin/H2 Antagonists; Proton Pump Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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) |
CHIRHOSTIM |
| Selpercatinib/Proton Pump Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The solubility of selpercatinib is pH dependent. Increase in gastric pH from proton pump inhibitors (PPIs) may decrease the solubility and absorption of selpercatinib.(1) CLINICAL EFFECTS: Use of proton pump inhibitors may result in decreased levels and effectiveness of selpercatinib.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid the use of proton pump inhibitors (PPIs), H2 antagonists, and locally acting antacids in patients receiving treatment with selpercatinib. If coadministration with PPIs cannot be avoided, take selpercatinib with food.(1) If the PPI is replaced with a H2 antagonist, take selpercatinib 2 hours before or 10 hours after the H2 antagonist.(1) If the PPI is replaced with an antacid, take selpercatinib 2 hours before or 2 hours after the antacid.(1) DISCUSSION: In a study, omeprazole decreased the area-under-curve (AUC) and maximum concentration (Cmax) of selpercatinib (administered fasting) by 69% and 88%, respectively. When selpercatinib was administered with food, omeprazole did not significantly affect selpercatinib levels.(1) |
RETEVMO |
| Selected Cephalosporins/Long Acting Antacids; H2s;PPIs 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) |
CEFPODOXIME PROXETIL, CEFUROXIME |
| Sotorasib/H2 Antagonists; Proton Pump Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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) |
LUMAKRAS |
| Methylphenidate XR-ODT/H2 Antagonists;Proton Pump Inhibitors 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) |
COTEMPLA XR-ODT |
| Levoketoconazole/H2 Antagonists; Proton Pump Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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) |
RECORLEV |
| Pemetrexed/Proton Pump Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Proton pump inhibitors may inhibit the active secretion of pemetrexed from the kidney via the organic anion transporter 3 (OAT3).(1,2,3) CLINICAL EFFECTS: The concurrent use of pemetrexed and proton pump inhibitors may result in increased levels and toxicities of pemetrexed, including severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia. PREDISPOSING FACTORS: Risk factors for pemetrexed toxicity include high-dose oncology regimens, impaired renal function, and concurrent use of nephrotoxic medications. PATIENT MANAGEMENT: For patients receiving pemetrexed, consider discontinuation of proton pump inhibitors for the duration of pemetrexed therapy. If concurrent use cannot be avoided, monitor closely for elevated pemetrexed levels and toxicity. DISCUSSION: A prospective observational study of 156 patients receiving pemetrexed-based therapy found that severe hematological toxicity, namely neutropenia and anemia, occurred in 34/55 patients (61.8%) taking concurrent proton pump inhibitors (PPIs) and in 36/101 patients (35.6%) who did not consume PPIs. In Cox regression multivariable analysis, the hazard ratio for severe hematological toxicity with PPI use was 2.51 (95% CI = 1.47-4.26). Esomeprazole, pantoprazole, and lansoprazole were the most consumed PPIs in the study, but no correlation was investigated.(1) A retrospective review of 61 patients investigated medication-related causes of severe hematological toxicity in patients on pemetrexed/carboplatin chemotherapy. Twenty-three patients took PPIs: lansoprazole (n=16), esomeprazole (n=5), omeprazole (n=1), and rabeprazole (n=1). In a multiple logistic regression analysis, use of PPIs in patients receiving pemetrexed/carboplatin combination chemotherapy was associated severe hematotoxicity (odds ratio: 5.34, 95% CI: 1.06-26.94, P = 0.042).(2) In an in vitro analysis and retrospective study, lansoprazole, rabeprazole, pantoprazole, esomeprazole, omeprazole, and vonoprazan were shown to inhibit OAT3-mediated uptake of pemetrexed, with lansoprazole having the greatest inhibitory effect. In the multivariate analysis of 108 patients, concurrent use of lansoprazole (but not other PPIs) and pemetrexed/carboplatin was a significant risk factor for the development of hematological toxicity (odds ratio: 10.004, P = 0.005).(3) In a retrospective study of 74 patients who received pemetrexed, 24 patients (32%) were on concomitant PPIs. Pemetrexed toxicity was associated with cystatin clearance (p=0.0135), albumin level (p=0.0333), and proton pump inhibitors (p=0.035) on multivariate analysis. Most patients (n=14) took esomeprazole or omeprazole, with the remainder taking lansoprazole (n=5), pantoprazole (n=4) or an unspecified agent.(4) |
ALIMTA, AXTLE, PEMETREXED, PEMETREXED DISODIUM, PEMFEXY, PEMRYDI RTU |
| Sparsentan/H2 Antagonists; Proton Pump Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The aqueous solubility of sparsentan 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 sparsentan.(1) CLINICAL EFFECTS: Coadministration of H2RAs or PPIs may reduce the bioavailability of sparsentan, leading to decreased systemic levels and effectiveness.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Coadministration of sparsentan with PPIs and H2RAs should be avoided.(1) DISCUSSION: Sparsentan is practically insoluble in water but has intrinsic solubility of 1.48 mg/mL and 0.055 mg/mL below pH 1.2 and 6.8, respectively. H2RAs and PPIs raise gastric pH and may impair dissolution and absorption of sparsentan.(1) |
FILSPARI |
| Nirogacestat/H2 Antagonists; Proton Pump Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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) |
OGSIVEO |
| Mavacamten/Moderate CYP2C19 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Moderate CYP2C19 inhibitors may decrease the metabolism of mavacamten.(1-3) CLINICAL EFFECTS: Concurrent use of a moderate CYP2C19 inhibitor increases plasma exposure of mavacamten which may increase the incidence and severity of adverse reactions of mavacamten.(1-3) PREDISPOSING FACTORS: CYP2C19 rapid and ultrarapid metabolizers may experience an increased incidence or severity of adverse effects.(1-3) PATIENT MANAGEMENT: The US manufacturer of mavacamten recommends initiating mavacamten at the recommended starting dosage of 2.5 mg orally once daily in patients who are on stable therapy with a moderate CYP2C19 inhibitor. Reduce dose by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients who are on mavacamten treatment and intend to initiate a moderate CYP2C19 inhibitor. Schedule clinical and echocardiographic assessment 4 weeks after inhibitor initiation, and do not up-titrate mavacamten until 12 weeks after inhibitor initiation.(1) Avoid initiation of concomitant moderate CYP2C19 inhibitors in patients who are on stable treatment with 2.5 mg of mavacamten because a lower dose is not available.(1) For short-term use (e.g. 1 week), interrupt mavacamten therapy for the duration of the moderate CYP2C19 inhibitor. After therapy with the moderate CYP2C19 inhibitor is discontinued, mavacamten may be reinitiated at the previous dose immediately upon discontinuation.(1) The Canadian manufacturer of mavacamten states concomitant use with moderate CYP2C19 inhibitors is contraindicated.(2) The UK manufacturer of mavacamten states concomitant use with moderate CYP2C19 inhibitors is dependent on CYP2C19 phenotype. Labeling recommends: -In patients who are CYP2C19 poor metabolizers, moderate CYP2C19 inhibitors may be used concurrently without dose adjustment of mavacamten. Monitor left ventricular ejection fraction (LVEF) in 4 weeks then resume usual monitoring schedule. -In patient who are CYP2C19 intermediate, normal, rapid, or ultrarapid metabolizers: Moderate CYP2C19 inhibitors may be used concurrently without dose adjustment of mavacamten starting dose of 5 mg daily. If starting a moderate CYP2C19 inhibitor, reduce mavacamten dose by one dose level or discontinue 2.5 mg. Monitor LVEF in 4 weeks then resume usual monitoring schedule. -If CYP2C19 phenotype is unknown, consider a mavacamten starting dose of 2.5 mg daily. If starting a moderate CYP2C19 inhibitor, reduce mavacamten dose from 5 mg to 2.5 mg or discontinue mavacamten if on 2.5 mg. Monitor LVEF in 4 weeks then resume usual monitoring schedule.(3) DISCUSSION: Concomitant use of mavacamten (15 mg) with omeprazole (20 mg), a weak CYP2C19 inhibitor, once daily increased mavacamten area-under-curve (AUC) by 48% with no effect on maximum concentration (Cmax) in healthy CYP2C19 normal metabolizers and rapid metabolizers.(1) Moderate CYP2C19 inhibitors linked to this monograph include: abrocitinib, cannabidiol, efavirenz, esomeprazole, etravirine, moclobemide, omeprazole, stiripentol, triclabendazole.(4,5) |
CAMZYOS |
There are 12 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| Itraconazole; Ketoconazole/Agents Affecting Gastric pH 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. |
ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KETOCONAZOLE, SPORANOX, TOLSURA |
| Amphetamines/H2 Antagonists; Proton Pump Inhibitors 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) |
ADDERALL, ADDERALL XR, ADZENYS XR-ODT, AMPHETAMINE SULFATE, DESOXYN, DEXEDRINE, DEXTROAMPHETAMINE SULFATE, DEXTROAMPHETAMINE SULFATE ER, DEXTROAMPHETAMINE-AMPHET ER, DEXTROAMPHETAMINE-AMPHETAMINE, DYANAVEL XR, EVEKEO, METHAMPHETAMINE HCL, MYDAYIS, PROCENTRA, ZENZEDI |
| Methotrexate(low strength inj, oral)/Proton Pump Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Proton pump inhibitors(PPIs) may inhibit the active secretion of methotrexate from the kidney via inhibition of the hydrogen-potassium ATPase(1) and may reduce uptake of methotrexate into breast cancer resistance protein via competitive inhibition.(2,3) CLINICAL EFFECTS: The concurrent use of methotrexate and proton pump inhibitors may result in elevated levels of methotrexate and increased methotrexate-related adverse effects and toxicities, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia.(1-7,9) PREDISPOSING FACTORS: High dose methotrexate therapy appears to increase the risk for and severity of this interaction.(4,9) PATIENT MANAGEMENT: Patients receiving concurrent use of methotrexate and proton pump inhibitors should be monitored closely for elevated methotrexate levels and methotrexate toxicity. The US manufacturer of omeprazole states that secretory ability returns gradually over three to five days following discontinuation.(4) This interaction has best described in patients receiving high dose methotrexate for cancer treatment. Therefore, it would seem prudent to discontinue proton pump inhibitors several days prior to high dose methotrexate therapy. The magnitude and frequency of this interaction in patients receiving less than or equal to 15 mg weekly is less clear. While a small study suggested lansoprazole was safe in rheumatoid arthritis patients taking 7.5 - 15 mg weekly(8), at least one case report of PPI associated methotrexate toxicity at a low dose (15 mg IM weekly) has been described.(7) DISCUSSION: In a clinical trial in 74 patients on high dose (1-5 G/m2) methotrexate therapy, data was examined to determine if proton pump inhibitor (omeprazole, pantoprazole, rabeprazole) use affects methotrexate elimination. Delayed elimination was found to be more frequent in those with co-administration of a proton pump inhibitor (31.7% vs. 13.8%), resulting in higher plasma methotrexate concentrations at 24, 48, and 74 hours. The effect was seen with lansoprazole, omeprazole, pantoprazole, and rabeprazole.(2) There are three case reports(1,5,6) of elevated methotrexate levels or delayed methotrexate elimination resulting from concurrent administration of high dose methotrexate and omeprazole, including one patient(6) that developed severe mucositis. In each case, omeprazole was discontinued and normal methotrexate kinetics were observed on subsequent cycles with no further adverse effects noted. In a case report of a 59 year-old male on low dose (15 mg weekly) methotrexate, administration of pantoprazole (20 mg daily) was found to increase the AUC of the metabolite 7-hydroxymethotrexate by 70%.(7) In a manufacturer sponsored clinical trial, 28 adults with rheumatoid arthritis on low dose (7.5-15 mg weekly) methotrexate were assigned to receive lansoprazole (30 mg daily) and naproxen (500 mg twice daily) on Days 1-7 of therapy. The half life of the metabolite 7-hydroxymethotrexate was prolonged with concurrent administration, but no other statistically significant differences were found in regards to the plasma concentration profiles of methotrexate or 7-hydroxymethotrexate.(8) |
JYLAMVO, METHOTREXATE, OTREXUP, RASUVO, TREXALL, XATMEP |
| Mycophenolate Mofetil/Proton Pump Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. One theory is that proton pump inhibitors may prevent mycophenolate mofetil from being converted to mycophenolic acid in the gastrointestinal tract.(1-5) CLINICAL EFFECTS: Concurrent use of proton pump inhibitors (PPIs) may result in decreased mycophenolic acid levels and effects, including increased risk of transplant rejection. PREDISPOSING FACTORS: Other factors which may affect systemic mycophenolate exposure include renal function, serum albumin, gender, race, the choice of calcineurin inhibitor (CNI), and use of other drugs which inhibit absorption or enterohepatic recirculation of mycophenolate. PATIENT MANAGEMENT: If concurrent treatment of mycophenolate mofetil and a PPI is needed, evaluate predisposing risk factors (e.g. renal function, gender, race, and presence of other interacting drugs) which may increase or decrease mycophenolate exposure. If a patient is at risk for low mycophenolic acid levels, options may include converting to delayed release mycophenolic acid (mycophenolate sodium) which is not susceptible to this interaction (4,8,9), or monitoring mycophenolic acid levels to assure therapeutic concentrations are attained. DISCUSSION: A study compared 21 heart transplant patients maintained on mycophenolate mofetil and pantoprazole (40 mg daily) to 12 patients maintained on mycophenolate without pantoprazole. There was no significant difference in mycophenolate dose between the groups. However, mycophenolic acid levels at 30 minutes, 1 hour, 2 hours, and 12 hours were significantly lower in patients who received pantoprazole (63%, 44%, 34%, 52%, respectively). Mycophenolic acid area-under-curve (AUC) and maximum concentration (Cmax) were also significantly lower in patients who received pantoprazole (30% and 78%, respectively). There was a trend for more acute rejection episodes and transplant vasculopathy in patients receiving pantoprazole.(1) A study compared 23 patients with autoimmune diseases maintained on mycophenolate mofetil and pantoprazole (40 mg daily) to 13 patients maintained on mycophenolate without pantoprazole. There was no significant difference in mycophenolate dose between the groups. The AUC and Cmax of mycophenolic acid decreased by 37% and 60%, respectively, in patients treated with pantoprazole. The activity of mycophenolic acid decreased by 42% in patients receiving pantoprazole.(2) In a study in 22 heart transplant patients receiving mycophenolate mofetil (1000 mg twice daily), mycophenolic acid levels at 30 and 60 minutes post-dose were 55% and 37% lower, respectively, when patients were receiving pantoprazole (40 mg daily). The AUC and Cmax of mycophenolic acid were both 41% when patients were receiving pantoprazole. The time to reach Cmax (Tmax) was 29% longer.(3) A study in 12 healthy subjects compared the effects of pantoprazole (40 mg twice daily) on single doses of mycophenolate mofetil (1000 mg) and enteric-coated mycophenolate sodium (720 mg). Pantoprazole decreased the Cmax and AUC of mycophenolic acid following mycophenolate mofetil administration by 57% and 27%, respectively. There were no effects on mycophenolate acid following mycophenolate sodium administration.(4) A study in renal transplant patients, patients receiving mycophenolate mofetil and tacrolimus without PPI therapy (n=22) were compared to patients receiving concurrent mycophenolate mofetil, tacrolimus, and lansoprazole (30 mg, n=22) and patients receiving concurrent mycophenolate mofetil, tacrolimus, and rabeprazole (10 mg, n=17). Mycophenolic acid Cmax, dose-adjusted Cmax, and AUC(0-6h) were significantly lower in patients receiving lansoprazole when compared to patients not receiving PPI therapy. There were no significant differences between patients receiving rabeprazole and those not receiving PPI therapy; however, rabeprazole acid lowering effects are lower than lansoprazole.(5) A cross-sectional, retrospective analysis of renal transplant patients on omeprazole, mycophenolate, and a calcineurin inhibitor found that in the first week post-transplant the mycophenolate active moiety levels were reduced to a point of clinical significance. However, after that first week, the effect seemed to be less clinically significant.(6) In a study of heart transplant patients, use of pantoprazole (20 mg to 80 mg daily) significantly reduced the AUC of mycophenolic acid produced from a mean daily dose of 2.2+/-0.8 mycophenolate mofetil (p=0.02). However, mycophenolic acid minimum concentration (Cmin) was not significantly different.(7) In a study in healthy subjects, the Cmax and AUC of mycophenolic acid were decreased when mycophenolate mofetil was administered with omeprazole (20 mg BID); however, there was no effect on the Cmax or AUC of mycophenolic acid when enteric-coated mycophenolate mofetil was administered with omeprazole.(8) In a study in heart or lung transplant patients, concurrent pantoprazole had no effect on the Cmax, Tmax, or AUC of mycophenolic acid following administration of enteric-coated mycophenolate sodium. Additionally no significant difference of inosine 5?-monophosphate dehydrogenase (IMPDH) activity was seen with EC-mycophenolate given alone or with pantoprazole.(9) In a subanalysis of the CLEAR Study, there were no significant effects of omeprazole or pantoprazole on mycophenolic acid levels in the study group randomized to received intensified dosing with mycophenolate mofetil (1.5 g BID for 5 days, then 1 g BID).(10) |
CELLCEPT, MYCOPHENOLATE MOFETIL, MYHIBBIN |
| Tacrolimus/Selected Proton Pump Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Some proton-pump inhibitors (PPIs) may inhibit the metabolism of tacrolimus by CYP3A4 and intestinal CYP3A5. CLINICAL EFFECTS: Concurrent use may increase tacrolimus levels in some patients and result in toxic effects, including nephrotoxicity, neurotoxicity, and prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes. PREDISPOSING FACTORS: This interaction may be is more severe in patients who are poor metabolizers of CYP2C19. The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(17) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(17) PATIENT MANAGEMENT: Consider monitoring tacrolimus levels when initiating or discontinuing a PPI other than pantoprazole in patients who are poor metabolizers of CYP2C19 or whose genotype is unknown. The dosage of tacrolimus may need to be adjusted. Pantoprazole may be an alternative to other PPIs in patients maintained on tacrolimus. When concurrent therapy of selected proton pump inhibitors and tacrolimus is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: In vitro studies have shown that omeprazole inhibits the metabolism of tacrolimus.(1,2) In a case report, tacrolimus levels increased 1.8-fold in a pediatric live-transplant patient following the initiation of omeprazole.(3) In another report, the tacrolimus concentration/dose ratio was higher during omeprazole therapy when compared to rabeprazole therapy.(4) In a study in 48 renal transplant patients, the dose/weight normalized trough levels of tacrolimus decreased 15% following the switch of cimetidine to omeprazole.(5) In contrast, in a study in 51 renal transplant patients found no difference in tacrolimus level/dose ratio following the discontinuation of omeprazole.(6) In a study in 12 renal transplant patients who were CYP3A5-nonexpressors, there was no effect by omeprazole on tacrolimus pharmacokinetics.(7) A study in 89 liver transplant patients showed that the interaction between omeprazole and tacrolimus was more severe in patients that are either poor or intermediate metabolizers of CYP2C19.(8) There are three reports of elevated tacrolimus levels during the use of lansoprazole.(9,10,11,12) In a study in 73 renal transplant patients, lansoprazole and rabeprazole had significant effects on tacrolimus levels only in patients who were poor or intermediate metabolizers of CYP2C19.(13) In a study in 19 healthy subjects, lansoprazole increased tacrolimus levels in extensive and poor CYP2C19 metabolizers by 81% and 20%, respectively.(14) In contrast, a study in 55 liver-transplant patients, rabeprazole had no effect on tacrolimus concentrations regardless of CYP3A5 or CYP2C19 genotype.(15) In a study in 12 transplant recipients, pantoprazole had no effect on tacrolimus levels.(16) |
ASTAGRAF XL, ENVARSUS XR, PROGRAF, TACROLIMUS, TACROLIMUS XL |
| Citalopram (Less than or Equal To 20 mg)/Selected CYP2C19 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Citalopram is primarily metabolized by the CYP2C19 isoenzyme.(1) CLINICAL EFFECTS: Concurrent use of an agent that inhibits CYP2C19 may result in elevated levels of and toxicity from citalopram, including including risks for serotonin syndrome or prolongation of the QTc interval.(1-5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(5) PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age, poor metabolizer status at CYP2C19, or higher blood concentrations of citalopram.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,5) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. PATIENT MANAGEMENT: The dose of citalopram should be limited to 20 mg in patients receiving concurrent therapy with an inhibitor of CYP2C19.(1,4) Evaluate the patient for other drugs, diseases and conditions which increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, hypocalcemia, hypomagnesemia, discontinue other QT prolonging drugs) when possible.(1,2) Weigh the specific benefits versus risks for each patient. The US manufacturer recommends ECG monitoring for citalopram patients with congestive heart failure, bradyarrhythmias, taking concomitant QT prolonging medications or receiving concurrent therapy.(4) Citalopram should be discontinued in patients with persistent QTc measurements greater than 500 ms.(2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. DISCUSSION: Concurrent use of citalopram (40 mg daily) and cimetidine (400 mg twice daily) for 8 days increased the maximum concentration (Cmax) and area-under-curve (AUC) of citalopram by 39% and 43%, respectively.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, and tecovirimat.(7,8) |
CELEXA, CITALOPRAM HBR |
| Escitalopram (Greater Than 15 mg)/Selected CYP2C19 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: At lower systemic concentrations, escitalopram is primarily metabolized by CYP2C19; at higher concentrations is also metabolized by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of an agent which significantly inhibits CYP2C19, or which inhibits both CYP2C19 and CYP3A4 may result in elevated concentrations and toxicity from escitalopram, including risks for serotonin syndrome or prolongation of the QTc interval.(1,5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3) PREDISPOSING FACTORS: The risk of QT prolongation may be increased in patients with congenital long QT syndrome, cardiovascular disease (e.g. heart failure, myocardial infarction), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female sex, advanced age, poor metabolizer status at CYP2C19, concurrent use of more than one agent known to cause QT prolongation, or with higher blood concentrations of escitalopram.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,3) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. PATIENT MANAGEMENT: Evaluate patient for other drugs, diseases and conditions which may further increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, discontinue other QT prolonging drugs) when possible.(2,3) It would be prudent to limit the escitalopram dose to 10 mg daily in patients with QT prolonging risk factors who also receive concurrent therapy with selected CYP2C19 inhibitors.(5) Weigh the specific benefits versus risks for each patient. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. DISCUSSION: A thorough QT study evaluating escitalopram 10 mg or 30 mg once daily was conducted; a change of 10 msec for upper bound of the 95% confidence level is the threshold for regulatory concern. In this study, changes to the upper bound of the 95% confidence interval were 6.4 msec and 12.6 msec for the 10 mg and supratherapeutic 30 mg dose respectively. The Cmax for 30 mg was 1.7-fold higher than the Cmax for the maximum recommended escitalopram dose of 20 mg. Systemic exposure at the 30 mg dose was similar to expected steady state concentrations in 2C19 poor metabolizers following a 20 mg escitalopram dose.(1) In an interaction study, 30 mg of omeprazole, an irreversible inhibitor of CYP2C19 was administered daily for 6 days. On day 5 a single dose of escitalopram 20 mg was also administered; the area-under-curve (AUC) of escitalopram was increased by 50%. Manufacturer prescribing information recommends a maximum citalopram dose of 20mg daily in patients receiving CYP2C19 inhibitors.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, and tipranavir.(4) |
ESCITALOPRAM OXALATE, LEXAPRO |
| Escitalopram (Less Than or Equal To 15 mg)/Selected CYP2C19 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: At lower systemic concentrations, escitalopram is primarily metabolized by CYP2C19; at higher concentrations is also metabolized by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of an agent which significantly inhibits CYP2C19, or which inhibits both CYP2C19 and CYP3A4 may result in elevated concentrations and toxicity from escitalopram, including risks for serotonin syndrome or prolongation of the QTc interval.(1,5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3) PREDISPOSING FACTORS: The risk of QT prolongation may be increased in patients with congenital long QT syndrome, cardiovascular disease (e.g. heart failure, myocardial infarction), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female sex, advanced age, poor metabolizer status at CYP2C19, concurrent use of more than one agent known to cause QT prolongation, or with higher blood concentrations of escitalopram.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,3) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. PATIENT MANAGEMENT: Evaluate patient for other drugs, diseases and conditions which may further increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, discontinue other QT prolonging drugs) when possible.(2,3) It would be prudent to limit the escitalopram dose to 10 mg daily in patients with QT prolonging risk factors who also receive concurrent therapy with selected CYP2C19 inhibitors.(5) Weigh the specific benefits versus risks for each patient. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. DISCUSSION: A thorough QT study evaluating escitalopram 10 mg or 30 mg once daily was conducted; a change of 10 msec for upper bound of the 95% confidence level is the threshold for regulatory concern. In this study, changes to the upper bound of the 95% confidence interval were 6.4 msec and 12.6 msec for the 10 mg and supratherapeutic 30 mg dose respectively. The Cmax for 30 mg was 1.7-fold higher than the Cmax for the maximum recommended escitalopram dose of 20 mg. Systemic exposure at the 30 mg dose was similar to expected steady state concentrations in 2C19 poor metabolizers following a 20 mg escitalopram dose.(1) In an interaction study, 30 mg of omeprazole, an irreversible inhibitor of CYP2C19 was administered daily for 6 days. On day 5 a single dose of escitalopram 20 mg was also administered; the area-under-curve (AUC) of escitalopram was increased by 50%. Manufacturer prescribing information recommends a maximum citalopram dose of 20mg daily in patients receiving CYP2C19 inhibitors.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, and tipranavir.(4) |
ESCITALOPRAM OXALATE, LEXAPRO |
| Esomeprazole; Omeprazole/Carbamazepine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Esomeprazole and omeprazole are primarily metabolized by CYP2C19. CYP3A4 plays a smaller role in metabolism.(1,2) Carbamazepine is a strong inducer of CYP2C19 and CYP3A4.(2) Esomeprazole and omeprazole are weak CYP3A4 inhibitors and may also affect the metabolism of carbamazepine by CYP3A4.(2) CLINICAL EFFECTS: Concurrent use of agents which induce both CYP2C19 and CYP3A4 decrease systemic exposure and may result in decreased effectiveness of esomeprazole and omeprazole. Concurrent use of esomeprazole or omeprazole with carbamazepine may increase systemic exposure and may result in increased toxicity of carbamazepine.(1-8) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with carbamazepine for reduced proton pump inhibitor (PPI) effectiveness. Although specific dosing recommendations are not available, a higher dose of esomeprazole or omeprazole may be considered to maintain PPI efficacy. Monitor patients receiving concurrent therapy for increased carbamazepine effects. Therapeutic drug monitoring should be completed routinely when carbamazepine is coadministered with esomeprazole or omeprazole.(7,8) DISCUSSION: In an interaction study, omeprazole increased the maximum concentration (Cmax), area-under-curve (AUC) and elimination half-life (t1/2) of carbamazepine. The effect of carbamazepine on omeprazole was not studied in these trials (3,4) or in other investigations. The effects of other CYP2C19 inducers on the pharmacokinetics of omeprazole have been reported. In an interaction study, subjects with prostate cancer received omeprazole before and after enzalutamide 160 mg daily (an inducer of CYP2C19 and CYP3A4) for at least 55 days. Enzalutamide decreased omeprazole AUC by 70.5%.(2,5) In an interaction study, rifampin 600 mg daily (an inducer of CYP2C19 and CYP3A4) for 7 days decreased omeprazole AUC by 89.5%.(2,6) In an interaction study, St. John's wort (an inducer of CYP2C19 and CYP3A4) decreased the Cmax and AUC of omeprazole by 37.5% and 49.6%, respectively. The Cmax and AUC of omeprazole sulfone (via CYP2C19) increased by 160.3% and 136.6%, respectively. The Cmax and AUC of 5-hydroxyomeprazole (via CYP3A4) increased by 38.1% and 37.2%, respectively.(7,8) |
CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, EPITOL, EQUETRO, TEGRETOL, TEGRETOL XR |
| Cilostazol (Less Than or Equal To 50 mg BID)/Selected Strong & Moderate CYP2C19 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong and moderate inhibitors of CYP2C19 may inhibit the metabolism of cilostazol.(1-4) CLINICAL EFFECTS: Concurrent use of strong or moderate inhibitors of CYP2C19 may result in elevated levels of 3,4-dehydro-cilostazol, a metabolite of cilostazol that is 4-7 times as active as cilostazol.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The dose of cilostazol should be limited to 50 mg twice daily in patients receiving concurrent therapy with strong and moderate inhibitors of CYP2C19.(1) The Australian manufacturer of esomeprazole states concomitant use with cilostazol is contraindicated.(5) DISCUSSION: In a study in 20 subjects examined the effects of omeprazole (40 mg daily) on a single dose of cilostazol (100 mg). Concurrent omeprazole increased the cilostazol maximum concentration (Cmax) and area-under-curve (AUC) by 18% and 26%, respectively. The Cmax and AUC of the 3,4-dehydro-cilostazol metabolite of cilostazol increased 29% and 69%, respectively. The Cmax and AUC of the OPC-13213 metabolite of cilostazol decreased by 22% and 31%, respectively.(4) |
CILOSTAZOL |
| Belumosudil/Proton Pump Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Belumosudil is best absorbed in an acidic environment. Proton pump inhibitors (PPIs) decrease gastric acidity and may decrease belumosudil absorption and systemic concentrations.(1) CLINICAL EFFECTS: Coadministration of PPIs with belumosudil decreases systemic concentrations of belumosudil, which may decrease the efficacy of belumosudil.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Increase the dosage of belumosudil to 200 mg twice daily when coadministered with PPIs.(1) DISCUSSION: Coadministration of rabeprazole decreased belumosudil maximum concentration (Cmax) by 87% and area-under-curve (AUC) by 80%, and omeprazole decreased belumosudil Cmax by 68% and AUC by 47% in healthy subjects.(1) |
REZUROCK |
| Palbociclib/Proton Pump Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The mechanism of this interaction is not fully understood and may involve dysbiosis or gastric pH changes resulting from proton pump inhibitors (PPIs).(1,2) The aqueous solubility of palbociclib is pH-dependent. Higher gastric pH leads to lower solubility which may reduce palbociclib absorption.(1) CLINICAL EFFECTS: Coadministration of PPIs may reduce the bioavailability of palbociclib, leading to decreased systemic levels and effectiveness.(1) Although administration of palbociclib with food minimizes the decrease in absorption,(1) retrospective studies and a meta-analysis have found lower survival rates among patients on concurrent PPIs.(2-7) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of palbociclib capsules states that palbociclib should be taken with food, whereas palbociclib tablets may be taken with or without food. There are no constraints on concurrent use of proton pump inhibitors.(1) Given the decreased survival rates observed in patients who received PPIs with palbociclib, the authors of some studies on concurrent use of these agents have made various recommendations, including avoiding PPIs with palbociclib, using ribociclib instead of palbociclib, using low strengths of PPIs, or using H2-antagonists or antacids.(2-7) DISCUSSION: Palbociclib solubility decreases significantly above pH 4.(1) In a study with healthy volunteers, rabeprazole decreased the maximum concentration (Cmax) and area-under-curve (AUC) of single-dose palbociclib without food by 80% and 62%, respectively. In another study of healthy volunteers in a fed state, rabeprazole decreased Cmax and AUC of single-dose palbociclib by 41% and 13%, respectively.(1) A systematic review and meta-analysis examined studies of HER2-negative, hormone receptor-positive patients with metastatic breast cancer treated with palbociclib or ribociclib with or without concomitant PPIs that reported on survival outcomes. Eight studies consisting of 2,584 patients (830 on PPIs, 1754 not on PPIs) were included. Patients on concurrent PPIs had a significantly higher risk of all-cause mortality (HR, 2.03; 95% CI, 1.49 to 2.77) and disease progression (HR, 1.75; 95% CI, 1.26 to 2.43) compared to patients not on PPIs, though there was a high degree of heterogeneity in disease progression.(2) A retrospective cohort of patients with advanced or metastatic breast cancer treated with palbociclib capsules (344 patients on PPIs, 966 patients not on PPIs) revealed that patients on PPIs had shorter progression-free survival (PFS) (HR 1.76 (95% CI, 1.46-2.13) and lower overall survival (HR, 2.71 [95% CI, 2.07-3.53]).(3) A post-hoc analysis of the phase 2 PARSIFAL trial evaluated PFS in patients on palbociclib capsules. 326 patients were PPI-naive, 64 patients were early users of PPIs (started on PPIs since starting palbociclib), and 91 patients were long-term users of PPIs. PPI use was associated with a shorter PFS (HR in early PPI users 1.5; 95% CI 1.1-2.2; HR in long-term PPI users 1.4; 95% CI 1.1-1.9).(4) A retrospective study of 50 patients with metastatic breast cancer on palbociclib found that concurrent PPI use was associated with a shorter PFS.(5) In an observational study of patients with metastatic breast cancer on palbociclib capsules, PFS was compared between 65 patients on PPIs and 40 patients not on PPIs. On multivariate analysis, PPI usage was an independent predictor of shorter PFS (HR 5.60; 95% confidence interval: 1.98-15.85).(6) A retrospective observational cohort of metastatic breast cancer patients on palbociclib found that patients on concurrent PPIs had a shorter PFS than those not on PPIs (14.0 versus 37.9 months, p < 0.0001).(7) In contrast to these findings, other studies have not found a detrimental effect of PPIs on palbociclib efficacy. A retrospective observational study focused on 112 patients with endocrine-resistant metastatic breast cancer on palbociclib capsules (n=58) and tablets (n=20). There was no difference in PFS in patients on concurrent PPIs compared to those not on PPIs.(8) A study looking at 82 patients with metastatic breast cancer treat 1st line with palbociclib tablets(9) and a retrospective observational study on metastatic breast cancer patients on palbociclib capsules(10) also did not find a significantly different PFS between patients with and without concurrent PPIs. |
IBRANCE |
The following contraindication information is available for NEXIUM (esomeprazole magnesium):
Drug contraindication overview.
Known hypersensitivity to esomeprazole or other substituted benzimidazoles (e.g., lansoprazole, omeprazole, pantoprazole, rabeprazole) or any ingredient in the formulation.
Known hypersensitivity to esomeprazole or other substituted benzimidazoles (e.g., lansoprazole, omeprazole, pantoprazole, rabeprazole) or any ingredient in the formulation.
There are 0 contraindications.
There are 5 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Clostridioides difficile infection |
| Interstitial nephritis |
| Severe hepatic disease |
| Subacute cutaneous lupus erythematosus |
| Systemic lupus erythematosus |
There are 5 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| CYp2c19 poor metabolizer |
| Fracture |
| Hypomagnesemia |
| Osteoporosis |
| Vitamin b12 deficiency |
The following adverse reaction information is available for NEXIUM (esomeprazole magnesium):
Adverse reaction overview.
Adverse effects occurring in 1% or more of patients receiving oral esomeprazole include headache, diarrhea, nausea, flatulence, abdominal pain, constipation, and dry mouth. Common adverse effects of IV esomeprazole generally are similar to those reported with oral esomeprazole, although injection site reaction, dizziness/vertigo, and pruritus also occur commonly with IV administration.
Adverse effects occurring in 1% or more of patients receiving oral esomeprazole include headache, diarrhea, nausea, flatulence, abdominal pain, constipation, and dry mouth. Common adverse effects of IV esomeprazole generally are similar to those reported with oral esomeprazole, although injection site reaction, dizziness/vertigo, and pruritus also occur commonly with IV administration.
There are 49 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
| None. |
Sinusitis |
| Rare/Very Rare |
|---|
|
Abnormal hepatic function tests Acute generalized exanthematous pustulosis Aggressive behavior Agitation Agranulocytosis Anaphylaxis Anemia Angioedema Arthralgia Atrial fibrillation Benign fundic gland polyposis of stomach Biliary calculus Blurred vision Bronchospastic pulmonary disease Clostridioides difficile infection Depression DRESS syndrome Erythema multiforme Fracture Gastritis Gastroenteritis Gastrointestinal candidiasis Goiter Hallucinations Hepatic failure Hepatitis Herpes simplex infection Hypertension Hypocalcemia Hypokalemia Hyponatremia Increased alanine transaminase Increased aspartate transaminase Interstitial nephritis Jaundice Muscle weakness Myalgia Pancreatitis Pancytopenia Skin inflammation Skin photosensitivity Stevens-johnson syndrome Stomatitis Subacute cutaneous lupus erythematosus Systemic lupus erythematosus Thrombocytopenic disorder Toxic epidermal necrolysis Urticaria |
There are 57 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Acute abdominal pain Constipation Diarrhea Dizziness Flatulence Headache disorder Injection site sequelae Nausea Pruritus of skin Vertigo |
Dyspepsia Dyspnea Insomnia Pharyngitis Symptoms of anxiety Urinary tract infection Vomiting Xerostomia |
| Rare/Very Rare |
|---|
|
Abdominal distension Alopecia Anorexia Back pain Blistering skin Bradycardia Chest pain Chills Colitis Dehydration Drowsy Dysgeusia Dysphagia Edema Erectile dysfunction Erythema Facial edema Fatigue Fever Flu-like symptoms Flushing General weakness Gynecomastia Hyperhidrosis Hypomagnesemia Increased appetite Increased defecation frequency Increased urinary frequency Malaise Pain Palpitations Peripheral edema Skin rash Tachycardia Tenesmus Upper respiratory infection Vitamin b12 deficiency Weight gain Weight loss |
The following precautions are available for NEXIUM (esomeprazole magnesium):
Safety and efficacy of oral esomeprazole for short-term (4-8 weeks) treatment of GERD in pediatric patients 1-17 years of age are supported by evidence from controlled clinical trials in adults and by safety and pharmacokinetic studies in children and adolescents. Safety and tolerability of oral esomeprazole 5, 10, or 20 mg daily for up to 8 weeks were evaluated in children 1-11 years of age with endoscopically diagnosed GERD; the presence or absence of erosive esophagitis was confirmed endoscopically in this study. Safety and tolerability of oral esomeprazole 20 or 40 mg daily for up to 8 weeks were evaluated in adolescents 12-17 years of age with clinically diagnosed GERD; the presence or absence of erosive esophagitis was not confirmed endoscopically in this study.
Adverse effects reported in children and adolescents were similar to those reported during clinical trials in adults; however, a higher incidence of somnolence was reported in children. Safety and efficacy of oral esomeprazole for short-term (up to 6 weeks) treatment of erosive esophagitis due to acid-mediated GERD in infants 1 month to less than 1 year of age are supported by controlled clinical trials in adults and by safety, pharmacokinetic, and pharmacodynamic studies in pediatric patients. The most commonly reported adverse effects in infants 1-11 months of age receiving oral esomeprazole include irritability and vomiting.
Safety and efficacy of oral esomeprazole for other uses in pediatric patients have not been established. In a randomized, controlled, treatment-withdrawal study in infants 1-11 months of age with symptomatic GERD (diagnosed clinically in most patients), the proportion of patients discontinuing treatment because of worsening symptoms was similar in the esomeprazole and placebo groups. Safety and efficacy of IV esomeprazole for short-term treatment of GERD with erosive esophagitis in pediatric patients 1 month to 17 years of age are supported by pharmacokinetic studies of IV esomeprazole in pediatric patients and adults and by pharmacodynamic studies of oral esomeprazole in pediatric patients and of IV esomeprazole in adults.
Adverse effects of IV esomeprazole in pediatric patients 1 month to 17 years of age were consistent with the known safety profile of the drug. Safety and efficacy of IV esomeprazole in neonates younger than 1 month of age have not been established.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Adverse effects reported in children and adolescents were similar to those reported during clinical trials in adults; however, a higher incidence of somnolence was reported in children. Safety and efficacy of oral esomeprazole for short-term (up to 6 weeks) treatment of erosive esophagitis due to acid-mediated GERD in infants 1 month to less than 1 year of age are supported by controlled clinical trials in adults and by safety, pharmacokinetic, and pharmacodynamic studies in pediatric patients. The most commonly reported adverse effects in infants 1-11 months of age receiving oral esomeprazole include irritability and vomiting.
Safety and efficacy of oral esomeprazole for other uses in pediatric patients have not been established. In a randomized, controlled, treatment-withdrawal study in infants 1-11 months of age with symptomatic GERD (diagnosed clinically in most patients), the proportion of patients discontinuing treatment because of worsening symptoms was similar in the esomeprazole and placebo groups. Safety and efficacy of IV esomeprazole for short-term treatment of GERD with erosive esophagitis in pediatric patients 1 month to 17 years of age are supported by pharmacokinetic studies of IV esomeprazole in pediatric patients and adults and by pharmacodynamic studies of oral esomeprazole in pediatric patients and of IV esomeprazole in adults.
Adverse effects of IV esomeprazole in pediatric patients 1 month to 17 years of age were consistent with the known safety profile of the drug. Safety and efficacy of IV esomeprazole in neonates younger than 1 month of age have not been established.
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
Category B. (See Users Guide.)
It is unknown whether esomeprazole is distributed into milk. However, omeprazole is distributed into human milk; discontinue nursing or drug because of potential risk in nursing infants.
No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity of some older patients cannot be ruled out.
The following prioritized warning is available for NEXIUM (esomeprazole magnesium):
No warning message for this drug.
No warning message for this drug.
The following icd codes are available for NEXIUM (esomeprazole magnesium)'s list of indications:
| Duodenal ulcer due to h. pylori | |
| B96.81 | Helicobacter pylori [h. pylori] as the cause of diseases classified elsewhere |
| Erosive esophagitis | |
| K21.0 | Gastro-esophageal reflux disease with esophagitis |
| K21.00 | Gastro-esophageal reflux disease with esophagitis, without bleeding |
| K21.01 | Gastro-esophageal reflux disease with esophagitis, with bleeding |
| K22.1 | Ulcer of esophagus |
| K22.10 | Ulcer of esophagus without bleeding |
| K22.11 | Ulcer of esophagus with bleeding |
| Gastric hypersecretion with systemic mastocytosis | |
| C96.21 | Aggressive systemic mastocytosis |
| D47.02 | Systemic mastocytosis |
| K31.89 | Other diseases of stomach and duodenum |
| Gastroesophageal reflux disease | |
| K21 | Gastro-esophageal reflux disease |
| K21.0 | Gastro-esophageal reflux disease with esophagitis |
| K21.00 | Gastro-esophageal reflux disease with esophagitis, without bleeding |
| K21.9 | Gastro-esophageal reflux disease without esophagitis |
| Heartburn | |
| R12 | Heartburn |
| Helicobacter pylori gastritis | |
| B96.81 | Helicobacter pylori [h. pylori] as the cause of diseases classified elsewhere |
| Maintenance of healing erosive esophagitis | |
| K22.1 | Ulcer of esophagus |
| K22.10 | Ulcer of esophagus without bleeding |
| K22.11 | Ulcer of esophagus with bleeding |
| Pathological gastric acid hypersecretory condition | |
| K31.89 | Other diseases of stomach and duodenum |
| Prevention of NSAId-induced gastric ulcer | |
| Z79.1 | Long term (current) use of non-steroidal anti-inflammatories (NSAId) |
| Zollinger-ellison syndrome | |
| E16.4 | Increased secretion of gastrin |
Formulary Reference Tool