Drug Interactions between atomoxetine and Seglentis

MONITOR: Coadministration with celecoxib may increase the plasma concentrations of drugs that are substrates of the CYP450 2D6 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by celecoxib.

MANAGEMENT: Caution is advised if celecoxib must be used concurrently with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever celecoxib is added to or withdrawn from therapy.

MONITOR: Serotonin syndrome has been reported following the concomitant use of atomoxetine with other serotonergic medicinal products. The use of agents with serotonergic activity (such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), tetracyclic antidepressants, tricyclic antidepressants, 5-HT1 receptor agonists (triptans), ergot alkaloids, lithium, St. John's wort, phenylpiperidine opioids, dextromethorphan, and tryptophan, among others) may potentiate the risk of serotonin syndrome, a rare but serious and potentially fatal condition. Symptoms of serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucination, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.

MONITOR: Atomoxetine can cause dose-related prolongation of the QT interval. There is the potential for an increased risk of QTc interval (QT interval corrected for heart rate) prolongation when atomoxetine is administered with other QT prolonging drugs (e.g., neuroleptics, class IA and III antiarrhythmics, moxifloxacin, erythromycin, methadone, mefloquine, tricyclic antidepressants, lithium or cisapride) and drugs that cause electrolyte imbalance (e.g., thiazide diuretics). In a study of 120 healthy male CYP450 2D6 poor metabolizers receiving atomoxetine (20 mg and 60 mg twice daily for 7 days), no large QTc changes were observed (i.e., >60 msec increase or QTc >480 msec); however, there were slight increases in the QTc interval with increased atomoxetine concentrations. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors including, but not limited to cardiac disease, uncontrolled hypothyroidism, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation may vary depending on the dosage(s) and specific drug(s) involved.

MANAGEMENT: If coadministration of atomoxetine with other agents that both prolong the QT interval and possess or enhance serotonergic activity is required, some authorities advise patients should have more frequent electrocardiograms (ECGs) than normally recommended, and be monitored closely for, and counseled about the signs and symptoms of serotonin syndrome (e.g., altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor), as well as prolonged QT interval (irregular heartbeat, dizziness, lightheadedness, fainting), especially during initiation and dose escalations. Due to variability and occasionally prolonged half-lives of these coadministered agents, consulting individual product labeling for specific guidance is advised.

MONITOR: Coadministration with drugs that are inhibitors of CYP450 2D6 may increase the plasma concentrations of atomoxetine, which is primarily metabolized by the isoenzyme. In patients who are extensive metabolizers of CYP450 2D6 (approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent), potent inhibitors of the isoenzyme such as fluoxetine and paroxetine have been shown to increase atomoxetine systemic exposure (AUC) by 6- to 8-fold and peak plasma concentration (Cmax) by 3- to 4-fold. These higher concentrations are similar to those observed in CYP450 2D6 poor metabolizers given the drug alone. In vitro studies suggest that coadministration of CYP450 2D6 inhibitors to poor metabolizers will not further increase atomoxetine plasma concentrations. The risk of QT prolongation may be increased with concomitant use of CYP450 2D6 inhibitors that also prolong the QT interval (e.g., abiraterone, osilodrostat, primaquine, propoxyphene, ranolazine). Additionally, the risk of serotonin syndrome may increase with concomitant use of CYP450 2D6 inhibitors that possess serotonergic activity (e.g., duloxetine, dexfenfluramine, fenfluramine).

MANAGEMENT: Pharmacologic response to atomoxetine should be monitored more closely whenever a CYP450 2D6 inhibitor is added to or withdrawn from therapy, as dosage adjustment of atomoxetine may be necessary in extensive metabolizers. If the CYP450 2D6 inhibitor also prolongs the QT interval, and/or has serotonergic activity, then obtaining more frequent electrocardiograms (ECGs) to monitor the QT interval as well as closer monitoring for signs and symptoms of serotonin syndrome is advised. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes (e.g., dizziness, lightheadedness, syncope, palpitations, irregular heartbeat, and/or shortness of breath) and/or symptoms of serotonin syndrome (e.g., altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, tremor). During coadministration, patients should also be advised to contact their doctor if they experience excessive adverse effects of atomoxetine such as dizziness, dry mouth, anorexia, sleep disturbances, and palpitations.