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5 Drug Interactions You Don't Want to Miss

5 Drug Interactions You Don't Want to Miss

Mary Onysko, PharmD, BCPS; Holly M. Anderson, PharmD; Songlin Cai, 5 drug interactions PharmD; Bradford T. Winslow, MD University of Wyoming, you don’t want to miss School of Pharmacy, Lara- mie (Drs. Onysko and Cai); Swedish Medical Center, These interactions can affect contraceptive efficacy, Englewood, Colo, and the Swedish Family Medi- increase bleeding risk, or lead to . This cine Residency, Littleton, Colo (Drs. Anderson and practical guide can help you avoid trouble. Winslow)

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The authors reported no potential conflict of interest here is a strong relationship between the number of relevant to this article. PRACTICE taken and the likelihood of a potentially RECOMMENDATIONS serious drug-drug interaction.1,2 Drug interaction soft- ❯ Recommend - T ware programs can help alert prescribers to potential prob- containing intrauterine lems, but these programs sometimes fail to detect important devices or long-acting proges- terone injections for women interactions or generate so many clinically insignificant alerts 3 using antiepileptic drugs. B that they become a nuisance. This review provides guidance about 5 clinically relevant drug interactions, including those ❯ Be aware that there is an in- that are common (TABLE 14-6)—and those that are less com- creased risk of gastrointestinal 6-10 bleeding when nonsteroidal mon, but no less important (TABLE 2 ). anti-inflammatory drugs are used with selective reuptake inhibitors. A a1. Antiepileptics & contraceptives Many antiepileptic medications decrease ❯ Do not prescribe novel oral anticoagulants for patients the efficacy of certain contraceptives taking , phe- Contraception management in women with is critical nytoin, or . B due to potential maternal and fetal complications. Many an- tiepileptic drugs (AEDs), including carbamazepine, ethosuxi- ❯ Choose over when combining mide, , phenobarbital, , , 11 a and a . B , and , are potentially teratogenic. A retrospective, observational study of 115 women of childbear- Strength of recommendation (SOR) ing age who had epilepsy and were seen at a neurology clinic A Good-quality patient-oriented 11 evidence found that 74% were not using documented contraception. B Inconsistent or limited-quality Of the minority of study participants using contraception, patient-oriented evidence most were using oral contraceptives (OCs) that could poten-  C Consensus, usual practice, opinion, disease-oriented tially interact with AEDs. evidence, case series ❚ CYP inducers. and progesterone are metabo- lized by the 3A4 . Some AEDs induce this enzyme, which can enhance the of OCs, thus reducing their efficacy.12 It is not known, however, if this in- teraction results in increased rates.13 Most newer AEDs (TABLE 36) do not induce cytochrome P450 3A4 and, thus, do not appear to affect OC efficacy, and may be safer for women with disorders.12 While enzyme-inducing AEDs may decrease the efficacy of progesterone-only OCs and

680 THE JOURNAL OF FAMILY PRACTICE | NOVEMBER 2017 | VOL 66, NO 11 TABLE 1 Common and clinically relevant drug interactions4-6 Drug interaction Mechanism of Clinical relevance Recommendation interaction Increases cyclic GMP in Severe , Contraindicated for smooth muscle, causing syncope, myocardial concomitant use. Do not PLUS vasodilation infarction, death prescribe together. phosphodiesterase type-5 inhibitors (eg, tadalafil, citrate) Calcium/iron//aluminum Chelation of metal ions Subtherapeutic antibi- Separate drug and supplements OR sucralfate to causes otic or thyroid medica- supplement administration reduced absorption tion levels in the body by 2 hours. PLUS fluoroquinolone or antibiotics or Simvastatin is a CYP3A4 Increased risk of myopa- Avoid concomitant use and inhibitor; simvastatin is a thy or rhabdomyolysis switch to a different statin PLUS CYP3A4 substrate. with less interaction risk or amiodarone limit simvastatin dose to Co-administration can re- 20 mg/d. sult in increased systemic exposure to simvastatin. Lithium It is theorized that Lithium toxicity presents Avoid concomitant use of prostaglandins involved with , lithium and NSAIDs; if both PLUS in renal of , drowsiness, are necessary, obtain lithium NSAID or diuretic lithium are inhibited by muscle , levels and assess for symp- NSAIDs, causing lithium impaired vision, and toms of toxicity. accumulation from impaired coordination. reduced clearance. Potassium chloride tablets Potassium chloride is Extended release and Potassium and anticholiner- acidic. Any medication wax matrix tablets have gics can be taken together. PLUS that could slow gastric been associated with Advise patients to take them emptying or dry oral severe esophageal with a full glass of water and gastric secretions damage and death; and remain upright for at could increase the risk however, there are no least 10 minutes after of potassium tablets clear data that swallowing the potassium. getting caught in the combining these Microencapsulated potas- gut and causing mucosal medications increases sium formulations (eg, damage. this risk.4 Micro-K, Klor-Con M) should cause less upper GI irritation than wax matrix formula- tions (eg, K-Tab, Klor-Con). GI, gastrointestinal; GMP, guanosine 3’5’ monophosphate; NSAID, nonsteroidal anti-inflammatory drug.

the morning-after pill,12,14,15 progesterone- els and, therefore, may increase the risk of containing intrauterine devices (IUDs), long- , but progesterone-only pills do not acting progesterone injections, and non-hor- produce this effect.12,16 monal contraceptive methods appear to be ❚ Do guidelines exist? There are no spe- unaffected.14-17 cific evidence-based guidelines that pertain ❚ OCs and seizure frequency. There is to the use of AEDs and contraception to- no strong evidence that OCs affect seizure gether, but some organizations have issued frequency in epileptic women, although recommendations. changes in hormone levels during the men- ❚ The American College of Obstetri- strual cycle do affect seizure susceptibility.12 cians and Gynecologists recommends us- Combination OCs decrease lev- ing a 30- to 35-mcg estrogen-containing OC

JFPONLINE.COM VOL 66, NO 11 | NOVEMBER 2017 | THE JOURNAL OF FAMILY PRACTICE 681 TABLE 2 Medications with multiple interactions

Medication Mechanism of interaction6 Clinical relevance Recommendation Amiodarone A substrate and inhibitor of many Bleeding has been reported Use extreme caution with CYP . Also inhibits OCT2 when used with ; narrow and P-glycoprotein has or high-risk medications. occurred when given with some antiarrhythmics; may occur when used with beta-blockers and blockers.7 Digoxin Substrate for CYP3A4 and With a narrow therapeutic Close monitoring in elderly P-glycoprotein index, potentially life-threat- patients or those with ening cardiac adverse effects renal disease is can occur when combined with recommended. medications such as macrolide antibiotics or amiodarone.8 A substrate and inhibitor of many Fatalities have been associated Only prescribers with CYP enzymes; a significant CNS with and extensive experience with ; may increase serotonin . withdrawal methadone should syndrome risk may occur when given with prescribe it. rifampin.9 Hepatitis C treatments P-glycoprotein/ABCB1 inhibitor, P-glycoprotein/ABCB1 inducers Avoid the use of PPIs at (ledipasvir/sofosbuvir; CYP3A4 substrate may decrease serum concen- doses greater than the elbasvir/grazoprevir) tration of ledipasvir/sofosbuvir; equivalent of antacids may decrease serum 20 mg; avoid CYP3A4 concentration of ledipasvir.6 inducers.6 Rifampin Induces many CYP enzymes; Decreases the concentration of Use extreme caution with substrate and inducer of many medications such as war- narrow therapeutic index P-glycoprotein farin or oral contraceptives6 or high-risk medications. Theophylline Substrate and inhibitor of CYP1A2, Has been reported to reduce 375 drugs are known to CYP2E1, CYP3A4 the effect of benzodiazepines; interact with theophylline, macrolides may decrease which supports its decline theophylline concentrations.6 in popularity.10 Avoid using this agent unless all other options have failed. ABCB1, ATP-binding cassette sub-family B member 1; TP, adenosine triphosphate; CNS, ; CYP, cytochrome P450 enzyme; OCT2, organic cation transporter 2; PPIs, proton pump inhibitors.

rather than a lower dose in women taking an considering IUDs and injectable contracep- enzyme-inducing AED. The group also rec- tive methods.21 ommends using condoms with OCs or using IUDs.18 ❚ The American Academy of Neurol- 2. SSRIs & NSAIDs. ogy suggests that women taking OCs and SSRIs increase the GI bleeding risk enzyme-inducing AEDs use an OC contain- associated with NSAIDs alone ing at least 50 mcg estrogen.19 Nonsteroidal anti-inflammatory drugs ❚ The National Institute for Health and (NSAIDs) and selective serotonin reuptake Care Excellence recommends that women inhibitors (SSRIs) are commonly prescribed taking enzyme-inducing AEDs avoid proges- worldwide.22,23 A well-established adverse tin-only pills.20 effect of NSAIDs is gastrointestinal (GI) bleed- ❚ The Faculty of Sexual and Reproduc- ing, and there is increasing evidence that con- tive Healthcare agrees that enzyme-inducing comitant use of an SSRI can further increase drugs may decrease efficacy and recommend that risk through a variety of mechanisms.23

682 THE JOURNAL OF FAMILY PRACTICE | NOVEMBER 2017 | VOL 66, NO 11 5 DRUG INTERACTIONS

SSRIs decrease platelet serotonin levels TABLE 3 resulting in defective platelet aggregation Antiepileptic drugs to avoid—and consider— and impaired hemostasis. Studies have also 6 shown that SSRIs increase gastric acidity, when the patient is taking certain OCs which leads to increased risk of peptic ulcer We recommend that patients taking enzyme-inducing antiepileptics avoid all oral contraceptives. disease and GI bleeding.23 These mecha- nisms, combined with the inhibition of Avoid these enzyme-inducing Consider these non-enzyme-inducing gastroprotective prostaglandin cyclooxygen- antiepileptic drugs antiepileptic drugs ase-1 and platelets by NSAIDs, further poten- • Carbamazepine (Tegretol) • (Zarontin) 24 tiate GI bleeding risk. • (Felbatol) • (Neurontin) Patients at high risk for bleeding with • Lamotrigine (Lamictal) • (Keppra) concomitant SSRIs and NSAIDs include older patients, patients with other risk factors for • (Trileptal) • Pregabalin (Lyrica) GI bleeding (eg, chronic steroid use), and pa- • Phenobarbital (Luminal) • (Gabitril) 23 tients with a history of GI bleeding. • Phenytoin (Dilantin) • Valproate (Depakote) ❚ The evidence. A 2014 meta-analysis • Primidone (Mysoline) • (Sabril) found that when SSRIs were used in combina- tion with NSAIDs, the risk of GI bleeding was • Topiramate (Topamax) • (Zonegran) significantly increased, compared with SSRI • Benzodiazepines 23 monotherapy. OCs, oral contraceptives. Case control studies found the risk of upper GI bleeding with SSRIs had a number needed to harm (NNH) of 3177 for a low-risk must also be aware of the potential for inter- population and 881 for a high-risk popula- action between the direct oral anticoagulants tion with an odds ratio (OR) of 1.66 (95% con- (DOACs) and AEDs. fidence interval [CI], 1.44-1.92; P<.00001).23 Apixaban, rivaroxaban, and dabigatran When SSRIs were used in combination with appear to interact with the AEDs carbam- NSAIDs, the NNH decreased to 645 for a low- azepine, phenytoin, and phenobarbital.27,28 risk population and 179 for a high-risk popu- These interactions occur due to AED induc- lation (OR=4.25; 95% CI, 2.82-6.42; P<.0001).23 tion of the CYP3A4 enzyme and effects on the Another meta-analysis found that the P-glycoprotein (P-gp) efflux pump.27,29 When OR for bleeding risk increased to 6.33 (95% taken together, the AED induces metabolism CI, 3.40-11.8; P<.00001; NNH=106) with and elimination of the DOAC medication to concomitant use of NSAIDs and SSRIs, com- occur more quickly than it would normally, pared with 2.36 (95% CI, 1.44-3.85; P=.0006; resulting in subtherapeutic concentrations of NNH=411) for SSRI use alone.25 the DOAC. This could theoretically result in a The studies did not evaluate results based venous thromboembolic event or stroke. on the indication, dose, or duration of SSRI ❚ A caveat. One thing to consider is that or NSAID treatment. If both an SSRI and an studies demonstrating interaction between NSAID must be used, select a cyclooxygenase-2 the DOAC and AED drug classes have been selective NSAID at the lowest effective dose and performed in healthy volunteers, making it consider the addition of a proton pump inhibi- difficult to extrapolate how this interaction tor to decrease the risk of a GI bleed.23,26 may increase the risk for thrombotic events in other patients. Some studies demonstrated reduc- 3. Direct oral anticoagulants. tions in drug levels of up to 50% with strong and antiepileptics CYP3A4 and P-glycoprotein inducers.30 Don’t use DOACs in patients Common inducers include carbamazepine, taking certain antiepileptic medications rifampin, and St. John’s Wort.6 Patients tak- Drug interactions with anticoagulants, such ing such agents could theoretically have de- as warfarin, are well documented and have creased exposure to the DOAC, resulting in been publicized for years, but physicians an increase in thromboembolic risk.31 CONTINUED

JFPONLINE.COM VOL 66, NO 11 | NOVEMBER 2017 | THE JOURNAL OF FAMILY PRACTICE 683 4. & certain CYP inhibitors tatin ( is no longer available in the Combining simvastatin with United States).35 warrants extra attention The efficacy of statin medications in the prevention of atherosclerotic cardiovascu- 5. One drug & another lar disease (ASCVD) is clear. However, the is associated clinical significance of many identified drug with more than just SSRIs interactions involving statins is difficult to Serotonin syndrome is a constellation of interpret. Interactions that cause increased symptoms (hyperthermia, hyperreflexia, serum concentrations of statins can increase muscle clonus, tremor and altered mental the risk for enzyme elevations and skel- status) caused by increases in serotonin levels etal muscle abnormalities ( to rhab- in the central and peripheral nervous systems domyolysis).32 Strong inhibitors of CYP3A4 that can lead to mild or life-threatening com- (amiodarone, cyclosporine, , plications such as seizures, muscle break- etc.) significantly increase concentrations down, or hyperthermia. Serotonin syndrome of , simvastatin, and . is most likely to occur within 24 hours after , , and are a dose increase, after starting a new medica- not susceptible to any CYP-mediated drug in- tion that increases serotonin levels, or after a teractions;33 therefore, rosuvastatin (a high- .36 Enzyme-inducing intensity statin) is usually recommended SSRIs are the most commonly reported antiepileptic over other statins for patients taking strong drug associated with serotonin syndrome; drugs can inhibitors of CYP3A4. however, other medications (TABLE 437) may enhance the ❚ When to limit simvastatin. Doses of be responsible, especially when used in com- metabolism simvastatin should not exceed 10 mg/d when bination with agents that act on serotonin of oral combined with , , or receptors or in patients with impaired me- contraceptives, , and doses should not exceed tabolism of the drugs being used.37 thus reducing 20 mg/d when used with amiodarone, am- ❚ Other culprits. Serotonergic effects their efficacy. lodipine, or .6 These recommen- can also be associated with illicit drugs, some dations are in response to results from the nonprescription medications, and supple- SEARCH (Study of the Effectiveness of Ad- ments. And in March 2016, the FDA issued ditional Reductions in and ho- a warning about the risks of taking mocysteine) trial, which found a higher with serotonergic medications.38 Although la- incidence of myopathies and rhabdomy- beling changes have been recommended for olysis in patients taking 80 mg of simvastatin all opioids, the cases of serotonin syndrome compared with those taking 20-mg doses.34 were reported more often with normal doses CYP3A4-inducing medications, especially of and methadone. diltiazem, were thought to also contribute to ❚ There are 2 mechanisms by which an increased risk.34 drugs may increase a patient’s risk for sero- ❚ Avoid gemfibrozil with statins. Using tonin syndrome. The first is a pharmacody- fibrates with statins is beneficial for some pa- namic interaction, which can occur when tients; however, gemfibrozil significantly in- 2 or more medications act at the same recep- teracts with statins by inhibiting CYP2C8 and tor site (serotonin receptors in this example), organic anion transporting polypeptide 1B1 which may result in an additive or synergistic (OATP1B1).33 The safer choice is fenofibrate effect.39 because it does not interfere with statin me- The second mechanism is a pharmaco- tabolism and can be safely used in combina- kinetic alteration (an agent alters absorption, tion with statins.6 distribution, metabolism, or ) of A retrospective review of the FDA Ad- CYP enzymes.40 Of the more commonly used verse Event Reporting System (AERS) da- , , , tabase found that 88% of fibrate and statin , and seem to have combinations that resulted in rhabdomyoly- the least potential for clinically significant sis were associated with gemfibrozil/cerivas- pharmacokinetic interactions.41

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TABLE 4 CORRESPONDENCE Mary Onysko, PharmD, BCPS, 191 East Orchard Road, Suite Drugs/supplements that can 200, Littleton, CO 80121; [email protected]. affect serotonin levels and cause serotonin syndrome*37 References

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