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 rhabdomyolysis. This cine Residency, Littleton, Colo (Drs. Anderson and practical guide can help you avoid trouble. Winslow) [email protected] The authors reported no potential conflict of interest here is a strong relationship between the number of relevant to this article. PRACTICE medications taken and the likelihood of a potentially RECOMMENDATIONS serious drug-drug interaction.1,2 Drug interaction soft- ❯ Recommend progesterone- 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 serotonin reuptake inhibitors. A a1. Antiepileptics & contraceptives Many antiepileptic medications decrease ❯ Do not prescribe novel oral anticoagulants for patients the efficacy of certain contraceptives taking carbamazepine, phe- Contraception management in women with epilepsy is critical nytoin, or phenobarbital. B due to potential maternal and fetal complications. Many an- tiepileptic drugs (AEDs), including carbamazepine, ethosuxi- ❯ Choose fenofibrate over gemfibrozil when combining mide, fosphenytoin, phenobarbital, phenytoin, primidone, 11 a fibrate and a statin. B topiramate, and valproate, 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. Estrogen and progesterone are metabo- lized by the cytochrome P450 3A4 enzyme. Some AEDs induce this enzyme, which can enhance the metabolism of OCs, thus reducing their efficacy.12 It is not known, however, if this in- teraction results in increased pregnancy 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 seizure 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 Nitrates Increases cyclic GMP in Severe hypotension, Contraindicated for smooth muscle, causing syncope, myocardial concomitant use. Do not PLUS vasodilation infarction, death prescribe together. phosphodiesterase type-5 inhibitors (eg, tadalafil, sildenafil citrate) Calcium/iron/magnesium/aluminum Chelation of metal ions Subtherapeutic antibi- Separate drug and supplements OR sucralfate to medication causes otic or thyroid medica- supplement administration reduced absorption tion levels in the body by 2 hours. PLUS fluoroquinolone or tetracycline antibiotics or levothyroxine Simvastatin Amiodarone 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 diarrhea, lithium and NSAIDs; if both PLUS in renal clearance of vomiting, drowsiness, are necessary, obtain lithium NSAID or diuretic lithium are inhibited by muscle weakness, 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 anticholinergics 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- seizures, 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 lamotrigine 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 enzymes. Also inhibits OCT2 when used with warfarin; narrow therapeutic index and P-glycoprotein Torsades de pointes has or high-risk medications. occurred when given with some antiarrhythmics; bradycardia may occur when used with beta-blockers and calcium channel 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 Methadone A substrate and inhibitor of many Fatalities have been associated Only prescribers with CYP enzymes; a significant CNS with benzodiazepines and extensive experience with depressant; may increase serotonin alcohol. Opiate 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 omeprazole 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, central nervous system; 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