Diminished Mycophenolic Acid Exposure Caused by Omeprazole May Be Clinically Relevant in the First Week Posttransplantation

David‐Neto, Elias; Takaki, Kelly M.; Agena, Fabiana; Romano, Paschoalina; Sumita, Nairo Massakazu; Mendes, Maria E.; Neri, Letícia Aparecida Lopes; Nahas, William Carlos

doi:10.1097/ftd.0b013e31824d6e8e

Cited by 13 publications

(22 citation statements)

References 20 publications

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“…32 The severe adverse events that have been described comprise inhibition of the antiplatelet effects of drugs such as clopidogrel, which increases the risk of developing heart problems that may lead to death; and decreased absorption of mycophenolic acid, which leads to rejection of transplanted organs. 49 Nevertheless, it is not possible to say with certainty that the adverse events described in these studies occurred due to drug interactions with omeprazole, since some of the studies included did not present statistically significant results. 71,[94][95][96] In two studies in which omeprazole was added to dual antiplatelet therapy (a combination of clopidogrel and acetylsalicylic acid), it reduced the stomach pain resulting from this therapy and no risk was found in this combination.…”

Section: Discussionmentioning

confidence: 89%

“…The frequency of adverse reactions was classified according to the leaflet of the reference drug product, except for the 28 studies for which there was no information on the leaflet. 80 3* 2* 3* Galante et al, 2012 96 4* 1* 3* Lin et al, 2012 81 4* 2* 3* David-Neto et al, 2012 49 4* 1* 3* Soriano et al, 2014 16 4* 2* 3* Chen et al, 2014 28 4* 2* 3* Wang et al, 2017 97 4* 2* 3* Gomm et al, 2016 44 4* 2* 3* Yi et al, 2017 47 4* 2* 3* Varallo et al, 2018 41 4* 2* 3* Imperatore et al, 2018 45 4* 2* 3* Lazzerini et al, 2018 42 4* 1* 3* Li et al, 2018 48 4 Table 3. Continuation Several drug interactions relating to omeprazole, especially with antiplatelet agents, are known.…”

Section: Discussionmentioning

confidence: 99%

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Safety assessment of omeprazole use: a review

2018

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BACKGROUND: Risks regarding hospital admission due to adverse drug reactions and drug interactions from use of omeprazole have been reported. The question guiding the present review was "Which adverse events occur in patients using omeprazole in a Food and Drug Administration-approved and/or off-label manner?" It was also proposed to evaluate the safety of use of omeprazole. DESIGN AND SETTING: Qualitative narrative review with critical evaluation, in a public university. METHODS: The PubMed, SCOPUS, LILACS, SciELO, EMBASE and EBSCO databases were searched on July 31, 2018. Studies evaluating adverse events were screened. RESULTS: 72 articles were included, among which 58 reported on adverse drug events (47, adverse drug reactions; 5, drug interactions; and 6, situations of ineffectiveness). 28 adverse drug reactions not described in compendia and drug leaflets were described in these studies: myocardial infarction (6); stroke (2); spontaneous abortion (1); proliferative changes (1); chills (1); heart failure (1); thrombosis (2); and dementia (1), among others. Severe adverse reactions, for instance cardiac problems, Steven-Johnson syndrome and proliferative changes, were identified. The antiplatelet effects of drugs such as clopidogrel, in patients who underwent heart-related surgery, increased the risk of developing cardiac problems, such as cardiovascular death, myocardial infarction and stroke. In newly transplanted patients, decreased absorption of mycophenolate mofetil occurred, thus leading to rejection of transplanted organs. CONCLUSION: Use of omeprazole should be monitored primarily in patients with heart disorders using antiplatelet agents concomitantly, and in newly transplanted patients using mycophenolic acid, in order to avoid serious adverse reactions.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Safety assessment of omeprazole use: a review

2018

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“…The proposed mechanism of this drug interaction is attributed to PPI‐induced elevation of gastric pH, which may lead to reduced MMF dissolution, absorption, and exposure by AUC . This is imperative to consider in solid organ transplant recipients, as it may increase the risk of allograft rejection, especially within the first week after kidney transplantation . Although the effect of gastric acid suppressive therapy on the absorption of MMF has been well documented, the majority of the studies that have evaluated this interaction either have included transplant recipients maintained on chronic corticosteroid immunosuppression or have only evaluated the effects on MMF.…”

Section: Discussionmentioning

confidence: 99%

Routine prophylaxis with proton pump inhibitors and post‐transplant complications in kidney transplant recipients undergoing early corticosteroid withdrawal

Courson

Lee

Aull

et al. 2016

Clinical Transplantation

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Surgical stress, corticosteroids, and mycophenolate may contribute to gastrointestinal ulcers/bleeding after kidney transplantation. Prophylactic acid suppression with H2RAs or PPIs is often utilized after transplantation, although unclear if truly indicated after early corticosteroid withdrawal (CSWD). PPIs have been associated with increased risks of Clostridium difficile infection (CDI), pneumonia, and acute rejection. This retrospective cohort study investigated benefits and risks of prolonged PPI use following kidney transplantation and included 286 kidney recipients undergoing CSWD within five d of transplant who were maintained on tacrolimus and mycophenolate mofetil/sodium. Patients on PPI before transplant, H2RA before/after transplant, and/or those with pre-transplant GI complications were excluded. A total of 171 patients received PPI>30 d, mean duration 287 ± 120 d (PPI group); 115 patients were not maintained on acid suppression (No-PPI group). GI ulceration and bleeding events were rare in PPI group (1.2% and 2.3%, respectively) and not observed in No-PPI group (p = NS). The incidence of infectious or hematological complications was not significantly different between groups. The PPI group experienced more biopsy-proven acute rejection (9.4% vs. 2.6%, p = 0.03). No direct benefit was observed with PPI in reducing the incidence of GI ulcers and bleeding events in kidney transplant recipients undergoing early CSWD. Further studies are needed to investigate the association of PPI and acute rejection.

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“…Combination use of PPIs and MMF is possible because gastrointestinal adverse effects are common after organ transplantation. Unfortunately, PPI comedication could reduce active drug exposure in heart transplant recipients and renal transplant patients, thereby increasing the risk for treatment failure 50,51…”

Section: Circumstance 1: Omeprazole Is Comedicated As a Precipitant Drugmentioning

confidence: 99%

“…David-Neto et al51 presented the valuable finding that the mean AUC (0–12h) of MPA was in the lower limit of the therapeutic window on day 7 in patients using omeprazole but quickly increased on day 14 and thereafter, and that most patients were within the therapeutic window after day 7. This information is important for clinicians because there is a decreased incidence of acute rejection when the patients are adequately exposed to MPA during the first week.…”

Section: Circumstance 1: Omeprazole Is Comedicated As a Precipitant Drugmentioning

confidence: 99%

Pharmacokinetic drug interaction profile of omeprazole with adverse consequences and clinical risk management

Li¹,

Zeng²,

Yu³

et al. 2013

TCRM

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BackgroundOmeprazole, a proton pump inhibitor (PPI), is widely used for the treatment of dyspepsia, peptic ulcer, gastroesophageal reflux disease, and functional dyspepsia. Polypharmacy is common in patients receiving omeprazole. Drug toxicity and treatment failure resulting from inappropriate combination therapy with omeprazole have been reported sporadically. Systematic review has not been available to address the pharmacokinetic drug-drug interaction (DDI) profile of omeprazole with adverse consequences, the factors determining the degree of DDI between omeprazole and comedication, and the corresponding clinical risk management.MethodsLiterature was identified by performing a PubMed search covering the period from January 1988 to March 2013. The full text of each article was critically reviewed, and data interpretation was performed.ResultsOmeprazole has actual adverse influences on the pharmacokinetics of medications such as diazepam, carbamazepine, clozapine, indinavir, nelfinavir, atazanavir, rilpivirine, methotrexate, tacrolimus, mycophenolate mofetil, clopidogrel, digoxin, itraconazole, posaconazole, and oral iron supplementation. Meanwhile, low efficacy of omeprazole treatment would be anticipated, as omeprazole elimination could be significantly induced by comedicated efavirenz and herb medicines such as St John’s wort, Ginkgo biloba, and yin zhi huang. The mechanism for DDI involves induction or inhibition of cytochrome P450, inhibition of P-glycoprotein or breast cancer resistance protein-mediated drug transport, and inhibition of oral absorption by gastric acid suppression. Sometimes, DDIs of omeprazole do not exhibit a PPI class effect. Other suitable PPIs or histamine 2 antagonists may be therapeutic alternatives that can be used to avoid adverse consequences. The degree of DDIs associated with omeprazole and clinical outcomes depend on factors such as genotype status of CYP2C19 and CYP1A2, ethnicity, dose and treatment course of precipitant omeprazole, pharmaceutical formulation of object drug (eg, mycophenolate mofetil versus enteric-coated mycophenolate sodium), other concomitant medication (eg, omeprazole-indinavir versus omeprazole–indinavir–ritonavir), and administration schedule (eg, intensified dosing of mycophenolate mofetil versus standard dosing).ConclusionDespite the fact that omeprazole is one of the most widely prescribed drugs internationally, clinical professionals should enhance clinical risk management on adverse DDIs associated with omeprazole and ensure safe combination use of omeprazole by rationally prescribing alternatives, checking the appropriateness of physician orders before dispensing, and performing therapeutic drug monitoring.

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Diminished Mycophenolic Acid Exposure Caused by Omeprazole May Be Clinically Relevant in the First Week Posttransplantation

Cited by 13 publications

References 20 publications

Safety assessment of omeprazole use: a review

Safety assessment of omeprazole use: a review

Routine prophylaxis with proton pump inhibitors and post‐transplant complications in kidney transplant recipients undergoing early corticosteroid withdrawal

Pharmacokinetic drug interaction profile of omeprazole with adverse consequences and clinical risk management

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