3. Direct oral anticoagulants and antiepileptics
Don’t use DOACs in patients taking certain antiepileptic medications
Drug interactions with anticoagulants, such as warfarin, are well documented and have been publicized for years, but physicians must also be aware of the potential for interaction between the direct oral anticoagulants (DOACs) and AEDs.
Apixaban, rivaroxaban, and dabigatran appear to interact withthe AEDs carbamazepine, phenytoin, and phenobarbital.27,28 These interactions occur due to AED induction of the CYP3A4 enzyme and effects on the P-glycoprotein (P-gp) efflux pump.27,29 When taken together, the AED induces metabolism and elimination of the DOAC medication to occur more quickly than it would normally, resulting in subtherapeutic concentrations of the DOAC. This could theoretically result in a venous thromboembolic event or stroke.
A caveat. One thing to consider is that studies demonstrating interaction between the DOAC and AED drug classes have been performed in healthy volunteers, making it difficult to extrapolate how this interaction may increase the risk for thrombotic events in other patients.
Some studies demonstrated reductions in drug levels of up to 50% with strong CYP3A4 and P-glycoprotein inducers.30 Common inducers include carbamazepine, rifampin, and St. John’s Wort.6 Patients taking such agents could theoretically have decreased exposure to the DOAC, resulting in an increase in thromboembolic risk.31
4. Statins & certain CYP inhibitors
Combining simvastatin with fibrates warrants extra attention
The efficacy of statin medications in the prevention of atherosclerotic cardiovascular disease (ASCVD) is clear. However, the clinical significance of many identified drug interactions involving statins is difficult to interpret. Interactions that cause increased serum concentrations of statins can increase the risk for liver enzyme elevations and skeletal muscle abnormalities (myalgias to rhabdomyolysis).32 Strong inhibitors of CYP3A4 (amiodarone, cyclosporine, ketoconazole, etc.) significantly increase concentrations of lovastatin, simvastatin, and atorvastatin. Pitavastatin, pravastatin, and rosuvastatin are not susceptible to any CYP-mediated drug interactions;33 therefore, rosuvastatin (a high-intensity statin) is usually recommended over other statins for patients taking strong inhibitors of CYP3A4.
When to limit simvastatin. Doses of simvastatin should not exceed 10 mg/d when combined with diltiazem, dronedarone, or verapamil, and doses should not exceed 20 mg/d when used with amiodarone, amlodipine, or ranolazine.6 These recommendations are in response to results from the SEARCH (Study of the Effectiveness of Additional Reductions in cholesterol and homocysteine) trial, which found a higher incidence of myopathies and rhabdomyolysis in patients taking 80 mg of simvastatin compared with those taking 20-mg doses.34 CYP3A4-inducing medications, especially diltiazem, were thought to also contribute to an increased risk.34
Avoid gemfibrozil with statins. Using fibrates with statins is beneficial for some patients; however, gemfibrozil significantly interacts with statins by inhibiting CYP2C8 and organic anion transporting polypeptide 1B1 (OATP1B1).33 The safer choice is fenofibrate because it does not interfere with statin metabolism and can be safely used in combination with statins.6
A retrospective review of the FDA Adverse Event Reporting System (AERS) database found that 88% of fibrate and statin combinations that resulted in rhabdomyolysis were associated with gemfibrozil/cerivastatin (cerivastatin is no longer available in the United States).35
5. One serotonergic drug & another
Serotonin syndrome is associated with more than just SSRIs
Serotonin syndrome is a constellation of symptoms (hyperthermia, hyperreflexia, muscle clonus, tremor and altered mental status) caused by increases in serotonin levels in the central and peripheral nervous systems that can lead to mild or life-threatening complications such as seizures, muscle breakdown, or hyperthermia. Serotonin syndrome is most likely to occur within 24 hours after a dose increase, after starting a new medication that increases serotonin levels, or after a drug overdose.36
SSRIs are the most commonly reported drug associated with serotonin syndrome; however, other medications (TABLE 437) may be responsible, especially when used in combination with agents that act on serotonin receptors or in patients with impaired metabolism of the drugs being used.37
Other culprits. Serotonergic effects can also be associated with illicit drugs, some nonprescription medications, and supplements. And in March 2016, the FDA issued a warning about the risks of taking opioids with serotonergic medications.38 Although labeling changes have been recommended for all opioids, the cases of serotonin syndrome were reported more often with normal doses of fentanyl and methadone.
There are 2 mechanisms by which drugs may increase a patient’s risk for serotonin syndrome. The first is a pharmacodynamic interaction, which can occur when 2 or more medications act at the same receptor site (serotonin receptors in this example), which may result in an additive or synergistic effect.39
The second mechanism is a pharmacokinetic alteration (an agent alters absorption, distribution, metabolism, or excretion) of CYP enzymes.40 Of the more commonly used antidepressants, citalopram, escitalopram, venlafaxine, and mirtazapine seem to have the least potential for clinically significant pharmacokinetic interactions.41
Guidelines? Currently there are no guidelines for preventing serotonin syndrome. Clinicians should exercise caution in patients at high risk for drug adverse events, such as the elderly, patients taking multiple medications, and patients with comorbidities. Healthy low-risk patients can generally take 2 or 3 serotonergic medications at therapeutic doses without a major risk of harm.
CORRESPONDENCE
Mary Onysko, PharmD, BCPS, 191 East Orchard Road, Suite 200, Littleton, CO 80121; monysko@uwyo.edu.