Prescribed Medications and OTCs: Interactions and Timing Issues

In Brief This article describes some common drug-drug interactions between prescription medications and over-the-counter medications that people with diabetes might encounter. With each interaction listed, there is a description of how to appropriately manage it. Also, proper timing of the medications in relation to food intake is described. The data presented are not all-inclusive but do detail the common medications used in people with diabetes. Prescribed Medications and OTCs: Interactions and Timing Issues 256 Kimberly R. Rhoades, RPh, CDE An estimated 17 million people in the United States have diabetes. This is ~6.2% of the population. 1 The majority of the premature deaths attributed to diabetes are a result of complications from the disease. 2 Approximately 73% of adults with diabetes have high blood pressure or use prescription medications to help control hypertension. Adults with diabetes are also two to four times more likely to die from heart disease or to have a stroke than are those without diabetes. 1 The macrovascular diseases, such as arteriosclerosis, are one of the many reasons for the increased incidence of heart disease and stroke. National guidelines now suggest more stringent blood pressure and cholesterol targets than in the past. Therefore, people with diabetes are more likely to be prescribed multiple medications to control these concurrent disease states. The greater the number of medications a person is taking, the greater the risk for drug-drug interactions. According to one hospital study, 3 33% of all adverse drug reactions (ADRs) were a result of preventable drug interactions. This percentage may be even larger if over-the-counter (OTC) product use were taken into account. Drug interactions between common prescription medications and OTCs that a person with diabetes might encounter will be discussed further in this article. Common classes of prescription medications used in diabetes are antidiabetic agents, antihypertensive agents, and antilipemic agents. Common OTCs include analgesics, cough and cold products, and antacids/laxatives. Drug-drug interactions among these classes of medications, as well as the few drug-disease interactions possible with these agents, will be reviewed. Thousands of drug-drug interactions have been documented. However, only a small percentage of these are clinically important. To help clinicians determine the clinical significance of a drug interaction, rating systems have been established. Most rating systems use a numerical scale. This article will draw upon the rating scales developed by Facts and Comparisons 4 and Hansten and Horn. 5 The two scales stratify drug interactions by their severity and documentation of supporting biomedical literature. Hansten and Horn assess severity and documentation together, whereas Facts and Comparisons assesses each of these individually first and then assigns a rating. Facts and Comparisons ratings will be referred to as significance rating A, and the rating provided by Hansten and Horn will be referred to as significance rating B. When assessing severity, Facts and Comparisons labels the interactions as Major, Moderate, or Minor. Major interactions are those in which the effect is potentially capable of causing permanent damage. Moderate interactions are those that may cause deterio-

ration in the clinical status of a patient. Minor interactions are those in which the consequences may be bothersome but should not significantly affect outcomes. Facts and Comparisons categorizes the documentation in the literature as Established, Probable, Suspected, Possible, or Unlikely. Established documentation has been proven to occur in well-controlled studies. Probable documentation is very likely to occur but not proven clinically. Suspected documentation means that it may occur and that there are good data, but that more studies are needed to confirm. Possible documentation means that it may occur, however there is limited data. Unlikely documentation means the interaction is doubtful because there is no good evidence supporting it. Finally, a numerical rating of 1 to 5 is assigned. A level 1 rating is most Prescription Drug Antihypertensive Agents Table 1. Significance Rating Scales Source A 4 Source B 5 Severity of Support from Assigned Rating Avoidance Risk Consequences Literature A & B Major Probable or 1 Avoid Suspected combination Moderate Probable or 2 Avoid combination Suspected if possible Minor Probable 3 Monitor and take or Suspected action if necessary Major/Moderate Possible 4 No action necessary Minor Unlikely or Possible 5 No interaction severe and has a very high probability of occurring. A level 4 or 5 rating is considered mild and of low probability. Table 1 outlines the stratification and the assigned numerical rating. The majority of pharmacies throughout the country screen for drug-drug Table 2. Prescription Drug and OTC Interactions OTC Significance Rating A 4 B 5 interactions among prescription medications dispensed. Unfortunately, this screening process is not available when OTCs are purchased. Labeling regulations for OTCs require the manufacturers to list potential interactions with medications and disease states. Description and Management From Research to Practice / Polypharmacy: Boon or Bane? ACE INHIBITORS Benazepril (Lotensin), captopril (Capoten),* enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), ramipril (Altace), quinapril (Accupril) Antacids (aluminum hydroxide, magnesium hydroxide) 5 Not rated Antacids may reduce the absorption and effectiveness of captopril. Separate the administration of each by 2 hours. Benazepril, captopril, enalapril, fosinopril, lisinopril, ramipril, quinapril Capsaicin 5 Not rated Capsaicin may exacerbate the ACE inhibitor related cough. Case reports have occurred with topical application as well as inhaled capsaicin. Benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril (Univasc), ramipril, quinapril, trandolapril (Tarka) bismuth subsalicylate, High-dose salicylates inhibit prostacyclin synthesis, which may decrease the hypotensive and vasodilator effects of ACE inhibitors. Monitor blood pressure and either reduce the dosage of aspirin or change to an alternative agent. -BLOCKERS Acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone), bisoprolol (Zebeta), carteolol (Cartrol), metoprolol (Lopressor, Toprol), nadolol (Corgard), penbutolol (Levatol), pindolol (Visken), propranolol (Inderal), timolol (Blocadren), sotalol (Betapace) Aluminum salts (aluminum carbonate, aluminum hydroxide, aluminum phosphate, attapulgite, kaolin, magaldrate) 3 4 Reduced absorption and delayed gastric emptying may alter the effect of -blockers. Separate the administration of each by 2 hours. propranolol, timolol, sotalol Calcium salts (calcium carbonate, calcium citrate, calcium gluconate, calcium lactate, dibasic calcium phosphate) Calcium salts may impair the absorption of -blockers. Monitor for signs of decreased efficacy and adjust dosage if necessary. Continued on p. 258 257

Table 2. Prescription Drug and OTC Interactions, Cont. Prescription Drug OTC Significance Rating A 4 B 5 Description and Management -BLOCKERS cont. propranolol, timolol, sotalol Cimetidine 2 4 Cimetidine may reduce hepatic clearance of -blockers creating an increased effect. Monitor for signs of toxicity and adjust dosage if necessary or change to alternative histamine2-blocker. propranolol, timolol NSAIDs (ibuprofen, indomethacin, naproxen, piroxicam) NSAIDs may decrease the antihypertensive effect of -blockers by inhibiting prostaglandin synthesis. Monitor blood pressure and adjust -blocker dosage if necessary. propranolol, timolol bismuth subsalicylate, 4 4 High-dose salicylates may alter the effect of -blockers by inhibition of prostaglandins. Monitor blood pressure and adjust dosage if necessary or change to alternative agent. CALCIUM-CHANNEL BLOCKERS Diltiazem (Cardizem, Cartia XL, Dilacor, Tiazac), nifedipine (Adalat, Procardia), nisoldipine (Sular), verapamil (Calan, Covera, Isoptin, Verelan) Calcium salts (calcium carbonate, calcium citrate, calcium gluconate, calcium lactate, dibasic calcium phosphate) When large doses of calcium salts are given, a reduction of the hypotensive effects of calcium-channel blockers may be seen. Monitor vital signs and adjust dosages if necessary. Diltiazem, nifedipine, nisoldipine, verapamil Histamine2 antagonists (cimetidine, ranitidine, famotidine) Cimetidine may increase the plasma concentration of calcium-channel blockers, creating an increase in hypotensive effects. Monitor blood pressure and adjust dosage if necessary or change to alternative agent. LOOP DIURETICS Bumetanide (Bumex), ethacrynic acid (Edecrin), furosemide (Lasix), torsemide (Demadex) NSAIDs (diclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, sulindac, oxaprozin, piroxicam) 3 3 NSAIDs may decrease the effectiveness of loop diuretics. Monitor for reduction of efficacy and adjust loop diuretic dosage if necessary or change to alternative NSAID. Bumetanide, ethacryinic acid, furosemide, torsemide bismuth subsalicylate, 5 4 A decreased diuretic response may be possible in patients with cirrhosis and ascites. Monitor these patients for decreased effect and adjust dosage if necessary. THIAZIDE DIURETICS Chlorothiazide (Diuril), chlorthalidone (Hygroton), hydrochlorothiazide (Esidrix, HydroDiuril, Oretic), indapamide (Lozol), metolazone (Zaroxolyn) Calcium salts (calcium carbonate, calcium citrate, calcium gluconate, calcium lactate, dibasic calcium phosphate) Hypercalcemia may result from this combination. Monitor serum calcium and for signs of hypercalcemia. Avoid excessive or prolonged administration of calcium salts. Chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone NSAIDs (diclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, sulindac, oxaprozin, piroxicam) 5 4 NSAIDs may cause a mild reduction in antihypertensive effects of thiazide-type diuretics by induction of sodium/water retention and inhibition of renal prostaglandin. Monitor blood pressure and adjust dosage if necessary. Continued on p. 259 258

Prescription Drug Antidiabetic Agents INSULINS AND SULFONYLUREAS Insulin, chlorpropamide (Diabenese), glipizide (Glucotrol), glyburide (DiaBeta,Micronase), tolbutamide (Orinase) Chlorpropamide, glipizide, glyburide, tolbutamide Acetohexamide (Dymelor), chlorpropamide, glipizide, glyburide, tolazamide (Tolinase), tolbutamide) Metformin (Glucophage) Antihyperlipemic Agents BILE AND SEQUESTRANTS Cholestyramine (Questran, Prevalite), colestipol (Colestid), colesevelam (Welchol) Table 2. Prescription Drug and OTC Interactions, Cont. OTC Magnesium salts (magnesium-aluminum hydroxide, magnesium hydroxide) Histamine2 antagonists (cimetidine, ranitidine, famotidine) Cimetidine NSAIDs (ibuprofen, ketoprofen, naproxen sodium) Significance Rating A 4 B 5 5 3 3 3 Description and Management Salicylates may enhance insulin secretion and may increase the effectiveness of sulfonylureas. Monitor blood glucose and adjust medications if necessary. Magnesium salts may enhance absorption of sulfonylureas, therefore increasing the hypoglycemic effect. Monitor blood glucose and adjust dosage if necessary. Reduced hepatic metabolism of sulfonylureas may occur, and changes in gastric ph may lead to increases in efficacy of sulfonylureas. Monitor blood glucose levels and adjust dosages if necessary. Cimetidine increases metformin concentrations by reducing renal clearance, thereby increasing the blood glucose lowering effect. Monitor blood glucose and adjust dosage if necessary or change to alternative histamine2 antagonist. Bile acid sequestrants may decrease the effectiveness of NSAIDs. Take the NSAID either 2 hours before or 6 hours after the administration of the bile acid sequestrant. From Research to Practice / Polypharmacy: Boon or Bane? OTHERS Niacin (Niacor, Niaspan) Salicylates (aspirin) 5 4 Aspirin reduces the cutaneous flushing and increases the plasma concentration of niacin. *Italics indicate medications specifically reported in the literature Certain classes of medications tend to have a higher incidence of drug interactions. According to one hospital study in Germany, 6 thiazide diuretics and angiotensin-converting enzyme (ACE) inhibitors had the highest percentage of potential interactions compared to other classes of antihypertensive medications. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) recommends these two classes of medications as preferred agents in people with diabetes. While these medications clearly benefit this patient population, their use also puts this group of patients at higher risk for drug-drug interactions. Because this patient population is at high risk for cardiovascular events, blood pressure control must be aggressively approached. JNC VI recommends lowering blood pressure in this population to <130/85 mmhg, whereas the American Diabetes Association recommends lowering it to <130/80 mmhg. 7,8 People with diabetes and hypertension are more likely to be taking more than one class of antihypertensive medication regardless of the target recommended. Five classes of antihypertensive medications have been included in this article. ACE inhibitors, -adrenergic blockers, calcium-channel blockers, loop diuretics, and thiazide diuretics, and their interactions with OTC analgesics and antacids are described. By far, the antihypertensives have more interactions with OTCs than do the two other classes reviewed. Table 2 outlines the interactions, significance ratings assigned, and possible courses of management. OTC cough and cold medications have more drug-disease interactions than drug-drug interactions. Table 3 outlines the OTCs and their possible negative effects in people with diabetes. Because people with diabetes are more likely to have high blood glucose, hypertension, and poor circulation, OTCs to be concerned about are those that may increase blood glucose, increase blood pressure, or constrict blood vessels. Decongestants may affect blood pressure and circulation. Cough syrups may contain several different ingredients, including decongestants, and are available with and without added sugar. Therefore, they 259

Medication ANTIHISTAMINES Brompheniramine, chlorpheniramine, clemastine, dexbrompheniramine, diphenhydramine, triprolidine ANTITUSSIVES Dextromethorphan, diphenhydramine ANTIHYPERLIPEMICS Niacin Effect on Disease State Typically this class of medication causes no detrimental effect on the disease state. Typically this class of medication has no effect on blood glucose. However, there are two pediatric case reports in which high doses of dextromethorphan caused a reversible type 1 diabetes. 10 Niacin may increase blood glucose levels. Monitor blood glucose and make appropriate adjustments if necessary or change to alternative agent. DECONGESTANTS Ephedrine, naphazoline,* oxymetazoline, Decongestants may increase blood phenylephrine, pseudoephedrine, pressure secondary to vasoconstrictive xylometazoline properties. Monitor blood pressure and adjust dosage if necessary. EXPECTORANTS Guaifenesin Table 3. OTC Drug-Disease Interactions Typically this medication causes no detrimental effect on the disease state. *The products underlined represent the topical nasal decongestants. Systemic effects are less likely to occur with topical use. of a medication, it is helpful to know when the medication should be administered with regard to meals. As outlined in Table 4, most antidiabetic medications achieve maximum efficacy when taken before meals. Yet, most antihypertensive medications can be taken without regard to food. Generally speaking, if a medication causes stomach upset when taken on an empty stomach, taking it with a little bit of food may hinder the absorption slightly but certainly not as significantly as not taking the medication at all. In conclusion, medications are prescribed to improve quality and quantity of life. Medications should be effective for the diagnosis, be easy to administer, and cause a minimum of side effects. To achieve maximum efficacy of a medication, drug-drug interactions, drug-disease interactions, and the timing of administration with respect to food should be examined thoroughly before coadministration of multiple medications. This article provides a reference to may alter glucose, circulation, and/or blood pressure. It would be prudent to counsel patients to read labels on these products to identify potential interactions. A study performed in a U.S. Army Medical Center 9 showed no significant adverse effects on blood glucose levels when people with diabetes took sugar-containing cough formulas in short courses. Most health care providers would agree that if a patient s glucose and blood pressure are stable and reasonably well controlled, the short-term use of OTC cough and cold products should be of little risk. In summary, the effects of OTCs on patients with diabetes are variable and unpredictable. The best advice is to monitor glucose and blood pressure routinely when starting or stopping any OTC agent and to adjust medications if necessary. In addition to assessing the potential for drug-drug and drug-disease interactions, diabetes health care professionals must also monitor for drugfood interactions. In other words, what is the most appropriate time to take medications in regard to food intake? Food may hinder absorption or increase absorption of a medication. To obtain the maximum efficacy Medication Antidiabetic Agents INSULIN Aspart (Novolog) Lispro (Humalog) Regular (Humulin, Novolin) Glargine (Lantus) Isophane and zinc suspensions (Humulin, Novolin) SULFONYLUREAS Chlorpropamide Glimepiride (Amaryl) Glipizide Glyburide Tolazamide Tolbutamide -GLUCOSIDASE INHIBITORS Acarbose (Precose) Miglitol (Glyset) BIGUANIDES Metformin Table 4. Timing of Administration 11 Timing of Administration Within 5 10 minutes before a meal Within 15 minutes before a meal Take 30 60 minutes before a meal Take at the same time of day, usually in the evening May be given with a meal or upon awakening or at bedtime Take 30 minutes before a meal to improve effectiveness Take with the first bite of each main meal Take with the first bite of each main meal Take with meals to lessen gastrointestinal upset Continued on p.261 260

Medication MEGLITINIDES Repaglinide (Prandin) Nateglinide (Starlix) THIAZOLIDINEDIONES Rosiglitazone (Avandia) Pioglitazone (Actos) Antihypertensive Agents ACE INHIBITORS Benazepril, enalapril, fosinopril, lisinopril, ramipril Captopril, moexipril Timing of Administration Usually taken 15 minutes before meals but may be taken immediately preceding meal to 30 minutes before the meal Take 1 30 minutes before meals Take 1 hour before meals ANGIOTENSIN II RECEPTOR ANTAGONISTS Candesartan (Atacand), losartan (Cozaar), irbesartan (Avapro) Telmisartan (Micardis), valsartan Take 1 hour before meals (Diovan) -BLOCKERS bisoprolol, carteolol, nadolol, sotalol Metoprolol, propranolol ; however, food may enhance the bioavailability CALCIUM-CHANNEL BLOCKERS Amlodipine (Norvasc), bepridil (Vascor), diltiazem, felodipine (Plendil), isradipine (Dynacirc), nicardipine (Cardene), nifedipine, verapamil THIAZIDE DIURETICS Benzthiazide, chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone Antihyperlipemic Agents Table 4. Timing of Administration 11, Cont. BILE ACID SEQUESTRANTS Cholestryramine, colestipol, colesevelam FIBRIC ACID DERIVATIVES Clofibrate (Atromid), fenofibrate (Tricor), gemfibrozil (Lopid) Usually taken before meals HMG CoA REDUCTASE INHIBITORS Atorvastatin (Lipitor), fluvastatin, (Lescol), pravastatin (Pravachol), usually taken in the evening; however, simvastatin (Zocor) high doses may be split between morning and evening Lovastatin (Mevacor) Take with meals, usually in the evening; however, high doses may be split between morning and evening aid in this evaluation. The data presented are not all-inclusive but do detail the common issues surrounding medication use in people with diabetes. References 1 National Diabetes Statistics, www.niddk.nih.gov/ health/diabetes/pubs/dmstats/dmstats.htm 2 Miyashiro LA: Diabetes mellitus. In Pharmacotherapy Self Assessment Program. 4th ed. Book 3. Kansas City, Mo. American College of Clinical Pharmacy, p. 113 3 Ferrill M: Clinically relevant drug interactions. In Drug Facts and Comparisons News. St. Louis, Mo., Facts and Comparisons, Nov. 1999, p. 83 86 4 Tatro DS: Drug Interaction Facts. St. Louis, Mo., Facts and Comparisons, April 2002 5 Hansten PD, Horn JR: Drug Interaction Analysis and Management. St. Louis, Mo., Facts and Comparisons, July 1999 6 Kohler GI, Bode-Boger SM, Busse R, Hoopmann M, Welte T, Boger RH: Drug-drug interactions in medical patients: effects of in-hospital treatment and relation to multiple drug use. Int J Clin Pharmacol Ther 38:504 513, 2000 7 The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI). NIH Publication No. 98-4080, Nov 1997, p. 49 8 American Diabetes Association: Treatment of hypertension in adults with diabetes (Position Statement). Diabetes Care 25 (Suppl. 1):S71 S73, 2002 9 LeMar HJ Jr, Georgitis WJ: Effect of cold remedies on metabolic control of NIDDM. Diabetes Care 16:426 428, 1993 10 Konrad D, Sobetzko D, Schmitt B, Schoenle EJ: Insulin-dependent diabetes mellitus induced by the antitussive agent dextromethorphan (Letter). Diabetologia 43:261 262, 2000 11 Drug Facts and Comparisons. St. Louis, Mo., Facts and Comparisons, April 2002 Kimberly R. Rhoades, RPh, CDE, is a clinical pharmacist with Kaiser Permanente Colorado in Lakewood, Colo. From Research to Practice / Polypharmacy: Boon or Bane? OTHERS Niacin Take with food 261