Drug Interactions: A Practical Approach The chart below provides practical tips and resources to help you respond to drug interaction alerts.

Transcription

1 This Clinical Resource gives subscribers additional insight related to the Recommendations published in February 2017 ~ Resource # Drug Interactions: A Practical Approach The chart below provides practical tips and resources to help you respond to drug interaction alerts. Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker Goal Suggested Approach or Resource Be alert for patient groups most vulnerable to drug interactions. In general, be alert for patients with a new med, dosage change, or recent health change that could change a tolerated interaction to a clinically significant interaction (e.g., an additional CYP450 enzyme inhibitor or inducer; renal impairment). Older age and polypharmacy are risk factors for clinically significant drug interactions. 9 Over 80% of patients taking seven or more drugs are at risk of a drug interaction. 9 When evaluating the significance of an interaction involving QT prolongation, keep in mind the risk factors for torsades de pointes: hospitalization, advanced age, female gender (2-fold risk), heart disease, long QT interval syndrome, QTc >500 ms (2- to 3-fold risk), renal or hepatic insufficiency, hypokalemia, hypomagnesemia, hypocalcemia, diuretic use, bradycardia, use of more than one QT-prolonging drug, and rapid intravenous administration of certain medications. 7 Risk factors for statin myopathy include multiple disease states (e.g., renal or hepatic insufficiency), polypharmacy, history of musculoskeletal symptoms or CK elevation, neuromuscular disease, personal or family history of statin or other myopathy, use of medications or foods (e.g., grapefruit) that increase statin levels, age over 75 years, Asian ancestry, female gender, low BMI or small frame, frailty, physical activity, and alcohol or drug abuse. 8 Be alert for drugs involved in clinically significant interactions. Continued Watch for interactions with drugs that are strong inhibitors or inducers of drug metabolizing enzymes or transporters, such as clarithromycin or carbamazepine, respectively. 10 See our charts, Cytochrome P450 Drug Interactions and P-glycoprotein Drug Interactions, for others. Watch for interactions with drugs with serious dose-dependent adverse effects or narrow therapeutic index drugs, such as statins, calcium channel blockers, methotrexate, colchicine, oral anticoagulants, atypical antipsychotics, ergots, opioids (e.g. methadone), antiarrhythmics (e.g., dofetilide), digoxin, warfarin, levothyroxine, lithium, theophylline, cancer chemotherapy (e.g., xanthine oxidase inhibitor [allopurinol or febuxostat]/thiopurine [e.g., 6-mercaptopurine] interaction 5 ), hypoglycemic agents (e.g., clopidogrel and repaglinide 5 ), or anticonvulsants (e.g., phenytoin, carbamazepine). Resources on our site that can help you identify and respond to potential interactions with these drugs include: Levothyroxine Absorption: The Effect of Food and Drugs Antimicrobial Drug Interactions and Warfarin Comparison of Oral Anticoagulants (highlights select drug interactions) More... Copyright 2017 by Therapeutic Research Center 3120 W. March Lane, Stockton, CA ~ Phone: ~ Fax: PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com ~ NursesLetter.com

2 (Clinical Resource #330201: Page 2 of 6) Goal Be alert for drugs involved in clinically significant interactions, continued Suggested Approach or Resource Comparison of Antiepileptic Drugs (highlights select drug interactions) Colchicine Dosing and Drug Interactions Clinically Significant Statin Drug Interactions Methadone for Pain: Focus on Safety Comparison of Atypical Antipsychotics (U.S.)(Canada) Calcium Channel Blocker-Macrolide Interaction Drug Interactions with Tramadol Using Methotrexate Safely for Rheumatoid Arthritis Watch for interactions with drugs that can increase the QT interval. Use of more than one QT-prolonging drug increases risk. See our chart, Drug-induced Long QT Interval, to help identify drugs that may prolong the QT interval or pose a torsades risk. Also see our CE, Prevention and Management of Drug-Induced QT Prolongation. Watch for interactions between opioids and drugs that cause respiratory or central nervous system depression, such as benzodiazepines. Watch for interactions that involve drugs that can increase potassium levels, such as sulfamethoxazole/trimethoprim, ACEIs, ARBs, potassium-sparing diuretics, or aldosterone antagonists. Watch for drug interactions that could result in reduced efficacy of medications for which reduced efficacy is not obvious until treatment failure occurs (e.g., enzyme inducers with contraceptives, hepatitis or HIV antivirals, chemotherapy, anticonvulsants, and anticoagulants). Resources on our site that can help you identify and respond to potential interactions with these drugs include: Hepatitis C Treatment Overview (highlights select drug interactions; for additional drug interactions, see U.S. MedGuide, and product labeling.) HIV/AIDS Pharmacotherapy Review (CE) Comparison of Oral Anticoagulants (highlights select drug interactions) Comparison of Antiepileptic Drugs (highlights select drug interactions) Cytochrome P450 Drug Interactions and P-glycoprotein Drug Interactions (to identify inducers) Watch for drug interactions involving serotonergic drugs. Facts About Serotonin Syndrome Drug Interactions with Tramadol SSRIs and SNRIs and Bleeding Risk: Focus on Drug Interactions For information on drug interactions with common transplant medications, see our CE, Managing Patients Receiving Transplant Medications. Copyright 2017 by Therapeutic Research Center 3120 W. March Lane, Stockton, CA ~ Phone: ~ Fax: PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com ~ NursesLetter.com More...

3 (Clinical Resource #330201: Page 3 of 6) Goal Identify potential drug interactions involving CYP450 substrates, inducers, or inhibitors. Identify potential drug interactions involving drug transporters such as P-glycoprotein or OATP. Continued Suggested Approach or Resource See our chart, Cytochrome P450 Drug Interactions. When considering the clinical significance of a potential drug interaction mediated via metabolic pathways, keep in mind that just because a medication interacts with one substrate of a particular cytochrome P450 pathway does not mean it affects all substrates (drugs) of that isozyme: Genetics, age, nutrition, stress, liver disease, hormones, and other endogenous chemicals also influence drug metabolism. Additional influences on drug interactions include drug dosing (e.g., dose, timing, sequence, route of administration, duration of therapy, etc), concomitant medications, potential for a concurrent pharmacodynamic interaction (e.g., atorvastatin and gemfibrozil), and specific drug features (narrow therapeutic index, high extraction ratio [clearance more dependent on hepatic blood flow than metabolic capacity], side effect profile, multiple metabolic pathways). For example, most drugs metabolized by CYP2C8 have alternate metabolic pathways, so inhibition of just one pathway might not be clinically important. It is prudent to use any combination with potential for interaction with caution (e.g., conservative dosing, appropriate monitoring), especially those involving drugs with a narrow therapeutic index and/or potentially serious dose-dependent side effects (e.g., chemotherapy, cardiac medications, anticonvulsants, etc). See our chart, P-glycoprotein Drug Interactions and commentary on OATP Drug Interactions. To understand drug interactions involving drug transporters, keep in mind that: There are two main families of drug transporters. One is comprised of P-glycoprotein (multidrug resistance protein 1 [MDR1]; P-gp) and its relatives, multidrug resistance-associated protein, breast cancer resistance protein, and bile salt export pump. 3 P-glycoprotein is found in the gut, liver, kidney, blood-brain barrier, and cancer cells. 2 It pumps drugs out of cells and into the gut, bile, and/or urine for excretion. 2 P-glycoprotein can be thought of as a defense against potential poisons. 3 P-gp inhibitors may increase levels of P-gp substrates, and P-gp inducers may decrease levels of P-gp substrates. 2 For most P-gp interactions, CYP450 enzyme inhibition or induction is also involved, and many P- glycoprotein substrates are also CYP3A4 substrates (P-gp helps prevent saturation of CYP3A4), so the contribution of P-gp inhibition/induction vs CYP450 inhibition/induction can be difficult to discern. Keep in mind that P-gp inhibition potency in patients is not well defined, and is unknown for many inhibitors. It is prudent to use any combination with potential for interaction with caution (e.g., conservative dosing, appropriate monitoring, etc), especially those involving drugs with a narrow therapeutic index and/or potentially serious dose-dependent side effects (e.g., chemotherapy, cardiac medications, anticonvulsants, etc). For drugs or drug combinations that are both substrates and inhibitors, the net effect is difficult to predict. 2 Copyright 2017 by Therapeutic Research Center 3120 W. March Lane, Stockton, CA ~ Phone: ~ Fax: PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com ~ NursesLetter.com More...

4 (Clinical Resource #330201: Page 4 of 6) Goal Identify potential drug interactions involving drug transporters such as P-glycoprotein or OATP, continued Suggested Approach or Resource In opposition to P-glycoprotein (which is an efflux pump) are organic anion transporting polypeptides (OATPs), which are uptake transporters. OATPs transport drugs into cells. Like P-glycoprotein, they are located in the gut, liver, kidney, and blood-brain barrier. Several OATPs have been identified, such as OATP1A2 and OATP2B1, which are located on the enterocytes (cell of the intestinal lining) and aid drug absorption. 3 Patients can have varying OATP activity due to genetic variation. For example, reduced responsiveness to montelukast (Singular) is associated with a variant of the gene coding for OAT2B1. Such genetic variation can influence susceptibility to drug interactions. For example, OATP inhibition may not be significant in patients with impaired baseline OATP function. 3 OATP1B1 and OATP1B3 are located on the hepatocytes. They transport drugs into the liver for metabolism. Therefore, inhibition of these transporters results in increased drug levels. 3 Identify significant drug/food interactions. Guard against alert fatigue. Continued See our chart, Alcohol and Drug Interactions, for recommendations regarding alcohol consumption with various medications. For strategies to help minimize levothyroxine/food interactions, see our chart, Levothyroxine Absorption: The Effect of Food and Drugs. Our chart, Potential Drug Interactions with Grapefruit, lists oral drugs or drug classes that have been studied with grapefruit or are predicted to interact with grapefruit based on the drug s pharmacokinetics, and explains potential clinical implications. For information on interactions with other fruit juices, see our commentary, OATP Drug Interactions. Optimization of Medication Administration Timing may minimize or eliminate these interactions. Pharmacy technicians can learn how they can help in our technician tutorial, Med Administration: Timing is Everything. Recognize commonly flagged interactions that are usually not clinically significant (e.g., triptans and SSRIs, levothyroxine added to stable warfarin therapy, antibiotics and hormonal contraceptives, clopidogrel and proton pump inhibitors). 4,11 Discontinued drugs cause many alerts, but most aren t serious. Watch for those with lingering effects, such as amiodarone, fluoxetine, and MAOIs. Interactions can occur for weeks after discontinuation. 5 Be mindful that discontinuation of a CYP450 inhibitor or inducer can require dose adjustment for other meds. 5 Drug class alerts can be inappropriate when they apply only to certain drugs within a class; for example, only simvastatin, lovastatin, atorvastatin, and to a lesser extent pravastatin rely on CYP3A4 for metabolism, and the macrolide clarithromycin, but not azithromycin, is a strong CYP3A4 inhibitor. 1,6 (Note that azithromycin might interact with certain CYP3A4 substrates through other mechanisms. For example, azithromycin has been reported Copyright 2017 by Therapeutic Research Center 3120 W. March Lane, Stockton, CA ~ Phone: ~ Fax: PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com ~ NursesLetter.com More...

5 (Clinical Resource #330201: Page 5 of 6) Goal Guard against alert fatigue, continued Suggested Approach or Resource to interact rarely with statins, perhaps via drug transporter inhibition, but it is usually the safest choice when a macrolide is needed in a patient taking a statin. 5,6,12 ) Our CE, Drug Interaction Overload: How to Sort Through Interaction Alerts, has more examples and tips for combating alert fatigue. Communicate about drug interactions and document the outcome. Use our patient education handout, Answers To Your Questions About Levothyroxine, when talking to patients about levothyroxine interactions. When a patient needs a combo that could result in serotonin syndrome, use our patient education handout, What You Should Know About Serotonin Syndrome, to explain what they need to watch for. Pharmacists can use our Suggestion to Switch Medication fax letter to communicate with prescribers and document your findings and discussions. Pharmacists can enlist pharmacy technicians to assist with preventing drug interactions. For example, it is important to keep patient profiles updated with over-the-counter meds, vitamins, calcium, supplements, etc. Our technician tutorials, Drug Interactions 101 and Safety Considerations With OTC Drugs, explain what techs can do to help. Users of this resource are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication. Copyright 2017 by Therapeutic Research Center 3120 W. March Lane, Stockton, CA ~ Phone: ~ Fax: PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com ~ NursesLetter.com More...

6 (Clinical Resource #330201: Page 6 of 6) Project Leader in preparation of this clinical resource (330201): Melanie Cupp, Pharm.D., BCPS References 1. Clinical Resource, Cytochrome P450 Drug Interactions. Pharmacist s Letter/Prescriber s Letter. May Clinical Resource, P-glycoprotein Drug Interactions. Pharmacist s Letter/Prescriber s Letter. May Clinical Resource, OATP Drug Interactions. Pharmacist s Letter/Prescriber s Letter. March Clinical Resource, Facts About Serotonin Syndrome. Pharmacist s Letter/Prescriber s Letter. October Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; (Accessed January 10, 2017). 6. Clinical Resource, Clinically Significant Statin Drug Interactions. Pharmacist s Letter/Prescriber s Letter. March Clinical Resource, Drug-induced Long QT Interval. Pharmacist s Letter/Prescriber s Letter. October Clinical Resource, Statin Muscle Symptoms: Managing Statin Intolerance. Pharmacist s Letter/Prescriber s Letter. October Bucsa C, Farcas A, Cazacu I, et al. How many potential drug-drug interactions cause adverse drug reaction in hospitalized patients? Eur J Intern Med 2013;24: U.S. Food and Drug Administration. Drug development and drug interactions: table of substrates, inhibitors and inducers. September 27, ess/developmentresources/druginteractionslabelin g/ucm htm#pgptransport. (Accessed January 13, 2016). 11. Wood MD, Delate T, Clark M, et al. An evaluation of the potential drug interaction between warfarin and levothyroxine. J Thromb Haemost 2014;12: Alreja G, Inayatullah S, Goel S, Braden G. Rhabdomyolysis caused by an unusual interaction between azithromycin and simvastatin. J Cardiovasc Dis Res 2012;3: Cite this document as follows: Clinical Resource, Drug Interactions: A Practical Approach. Pharmacist s Letter/Prescriber s Letter. February Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA ~ TEL (209) ~ FAX (209) Copyright 2017 by Therapeutic Research Center Subscribers to the Letter can get clinical resources, like this one, on any topic covered in any issue by going to PharmacistsLetter.com, PrescribersLetter.com, PharmacyTechniciansLetter.com, or NursesLetter.com

7 Pharmacy Name: Pharmacy Phone: Pharmacy Fax: Pharmacy Pharmacy Address: SUGGESTION TO SWITCH MEDICATION Date: Dear Prescriber, Your patient,, has presented his/her prescription for (medication, dose, dosing interval) to be filled at our pharmacy. I m suggesting a switch to (there may be more than one option): ( ) (medication, dose, dosing interval) OR ( ) (medication, dose, dosing interval) OR ( ) (medication, dose, dosing interval) The reason for this suggested change is to: ( ) Comply with insurance formulary/prior authorization requirements. ( ) Suggest an alternative for a drug that is unavailable. ( ) Reduce the patient s drug cost. Specifically, ( ) Other If you are in agreement with this switch, please fax or phone a new prescription to us. Please feel free to contact me if you have any questions or concerns. Best regards, [Pharmacist]

8 (Page 1 of 5) Technician Tutorial: Drug Interactions 101 A variety of factors affect the way drugs act in the body. These factors can include other drugs a patient is taking, when and what food a patient eats or drinks, and a patient s medical conditions and diseases. If you are entering prescriptions or drug orders into the pharmacy computer system, you may see computer alerts warning of these potential drug-drug, drug-food, and drug-disease interactions. Some drug interactions are considered to be minor. This means that the effects of the interaction aren t likely to cause serious consequences, or aren t likely to occur at all. Others are considered to be major, which means that the interaction could have very serious, sometimes life-threatening consequences, or might be quite likely to occur. While inputting prescriptions, you may see these interaction alerts pop up on your screen. You need to have a pharmacist review all interaction alerts. Even if you are able to bypass alerts, as a general rule you shouldn t bypass interaction alerts until the pharmacist has reviewed them. Refer to your pharmacy s policies and procedures for more detailed guidance on how to handle interaction alerts and other types of alerts. Annie Brach is a 55-year-old female patient. She comes in with this single prescription, although she gets several others filled regularly at your pharmacy. You enter the prescription into the computer, selecting the generic alternative, fluconazole 150 mg, and type take 1 tablet for a single dose in the directions field. You enter a quantity of one with zero refills. Before you can continue any further, you get a drug-drug interaction warning between her cholesterol-lowering med, atorvastatin, and the new fluconazole prescription. Since your computer system doesn t allow you to continue processing the prescription until a pharmacist checks the interaction, you let the pharmacist know. What are the different types of drug-drug interactions? Drug-drug interactions are often caused when one drug affects the way another drug is broken down, or metabolized, in the body. For example, the cytochrome P450, or CYP450, enzymes help break down certain drugs in the liver and in the gastrointestinal tract. But many drugs can reduce (inhibit) or increase (induce) the activity of CYP450 enzymes. To help you understand CYP450 interactions, think about driving in heavy traffic. Your ability to get to your destination quickly is inhibited by other cars being on the road. The traffic buildup during heavy traffic (enzyme inhibition) is similar to the buildup of drug in the system. But if you are able to use the carpool lane which has less cars, then you will get to your destination quicker. The ability to get out of traffic and get to your destination quicker using the carpool lane (enzyme induction) is similar to drugs getting out of the system quicker. An example of a drug-drug interaction caused by CYP450 enzyme inhibition can be seen with the antibiotic clarithromycin. Clarithromycin (Biaxin) is considered a strong inhibitor of a CYP450 enzyme. This means that clarithromycin reduces the ability of CYP450 enzymes to break down certain drugs. For example, the blood pressure-lowering calcium channel blocking drugs (amlodipine, diltiazem, felodipine, etc) are Copyright 2016 by Therapeutic Research Center Phone: ~ Fax: PharmacistsLetter.com ~ PharmacyTechniciansLetter.com

9 (Page 2 of 5) metabolized by the same enzyme inhibited by clarithromycin. When clarithromycin and a calcium channel blocker are given together, the levels of the calcium channel blocker in the blood can get very high. It s best to avoid clarithromycin in patients taking calcium channel blockers because of the increased risk of kidney injury, heart problems, shock, or death. On the other hand, the antiseizure drug phenytoin induces the activity of CYP450 enzymes. This means that phenytoin increases the ability of CYP450 enzymes to break down certain drugs. Oral contraceptives get broken down by the same CYP450 enzyme that phenytoin induces. When phenytoin and oral contraceptives are used in the same patient, the effectiveness of the oral contraceptive can decrease because it may get broken down quicker. A decrease in effectiveness of oral contraceptives can increase the chance for an unintended pregnancy. Another type of drug-drug interaction is an additive effect. Some drugs have similar effects, and when they are given together, the risk for an adverse effect can be increased. For example, warfarin and heparin are both blood thinners. When they are given together (and sometimes there s actually a reason to give them together) the risk for bleeding can be increased. An example of additive adverse effects can be seen with drugs that cause QT prolongation such as clarithromycin, amiodarone, trazodone, ondansetron, citalopram, hydroxyzine, quetiapine, etc. Drugs that prolong the QT interval can change the heart s rhythm and increase the risk for sudden death. It can be dangerous to take multiple drugs that prolong the QT interval or to take other meds that can increase levels of QT prolonging drugs. Similarly, drugs that can increase the risk for serotonin syndrome, such as tramadol, linezolid (Zyvox [U.S.], Zyvoxam [Canada]), and antidepressants (SSRIs [sertraline, paroxetine, citalopram, etc], trazodone, venlafaxine, etc) can result in additive serotonin syndrome effects if taken together. Serotonin syndrome can cause mental status changes, tremor, restlessness, fever, flushing, diarrhea, sweating, and blood pressure changes. In rare cases, serotonin syndrome can be fatal. In contrast to the additive effect, some drugs can reduce the effects of others. For example, when cholestyramine and levothyroxine are given at the same time, cholestyramine binds to levothyroxine in the gastrointestinal tract. Only about half of the usual amount of levothyroxine gets absorbed into the bloodstream, and its effect is reduced. Patients who are taking levothyroxine because they don t make enough thyroid hormone can become hypothyroid (i.e., not have enough thyroid hormone) if they take cholestyramine at the same time as levothyroxine. Separating these drugs by a few hours can prevent this interaction. Another type of drug interaction is intravenous (IV) drug compatibility. This has to do with drugs that are being given through the same IV line, or through IV lines where drugs may come into contact at some point. Some drugs form solids, or precipitate, when they re given together. A good example of this is calcium (e.g., calcium chloride, calcium gluconate, etc) and phosphorous (e.g., potassium phosphate, sodium phosphate, etc), which can form a chalk-like substance. Another example of drugs that shouldn t be mixed together in an IV are the antibiotic drugs aminoglycosides (e.g., amikacin, gentamicin, tobramycin, etc) and penicillins (e.g., ampicillin, nafcillin, penicillin, etc). The penicillins can inactivate the aminoglycoside, which could make the aminoglycoside less effective at killing bacteria and treating an infection. The pharmacist reviews the drug-drug interaction alert for fluconazole and atorvastatin. She sees that Ms. Brach has been taking atorvastatin 10 mg daily for about a year. The pharmacist explains to you that the fluconazole can cause higher levels of atorvastatin in the body because it can inhibit the enzyme that breaks down atorvastatin. She says that this interaction could increase the risk for muscle aches and possibly muscle damage and damage to the kidneys. Copyright 2016 by Therapeutic Research Center Phone: ~ Fax: PharmacistsLetter.com ~ PharmacyTechniciansLetter.com

10 (Page 3 of 5) How can foods or drinks interact with drugs? Since most drugs that are taken orally are absorbed into the bloodstream through the gastrointestinal tract, it s easy to see how food or drinks can interact. A few drugs are actually absorbed better when there is food in the stomach. Examples of this are HIV meds such as ritonavir (Norvir) and etravirine (Intelence), antibiotics such as amoxicillin/clavulanate extendedrelease (Augmentin XR [U.S.]) and cefuroxime axetil (Ceftin), and lovastatin. Some drugs are absorbed less when taken with food and so they should be taken on an empty stomach. These drugs include the bisphosphonates (alendronate [Fosamax], risedronate [Actonel], etc), some antibiotics such as ampicillin and tetracyclines, levothyroxine, and some HIV meds such as didanosine (Videx) and efavirenz (Sustiva). Sometimes, patients will be instructed to take these drugs at the same time of day, and at the same time in relation to meals so that the effect of the drug remains consistent. A specified amount of time should separate administration of these meds from a meal or intake of food. For example, patients will be instructed to take levothyroxine and bisphosphonates in the morning on an empty stomach 30 to 60 minutes before eating. To learn more about timing of medication administration in relation to meals, check out our technician tutorial, Med Administration: Timing is Everything. Some foods can actually affect CYP450 metabolism of drugs. Grapefruit (including grapefruit juice) is probably the most widely recognized food that can do this. Grapefruit inhibits the metabolism of some drugs, and can increase their effects to a dangerous degree. Drugs that interact with grapefruit include simvastatin, lovastatin, felodipine, ticagrelor (Brilinta), and colchicine (Colcrys [U.S.]). Foods that are high in vitamin K (mainly dark, leafy green vegetables) can affect warfarin. Vitamin K can reverse the blood thinning effects of warfarin which increases the risk of forming blood clots. Patients taking warfarin should be consuming about the same amount of vitamin K each day to avoid fluctuations in clotting activity. Too much vitamin K can decrease the effect of warfarin which can increase the risk of stroke and heart attack. Too little vitamin K can enhance the effect of warfarin which can increase the risk of bleeding. Some drugs can be affected by alcoholic beverages. For example, the risk for enhanced sedative effects makes it dangerous for patients to mix alcohol with opioids (morphine, fentanyl, hydrocodone, oxycodone, etc), muscle relaxants (cyclobenzaprine, carisoprodol [U.S.-only], etc), and benzodiazepines (diazepam, lorazepam, alprazolam, etc). Additionally, mixing some extended-release opioids (e.g., Nucynta ER and Kadian) with alcohol can cause fatal doses of the opioid to be released. Alcohol can also be a problem by causing a disulfiram-like reaction in patients taking certain anti-infectives such as metronidazole and ketoconazole. Disulfiram-like reactions are very uncomfortable reactions characterized by flushing, fast heartbeat, nausea, vomiting, low blood pressure, and dizziness. What are some common drug-disease interactions? Patients with certain diseases may react differently to some drugs. Or, a drug might adversely affect a patient with a certain disease. For example, NSAIDs, like ibuprofen and naproxen, can have negative effects on the kidneys. For this reason, patients with kidney problems usually should not take NSAIDs. In addition, NSAIDs can increase blood pressure. So patients who have high blood pressure should usually avoid NSAIDs. Another example is use of the blood pressure drugs diltiazem and verapamil in patients with heart failure. These drugs can weaken the force of the contraction of the heart muscle. This is usually a bad thing for patients with heart failure, since their hearts already have a hard time pumping blood through the body. Copyright 2016 by Therapeutic Research Center Phone: ~ Fax: PharmacistsLetter.com ~ PharmacyTechniciansLetter.com

11 Copyright 2016 by Therapeutic Research Center Phone: ~ Fax: PharmacistsLetter.com ~ PharmacyTechniciansLetter.com (Page 4 of 5) Although pregnancy and breastfeeding are considered conditions and not diseases, alerts may look like drugdisease interactions. That s because there are some drugs that should be absolutely avoided during pregnancy such as ACE inhibitors (lisinopril, enalapril, etc), ARBs (losartan, valsartan, etc), and statins (lovastatin, atorvastatin, etc). These drugs either have a known or highly suspected ability to cause harm to the unborn child. With most drugs, the true risk to the unborn child isn t fully understood, so patients and prescribers need to weigh the risks versus the benefits. Help the pharmacist identify drug-disease interactions by updating patient profiles with information on disease states, pregnancy, and breastfeeding status. Many pharmacy systems allow you to enter a diagnosis code in order for drug-disease interaction alerts to be identified. There are several codes that can be used to represent each disease state or condition. If your pharmacy uses these codes to help generate drug-disease interaction alerts, work with your pharmacist to develop a list of some of the most common diagnosis codes. Post this list in the pharmacy and share it with other pharmacy team members. What action is required for drug interactions? Depending on the potential severity of an interaction, the pharmacist may choose to take several different actions. He or she is likely to contact the prescriber if there s a risk for serious problems, and offer alternative suggestions for drug therapy. Often, there will be ways to get around the interaction. These might include switching drugs, stopping a drug for a short period of time, adjusting the dose of one or both drugs, adjusting the times of day that the patient takes the drug, etc. If the risk for a problem from an interaction is very small, and the problem is likely to be very minor, the pharmacist may simply counsel the patient. The pharmacist may explain the potential for the interaction, and instruct the patient to call his or her prescriber if a specific problem does occur. Or, if the patient has been on two interacting meds for a long period of time, the pharmacist may want to make sure the patient isn t experiencing any issues before dispensing one or both of the interacting meds. The pharmacist asks Ms. Brach if she has ever had any trouble with muscle pain since starting atorvastatin. Ms. Brach says no. Since Ms. Brach is getting just a single dose of fluconazole, and her dose of atorvastatin is rather low, the pharmacist lets her know that there s a slight chance that she could have short-term muscle pain after taking fluconazole, since fluconazole can temporarily increase blood levels of atorvastatin. The pharmacist tells Ms. Brach to let her prescriber know if she does have muscle pain. What can I do to help prevent drug interactions? Let pharmacists know about all drug interaction alerts. If your computer system alerts you about a drug interaction, don t automatically override the alert, even if you are able. The pharmacy technicians responsibilities for prescription and order entry vary widely depending on the practice setting and on your computer system. So, ask your pharmacist how you should generally handle these alerts. Be aware that some alerts for discontinued meds can still be important to share with the pharmacist. For example, some drugs have lingering effects lasting two weeks or longer after discontinuation. These drugs include amiodarone, fluoxetine, and MAOIs (phenelzine [Nardil], isocarboxazid [U.S.-only, Marplan], and tranylcypromine [Parnate]). It s also important to be careful when CYP450 inducers or inhibitors are discontinued because doses of other drugs metabolized by those enzymes may need to be adjusted. Ask patients about meds filled at other pharmacies and over-the-counter meds, vitamins, and herbal supplements. The potential for drug interactions is a big reason that it s a good idea for patients to fill all of their prescriptions at one pharmacy. Or, at pharmacies that have common access to the patient s medication profile. When a pharmacist doesn t know ALL of the medications a patient is taking, important and potentially dangerous drug interactions could be missed. Each time a patient comes in, ask if he or she is taking any medications that aren t being filled at your pharmacy and if they are taking any OTC medications, vitamins, or herbal supplements. If the answer is yes, take the opportunity to update the

12 (Page 5 of 5) patient s profile. Some computer systems will allow you to enter OTCs or other drugs not filled at your pharmacy so that they can be screened for interactions with drugs filled by the pharmacy. Ask the pharmacist if your system allows you to do this and learn how it s done. The importance of gathering information on over-the-counter products can be illustrated with some examples of drug interactions with supplements and OTC meds: Drug-drug interactions with St. John s wort and drugs metabolized by CYP450 enzymes St. John s wort increases the activity of CYP450 enzymes and can make some drugs such as alprazolam, phenobarbital, and digoxin, less active in the body. Drug-drug interactions with proton-pump inhibitors (PPIs). Now that PPIs such as omeprazole (Prilosec [U.S.], Olex [Canada]) are available over the counter, it s important for technicians to alert the pharmacist when they see patients buying these drugs. PPIs can interact with several drugs, such as clopidogrel (Plavix), through its inhibitory action on a CYP450 enzyme. PPIs can also decrease the effectiveness of drugs requiring an acidic environment for absorption, such as the HIV med atazanavir (Reyataz), because PPIs decrease the acidity of the stomach. Drug-disease interaction with high blood pressure and the nasal decongestant pseudoephedrine pseudoephedrine can increase blood pressure. Drug-food/drink interaction with echinacea and caffeine echinacea, an herbal supplement that is commonly used to treat the common cold, can inhibit the breakdown of caffeine which can lead to jitteriness, headache, or insomnia for patients who drink coffee or other caffeinated beverages. Ask patients about changes to their health to help prevent drug-disease interactions. Each time a patient comes in, ask them if there have been any changes to their health. Follow your pharmacy s process for documenting disease states. If you know a patient to be pregnant or breastfeeding, this information is also important to document to help prevent drug-disease or condition interactions. Apply auxiliary labels when appropriate. Drug-food interactions can be avoided by labeling drugs with appropriate auxiliary labels. Apply Take on an empty stomach labels to drugs that shouldn t be taken with food and Do not take with grapefruit labels on drugs that are affected by grapefruit. Place Take with food labels on prescriptions for drugs that need to be taken with food for proper absorption. Drugs that shouldn t be used with alcoholic beverages should be labeled with a Do not drink alcohol label. Pay attention to labels that warn pregnant or breastfeeding women to avoid taking or handling certain drugs. Talk to your pharmacist about their preference for applying these labels on Rxs for men and older women. Since pregnant women could be helping their husbands, parents, or grandparents manage their meds, it might make sense to add these labels to all Rxs for meds that can be a problem. Do not overlook MedGuides. In the U.S., MedGuides must be dispensed with drugs that pose the most serious and significant public health concern. Drugs that are contraindicated or that should be used with caution with certain conditions or other drugs may have a MedGuide. MedGuides can help inform the patient of drug interactions. Many outpatient pharmacies will automatically print MedGuides when an Rx for one of these drugs is filled. Do not throw these away; they must be given to the patient with any new or refilled Rx. You can also access any MedGuide from our website if needed. Project Leader in preparation of this technician tutorial: Flora Harp, PharmD, Assistant Editor Cite this document as follows: Technician Tutorial, Drug Interactions 101. Pharmacist s Letter/Pharmacy Technician s Letter. October Copyright 2016 by Therapeutic Research Center Phone: ~ Fax: PharmacistsLetter.com ~ PharmacyTechniciansLetter.com