Drug Interactions between aspirin / omeprazole and citalopram

ADJUST DOSE: Coadministration with CYP450 2C19 inhibitors may increase the plasma concentrations of citalopram, which is partially metabolized by the isoenzyme. In 12 healthy subjects who had received citalopram 40 mg once a day for 21 days, administration of cimetidine 400 mg twice a day for 8 days increased the steady-state citalopram peak serum concentration (Cmax) and systemic exposure (AUC) by 39% and 43%, respectively. In addition to inhibiting CYP450 2C19, cimetidine is also an inhibitor of CYP450 2D6 and 3A4, both of which participates in the metabolism of citalopram. The extent to which sole inhibitors of CYP450 2C19 may inhibit citalopram metabolism is unknown. Clinically, high plasma levels of citalopram may increase the risk of QT interval prolongation and torsade de pointes arrhythmia. In a randomized, double-blind, crossover, escalating multiple-dose study consisting of 119 healthy subjects, the maximum mean increase in corrected QT interval from placebo was 8.5 msec for citalopram 20 mg and 18.5 msec for citalopram 60 mg. Based on the established exposure-response relationship, prolongation of the corrected QT interval was estimated to be 12.6 ms for citalopram 40 mg. Cases of QT interval prolongation and torsade de pointes have been reported during postmarketing use. In general, the risk of ventricular arrhythmia in association with QT prolongation is largely unpredictable, but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia).

MANAGEMENT: Given the risk of dose-dependent QT prolongation, citalopram dosage should not exceed 20 mg/day when prescribed in combination with CYP450 2C19 inhibitors such as cimetidine, esomeprazole, etravirine, felbamate, fluconazole, lansoprazole, letrozole, modafinil, omeprazole, oxcarbazepine, ticlopidine, and voriconazole. Alternatives should be considered when possible, and hypokalemia or hypomagnesemia should be corrected prior to initiation of citalopram treatment and periodically monitored. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, irregular heartbeat, shortness of breath, or syncope.

MONITOR: Serotonin reuptake inhibitors (SRIs) may potentiate the risk of bleeding in patients treated with ulcerogenic agents and agents that affect hemostasis such as anticoagulants, platelet inhibitors, thrombin inhibitors, thrombolytic agents, or agents that commonly cause thrombocytopenia. The tricyclic antidepressant, clomipramine, is also a strong SRI and may interact similarly. Serotonin release by platelets plays an important role in hemostasis, thus SRIs may alter platelet function and induce bleeding. Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic agents that interfere with serotonin reuptake. Bleeding events related to SRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Additional epidemiological studies have confirmed the association between use of these agents and the occurrence of upper gastrointestinal bleeding, and concurrent use of NSAIDs or aspirin was found to potentiate the risk. Preliminary data also suggest that there may be a pharmacodynamic interaction between SSRIs and oral anticoagulants that can cause an increased bleeding diathesis. Concomitant administration of paroxetine and warfarin, specifically, has been associated with an increased frequency of bleeding without apparent changes in the disposition of either drug or changes in the prothrombin time. Bleeding has also been reported with fluoxetine and warfarin, while citalopram and sertraline have been reported to prolong the prothrombin time of patients taking warfarin by about 5% to 8%. In the RE-LY study (Randomized Evaluation of Long-term anticoagulant therapy), SRIs were associated with an increased risk of bleeding in all treatment groups.

MANAGEMENT: Caution is advised if SRIs or clomipramine are used in combination with other drugs that affect hemostasis. Close clinical and laboratory observation for hematologic complications is recommended. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

Coadministration with proton pump inhibitors may decrease the oral bioavailability of aspirin and other salicylates. The interaction has been studied with omeprazole and aspirin, although data are conflicting. In one study, pretreatment with omeprazole (20 mg/day for 2 days) in 11 healthy volunteers led to a significant and progressively greater reduction in the mean serum salicylate level at 30, 60, and 90 minutes after administration of aspirin (650 mg single dose). The investigators suggest that acid suppression may reduce the lipophilic nature of aspirin, thereby adversely affecting its absorption from the gastrointestinal tract. Another study found no effect of omeprazole pretreatment (20 mg/day for 4 days) on plasma salicylate and aspirin levels, skin bleeding times, or antiplatelet effect of low-dose aspirin (125 mg single dose) in 14 healthy volunteers. However, these results do not exclude the possibility that omeprazole might interfere with the analgesic, antipyretic, or anti-inflammatory effects of aspirin, which has been demonstrated in rats.

Proton pump inhibitors may enhance the release rate of salicylates from enteric-coated formulations due to premature disruption of the coating and intragastric release of the drug secondary to an increase in gastric pH. In eight healthy volunteers, omeprazole pretreatment (20 mg/day for 4 days) did not affect the bioavailability of salicylate from uncoated aspirin tablets but significantly increased the absorption rate of salicylate from enteric-coated sodium salicylate tablets. The clinical significance of this interaction is unknown. Theoretically, it may increase the risk of gastric adverse effects associated with salicylates.