Prescribed Medications and Otcs: Interactions and Timing Issues

In Brief

This article describes some common drug-drug interactions between prescrip- tion 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

An estimated 17 million people in the pertensive agents, and antilipemic United States have diabetes. This is agents. Common OTCs include anal- ~6.2% of the population.1 The majori- gesics, cough and cold products, and Kimberly R. Rhoades, RPh, CDE ty of the premature deaths attributed antacids/laxatives. Drug-drug interac- to diabetes are a result of complica- tions among these classes of medica- tions from the disease.2 Approximately tions, as well as the few drug-disease 73% of adults with diabetes have high interactions possible with these blood pressure or use prescription agents, will be reviewed. medications to help control hyperten- Thousands of drug-drug interac- sion. Adults with diabetes are also two tions have been documented. However, to four times more likely to die from only a small percentage of these are heart disease or to have a stroke than clinically important. To help clinicians are those without diabetes.1 The determine the clinical significance of a macrovascular diseases, such as arte- drug interaction, rating systems have riosclerosis, are one of the many rea- been established. Most rating systems sons for the increased incidence of use a numerical scale. heart disease and stroke. National This article will draw upon the rat- guidelines now suggest more stringent ing scales developed by Facts and blood pressure and cholesterol targets Comparisons4 and Hansten and than in the past. Therefore, people Horn.5 The two scales stratify drug with diabetes are more likely to be interactions by their severity and doc- prescribed multiple medications to umentation of supporting biomedical control these concurrent disease states. literature. Hansten and Horn assess The greater the number of medica- severity and documentation together, tions a person is taking, the greater whereas Facts and Comparisons the risk for drug-drug interactions. assesses each of these individually According to one hospital study,3 first and then assigns a rating. Facts 33% of all adverse drug reactions and Comparisons’ ratings will be (ADRs) were a result of preventable referred to as “significance rating A,” drug interactions. This percentage and the rating provided by Hansten may be even larger if over-the-counter and Horn will be referred to as “sig- (OTC) product use were taken into nificance rating B.” account. Drug interactions between When assessing severity, Facts and common prescription medications and Comparisons labels the interactions as OTCs that a person with diabetes Major, Moderate, or Minor. Major might encounter will be discussed fur- interactions are those in which the ther in this article. Common classes of effect is potentially capable of causing prescription medications used in dia- permanent damage. Moderate interac- betes are antidiabetic agents, antihy- tions are those that may cause deterio- 256 Diabetes Spectrum Volume 15, Number 4, 2002 ration in the clinical status of a Polypharmacy: Boon or Bane? / From Research to Practice patient. Minor interactions are those Table 1. Significance Rating Scales in which the consequences may be 4 5 bothersome but should not signifi- Source A Source B Severity of Support from Assigned Rating Avoidance Risk cantly affect outcomes. Consequences Literature A & B Facts and Comparisons categorizes the documentation in the literature as Major Probable or 1 Avoid Established, Probable, Suspected, Suspected combination Possible, or Unlikely. Established doc- umentation has been proven to occur Moderate Probable or 2 Avoid combination Suspected if possible in well-controlled studies. Probable documentation is very likely to occur Minor Probable 3 Monitor and take but not proven clinically. Suspected or Suspected action if necessary documentation means that it may Major/Moderate Possible 4 No action necessary occur and that there are good data, but that more studies are needed to Minor Unlikely or Possible 5 No interaction confirm. Possible documentation means that it may occur, however severe and has a very high probability interactions among prescription med- there is limited data. Unlikely docu- of occurring. A level 4 or 5 rating is ications dispensed. Unfortunately, this mentation means the interaction is considered mild and of low probabili- screening process is not available when doubtful because there is no good evi- ty. Table 1 outlines the stratification OTCs are purchased. Labeling regula- dence supporting it. and the assigned numerical rating. tions for OTCs require the manufactur- Finally, a numerical rating of 1 to 5 The majority of pharmacies through- ers to list potential interactions with is assigned. A level 1 rating is most out the country screen for drug-drug medications and disease states.

Table 2. Prescription Drug and OTC Interactions

Prescription Drug OTC Significance Rating Description and A4 B5 Management

Antihypertensive Agents

ACE INHIBITORS Benazepril (Lotensin), captopril Antacids (aluminum 5 Not rated Antacids may reduce the absorption and (Capoten),* enalapril (Vasotec), hydroxide, magne- effectiveness of captopril. Separate the fosinopril (Monopril), lisinopril sium hydroxide) administration of each by 2 hours. (Prinivil, Zestril), ramipril (Altace), quinapril (Accupril)

Benazepril, captopril, enalapril, Capsaicin 5 Not rated Capsaicin may exacerbate the ACE fosinopril, lisinopril, ramipril, inhibitor–related cough. Case reports have quinapril occurred with topical application as well as inhaled capsaicin.

Benazepril, captopril, enalapril, Salicylates (aspirin, 43High-dose salicylates inhibit prostacyclin fosinopril, lisinopril, moexipril bismuth subsalicy- synthesis, which may decrease the hypoten- (Univasc), ramipril, quinapril, late, magnesium sali- sive and vasodilator effects of ACE inhib- trandolapril (Tarka) cylate, sodium salicy- itors. Monitor blood pressure and either late) reduce the dosage of aspirin or change to an alternative agent.

-BLOCKERS Acebutolol (Sectral), atenolol Aluminum salts (alu- 34Reduced absorption and delayed gastric (Tenormin), betaxolol (Kerlone), minum carbonate, emptying may alter the effect of -blockers. bisoprolol (Zebeta), carteolol aluminum hydroxide, Separate the administration of each by 2 (Cartrol), metoprolol (Lopressor, aluminum phosphate, hours. Toprol), nadolol (Corgard), pen- attapulgite, kaolin, butolol (Levatol), pindolol magaldrate) (Visken), propranolol (Inderal), timolol (Blocadren), sotalol (Betapace)

Acebutolol, atenolol, betaxolol, Calcium salts (calci- 43Calcium salts may impair the absorption of bisoprolol, carteolol, metoprolol, um carbonate, calci- -blockers. Monitor for signs of decreased nadolol, penbutolol, pindolol, um citrate, calcium efficacy and adjust dosage if necessary. propranolol, timolol, sotalol gluconate, calcium lactate, dibasic calci- Continued on p. 258 um phosphate) 257 Diabetes Spectrum Volume 15, Number 4, 2002 Table 2. Prescription Drug and OTC Interactions, Cont.

Prescription Drug OTC Significance Rating Description and A4 B5 Management

-BLOCKERS cont. Acebutolol, atenolol, betaxolol, Cimetidine 24Cimetidine may reduce hepatic clearance of bisoprolol, carteolol, metoprolol, -blockers creating an increased effect. nadolol, penbutolol, pindolol, Monitor for signs of toxicity and adjust propranolol, timolol, sotalol dosage if necessary or change to alternative histamine2-blocker.

Acebutolol, atenolol, betaxolol, NSAIDs (ibuprofen, 23NSAIDs may decrease the antihypertensive bisoprolol, carteolol, metoprolol, indomethacin, effect of -blockers by inhibiting prosta- nadolol, penbutolol, pindolol, naproxen, piroxicam) glandin synthesis. Monitor blood pressure and propranolol, timolol adjust -blocker dosage if necessary.

Acebutolol, atenolol, betaxolol, Salicylates (aspirin, 44High-dose salicylates may alter the effect of bisoprolol, carteolol, metoprolol, bismuth subsalicylate, -blockers by inhibition of prostaglandins. nadolol, penbutolol, pindolol, magnesium salicylate, Monitor blood pressure and adjust dosage if propranolol, timolol sodium salicylate) necessary or change to alternative agent.

CALCIUM-CHANNEL BLOCKERS Diltiazem (Cardizem, Cartia XL, Calcium salts (calci- 23When large doses of calcium salts are given, a Dilacor, Tiazac), nifedipine um carbonate, calci- reduction of the hypotensive effects of calci- (Adalat, Procardia), nisoldipine um citrate, calcium um-channel blockers may be seen. Monitor (Sular), verapamil (Calan, gluconate, calcium vital signs and adjust dosages if necessary. Covera, Isoptin, Verelan) lactate, dibasic calci- um phosphate)

Diltiazem, nifedipine, nisoldipine, Histamine2 antago- 23Cimetidine may increase the plasma concen- verapamil nists (cimetidine, ran- tration of calcium-channel blockers, creating itidine, famotidine) an increase in hypotensive effects. Monitor blood pressure and adjust dosage if necessary or change to alternative agent.

LOOP DIURETICS Bumetanide (Bumex), ethacrynic NSAIDs (diclofenac, 33NSAIDs may decrease the effectiveness of acid (Edecrin), furosemide ibuprofen, indometh- loop diuretics. Monitor for reduction of effi- (Lasix), torsemide (Demadex) acin, ketoprofen, cacy and adjust loop diuretic dosage if neces- naproxen, sulindac, sary or change to alternative NSAID. oxaprozin, piroxicam)

Bumetanide, ethacryinic acid, Salicylates (aspirin, 54A decreased diuretic response may be possi- furosemide, torsemide bismuth subsalicylate, ble in patients with cirrhosis and ascites. magnesium salicylate, Monitor these patients for decreased effect sodium salicylate) and adjust dosage if necessary.

THIAZIDE DIURETICS Chlorothiazide (Diuril), chlor- Calcium salts (calci- 43Hypercalcemia may result from this combi- thalidone (Hygroton), um carbonate, calci- nation. Monitor serum calcium and for signs hydrochlorothiazide (Esidrix, um citrate, calcium of hypercalcemia. Avoid excessive or pro- HydroDiuril, Oretic), indapamide gluconate, calcium longed administration of calcium salts. (Lozol), metolazone (Zaroxolyn) lactate, dibasic calci- um phosphate)

Chlorothiazide, chlorthalidone, NSAIDs (diclofenac, 54NSAIDs may cause a mild reduction in anti- hydrochlorothiazide, indapamide, ibuprofen, hypertensive effects of thiazide-type diuretics metolazone indomethacin, keto- by induction of sodium/water retention and profen, naproxen, inhibition of renal prostaglandin. Monitor sulindac, oxaprozin, blood pressure and adjust dosage if necessary. piroxicam)

Continued on p. 259

258 Diabetes Spectrum Volume 15, Number 4, 2002 Table 2. Prescription Drug and OTC Interactions, Cont. Polypharmacy: Boon or Bane? / From Research to Practice

Prescription Drug OTC Significance Rating Description and A4 B5 Management Antidiabetic Agents

INSULINS AND SULFONYLUREAS Insulin, chlorpropamide Salicylates (aspirin, 23Salicylates may enhance insulin secretion and (Diabenese), glipizide (Glucotrol), magnesium salicylate, may increase the effectiveness of sulfony- glyburide (DiaBeta,Micronase), sodium salicylate) lureas. Monitor blood glucose and adjust tolbutamide (Orinase) medications if necessary.

Chlorpropamide, glipizide, gly- Magnesium salts 53Magnesium salts may enhance absorption of buride, tolbutamide (magnesium-alu- sulfonylureas, therefore increasing the hypo- minum hydroxide, glycemic effect. Monitor blood glucose and magnesium hydrox- adjust dosage if necessary. ide)

Acetohexamide (Dymelor), chlor- Histamine2 antago- 43Reduced hepatic metabolism of sulfonylureas propamide, glipizide, glyburide, nists (cimetidine, ran- may occur, and changes in gastric pH may tolazamide (Tolinase), tolbu- itidine, famotidine) lead to increases in efficacy of sulfonylureas. tamide) Monitor blood glucose levels and adjust dosages if necessary.

Metformin (Glucophage) Cimetidine 23Cimetidine increases metformin concentra- tions 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.

Antihyperlipemic Agents

BILE AND SEQUESTRANTS Cholestyramine (Questran, NSAIDs (ibuprofen, 33Bile acid sequestrants may decrease the effec- Prevalite), colestipol (Colestid), ketoprofen, naproxen tiveness of NSAIDs. Take the NSAID either colesevelam (Welchol) sodium) 2 hours before or 6 hours after the adminis- tration of the bile acid sequestrant.

OTHERS Niacin (Niacor, Niaspan) Salicylates (aspirin) 54Aspirin reduces the cutaneous flushing and increases the plasma concentration of niacin.

*Italics indicate medications specifically reported in the literature

Certain classes of medications tend blood pressure control must be outlines the interactions, significance to have a higher incidence of drug aggressively approached. JNC VI rec- ratings assigned, and possible courses interactions. According to one hospi- ommends lowering blood pressure in of management. tal study in Germany,6 thiazide this population to <130/85 mmHg, OTC cough and cold medications diuretics and angiotensin-converting whereas the American Diabetes have more drug-disease interactions enzyme (ACE) inhibitors had the Association recommends lowering it than drug-drug interactions. Table 3 highest percentage of potential inter- to <130/80 mmHg.7,8 People with dia- outlines the OTCs and their possible actions compared to other classes of betes and hypertension are more likely negative effects in people with dia- antihypertensive medications. The to be taking more than one class of betes. Sixth Report of the Joint National antihypertensive medication regard- Because people with diabetes are Committee on Prevention, Detection, less of the target recommended. more likely to have high blood glu- Evaluation, and Treatment of High Five classes of antihypertensive cose, hypertension, and poor circula- Blood Pressure (JNC VI) recommends medications have been included in this tion, OTCs to be concerned about are these two classes of medications as article. ACE inhibitors, -adrenergic those that may increase blood glucose, preferred agents in people with dia- blockers, calcium-channel blockers, increase blood pressure, or constrict betes. While these medications clearly loop diuretics, and thiazide diuretics, blood vessels. Decongestants may benefit this patient population, their and their interactions with OTC anal- affect blood pressure and circulation. use also puts this group of patients at gesics and antacids are described. By Cough syrups may contain several dif- higher risk for drug-drug interactions. far, the antihypertensives have more ferent ingredients, including deconges- Because this patient population is interactions with OTCs than do the tants, and are available with and at high risk for cardiovascular events, two other classes reviewed. Table 2 without added sugar. Therefore, they 259 Diabetes Spectrum Volume 15, Number 4, 2002 of a medication, it is helpful to know Table 3. OTC Drug-Disease Interactions when the medication should be Medication Effect on Disease State administered with regard to meals. As outlined in Table 4, most ANTIHISTAMINES antidiabetic medications achieve max- Brompheniramine, chlorpheniramine, Typically this class of medication causes imum efficacy when taken before clemastine, dexbrompheniramine, no detrimental effect on the disease state. diphenhydramine, triprolidine meals. Yet, most antihypertensive medications can be taken without ANTITUSSIVES regard to food. Generally speaking, if Dextromethorphan, diphenhydramine Typically this class of medication has no a medication causes stomach upset effect on blood glucose. However, there when taken on an empty stomach, are two pediatric case reports in which high doses of dextromethorphan caused taking it with a little bit of food may a reversible type 1 diabetes.10 hinder the absorption slightly but cer- tainly not as significantly as not tak- ANTIHYPERLIPEMICS ing the medication at all. Niacin Niacin may increase blood glucose levels. In conclusion, medications are pre- Monitor blood glucose and make appro- priate adjustments if necessary or change scribed to improve quality and quan- to alternative agent. tity of life. Medications should be effective for the diagnosis, be easy to DECONGESTANTS administer, and cause a minimum of Ephedrine, naphazoline,* oxymetazoline, Decongestants may increase blood side effects. To achieve maximum phenylephrine, pseudoephedrine, pressure secondary to vasoconstrictive xylometazoline properties. Monitor blood pressure and efficacy of a medication, drug-drug adjust dosage if necessary. interactions, drug-disease interac- tions, and the timing of administra- EXPECTORANTS tion with respect to food should be Guaifenesin Typically this medication causes no examined thoroughly before co- detrimental effect on the disease state. administration of multiple medica- *The products underlined represent the topical nasal decongestants. Systemic effects tions. are less likely to occur with topical use. This article provides a reference to

may alter glucose, circulation, and/or Table 4. Timing of Administration11 blood pressure. It would be prudent to counsel patients to read labels on Medication Timing of Administration these products to identify potential interactions. Antidiabetic Agents A study performed in a U.S. Army Medical Center9 showed no signifi- INSULIN cant adverse effects on blood glucose Aspart (Novolog) Within 5–10 minutes before a meal levels when people with diabetes took Lispro (Humalog) Within 15 minutes before a meal sugar-containing cough formulas in Regular (Humulin, Novolin) Take 30–60 minutes before a meal short courses. Most health care Glargine (Lantus) Take at the same time of day, usually in the providers would agree that if a evening patient’s glucose and blood pressure Isophane and zinc suspensions May be given with a meal or upon awakening (Humulin, Novolin) or at bedtime are stable and reasonably well con- trolled, the short-term use of OTC SULFONYLUREAS cough and cold products should be of Chlorpropamide May be given 30 minutes before a meal or with a little risk. meal to lessen gastrointestinal upset In summary, the effects of OTCs Glimepiride (Amaryl) May be given 30 minutes before a meal or with a on patients with diabetes are variable meal to lessen gastrointestinal upset and unpredictable. The best advice is Glipizide Take 30 minutes before a meal to improve to monitor glucose and blood pres- effectiveness sure routinely when starting or stop- Glyburide May be given 30 minutes before a meal or with a ping any OTC agent and to adjust meal to lessen gastrointestinal upset Tolazamide May be given 30 minutes before a meal or with a medications if necessary. meal to lessen gastrointestinal upset In addition to assessing the poten- Tolbutamide May be given 30 minutes before a meal or with a tial for drug-drug and drug-disease meal to lessen gastrointestinal upset interactions, diabetes health care pro- fessionals must also monitor for drug- -GLUCOSIDASE INHIBITORS food interactions. In other words, Acarbose (Precose) Take with the first bite of each main meal what is the most appropriate time to Miglitol (Glyset) Take with the first bite of each main meal take medications in regard to food intake? Food may hinder absorption BIGUANIDES or increase absorption of a medica- Metformin Take with meals to lessen gastrointestinal upset tion. To obtain the maximum efficacy Continued on p.261

260 Diabetes Spectrum Volume 15, Number 4, 2002 aid in this evaluation. The data pre- Polypharmacy: Boon or Bane? / From Research to Practice Table 4. Timing of Administration11, Cont. sented are not all-inclusive but do Medication Timing of Administration detail the common issues surrounding medication use in people with dia- MEGLITINIDES betes. Repaglinide (Prandin) Usually taken 15 minutes before meals but may be taken immediately preceding meal to 30 minutes before the meal References Nateglinide (Starlix) Take 1–30 minutes before meals 1National Diabetes Statistics, www.niddk.nih.gov/ health/diabetes/pubs/dmstats/dmstats.htm THIAZOLIDINEDIONES 2Miyashiro LA: Diabetes mellitus. In Rosiglitazone (Avandia) May be taken with or without meals Pharmacotherapy Self Assessment Program. 4th Pioglitazone (Actos) May be taken with or without meals ed. Book 3. Kansas City, Mo. American College of Clinical Pharmacy, p. 113 Antihypertensive Agents 3Ferrill M: Clinically relevant drug interactions. ACE INHIBITORS In Drug Facts and Comparisons News. St. Louis, Mo., Facts and Comparisons, Nov. 1999, p. Benazepril, enalapril, fosinopril, May be taken with or without meals 83–86 lisinopril, ramipril Captopril, moexipril Take 1 hour before meals 4Tatro DS: Drug Interaction Facts. St. Louis, Mo., Facts and Comparisons, April 2002 ANGIOTENSIN II RECEPTOR ANTAGONISTS 5Hansten PD, Horn JR: Drug Interaction Candesartan (Atacand), losartan May be taken with or without meals Analysis and Management. St. Louis, Mo., Facts (Cozaar), irbesartan (Avapro) and Comparisons, July 1999

Telmisartan (Micardis), valsartan Take 1 hour before meals 6 (Diovan) Kohler GI, Bode-Boger SM, Busse R, Hoopmann M, Welte T, Boger RH: Drug-drug interactions in medical patients: effects of in-hos- -BLOCKERS pital treatment and relation to multiple drug use. Acebutolol, atenolol, betaxolol, May be taken with or without meals Int J Clin Pharmacol Ther 38:504–513, 2000 bisoprolol, carteolol, nadolol, sotalol 7 Metoprolol, propranolol May be taken with or without meals; how- The Joint National Committee on Prevention, ever, food may enhance the bioavailability Detection, Evaluation, and Treatment of High Blood Pressure: The Sixth Report of the Joint National Committee on Prevention, Detection, CALCIUM-CHANNEL BLOCKERS Evaluation, and Treatment of High Blood Amlodipine (Norvasc), bepridil May be taken with or without meals Pressure (JNC-VI). NIH Publication No. 98- (Vascor), diltiazem, felodipine (Plendil), 4080, Nov 1997, p. 49 isradipine (Dynacirc), nicardipine 8 (Cardene), nifedipine, verapamil American Diabetes Association: Treatment of hypertension in adults with diabetes (Position Statement). Diabetes Care 25 (Suppl. THIAZIDE DIURETICS 1):S71–S73, 2002 Benzthiazide, chlorothiazide, May be taken with or without meals chlorthalidone, hydrochlorothiazide, 9LeMar HJ Jr, Georgitis WJ: Effect of cold reme- indapamide, metolazone dies on metabolic control of NIDDM. Diabetes Care 16:426–428, 1993 Antihyperlipemic Agents 10Konrad D, Sobetzko D, Schmitt B, Schoenle EJ: Insulin-dependent diabetes mellitus induced by BILE ACID SEQUESTRANTS the antitussive agent dextromethorphan (Letter). Cholestryramine, colestipol, Usually taken before meals Diabetologia 43:261–262, 2000 colesevelam 11Drug Facts and Comparisons. St. Louis, Mo., Facts and Comparisons, April 2002 FIBRIC ACID DERIVATIVES Clofibrate (Atromid), fenofibrate May be taken with or without meals (Tricor), gemfibrozil (Lopid) Kimberly R. Rhoades, RPh, CDE, is a clinical pharmacist with Kaiser HMG CoA REDUCTASE INHIBITORS Permanente—Colorado in Lakewood, Atorvastatin (Lipitor), fluvastatin May be taken with or without meals, Colo. (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

OTHERS Niacin Take with food

261 Diabetes Spectrum Volume 15, Number 4, 2002