Clinically significant drug interactions in dermatology

CLINICAL REVIEW Clinically significant drug interactions in dermatology Vincent P. Barranco, MD Tulsa, Oklahoma Access to information on clinically significant drug interactions is not readily available. This can be a source of uncertainty, and locating this information can be tedious and timeconsuming. The pharmacology of drug interactions is briefly discussed. The most common drug interactions involve altered hepatic metabolism. At least 26 drugs are such frequent offenders that they can be considered “red flag” drugs. In addition, an extensive list of current significant and less significant drug interactions of particular importance to the dermatologist is presented. (J Am Acad Dermatol 1998;38:599-612.)

Understanding and avoiding drug interactions is an important aspect of clinical medicine. The purpose of this article is to make this subject readily available for integration into a busy clinical practice. Drug interactions may be extremely variable depending on the age and state of health of the patient as well as unanticipated idiosyncratic events. Genetic polymorphism among persons is important in this variability. Despite this, certain drug interactions are now well established that are potentially harmful or even life-threatening. Potential drug interactions number in the hundreds. An important and practical question is: “Which ones are significant or relevant?” Several approaches to rating significant drug interactions are possible.1,2 One highly respected source is Drug Interaction Facts.3 I have employed their rating system in this article. Drug interactions may have a significance rating of 1, 2, 3, 4, or 5. 1 is severe and well-documented, whereas 5 is, at worst, unlikely or only partially documented. Drug interactions that are well documented, or at least reasonably well documented, have a significance rating of 1, 2, or 3. Drug interactions that are possible or unlikely, but not substantiated, have a significance rating of 4 or 5. It is unlikely that a patient will be harmed or a physician considered negligent, except in drug interactions with significance ratings of 1, 2, or possibly 3. From the Department of Dermatology, University of Oklahoma Health Sciences Center. Reprints are not available from the author. Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/1/86507

All drug interactions involve either a pharmacokinetic or pharmacodynamic mechanism.3,4 In pharmacokinetic interactions, one drug alters the (1) rate or degree of absorption, (2) distribution from binding sites, (3) hepatic metabolism, or (4) excretion of another drug (Table I). The great majority of relevant drug interactions in dermatology are of this type. Pharmacodynamic interactions occur when one drug induces a change in another without altering its plasma level (Table II). There is usually an additive effect of the two drugs. Examples are the additive sedative effect of alcohol and antianxiety drugs, as well as the additive anticoagulation effect of aspirin and warfarin. Most drug interactions in dermatology are of the pharmacokinetic type and usually involve altered hepatic metabolism by their influence on the cytochrome P-450 isoenzyme system. At least four drugs are clinically important hepatic enzyme inducers (Table III), and 12 drugs are important hepatic enzyme inhibitors (Table IV). Hepatic enzyme inducers augment metabolism of the second drug, resulting in a decreased blood level. Hepatic enzyme inhibitors reduce the metabolism of phenobarbital, resulting in an increased blood level. A third group of at least 12 drugs (Table V) is particularly susceptible to hepatic enzyme inducers, resulting in their increased metabolism and decreased blood level. This totals 26 different drugs that are actively involved in drug interactions involving hepatic enzyme metabolism. Two of these drugs, verapamil and chloramphenicol, can inhibit enzymes that metabolize other drugs, 599

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600 Barranco Table I. Examples of pharmacokinetic drug interactions Mechanism

Absorption Distribution from binding sites Metabolism Excretion

Interaction

Effect

Calcium salts decrease GI absorption of tetracycline Sulfonamides displace metrotrexate from binding sites Azole antifungal agents decrease hepatic metabolism of astemizole and terfenadine Salicylates decrease excretion of metrotrexate

Decreased plasma tetracycline Increased plasma methotrexate Increased plasma astemizole and terfenadine Increased plasma methotrexate

GI, Gastrointestinal.

Table II. Examples of pharmacodynamic drug interactions Drug A

Drug B

Aspirin Alcohol Potassium-depleting diuretics

Warfarin (Coumadin) Antianxiety drugs Digoxin

Effect

Increased anticoagulation activity Increased CNS effects Decreased plasma potassium may induce digoxinmediated cardiac arrythmia

CNS, Central nervous system.

Table III. Important hepatic enzyme inducers* Carbamazepine Phenobarbital Phenytoin Rifampin *Blood

level of the second drug is reduced.

Table IV. Important hepatic enzyme inhibitors* Allopurinol Amiodarone Azole antifungal agents Chloramphenicol Cimetidine Disulfiram *Blood

Table V. Important drugs that are susceptible to hepatic enzyme inducers* Chloramphenicol Contraceptives, oral Cyclosporine Disopyramide Doxycycline Griseofulvin

Metronidazole Mexiletine Quinidine Theophylline Verapamil Warfarin

*The blood level of the drugs listed is decreased.

Erythromycin Isoniazid Monamine oxidase inhibitors Serotonin reuptake inhibitors Sulfonamides Verapamil

level of the second drug is elevated.

as well as have their effects altered by other hepatic enzyme inhibitors. Another aspect of the cytochrome P-450 enzymes is attracting considerable attention. It is now possible to subdivide the cytochrome P-450 enzymes primarily involved with drug metabolism into three gene families: CYP1, CYP2, and CYP3.5 Although the CYP3 subfamily is involved most often in drug interactions in dermatology, some also occur with the other two. With these

new developments, it is likely that drug interactions can be predicted before clinical trials. This article discusses clinically significant drug interactions with a significance rating of 1 to 3, as well as less significant interactions that are controversial and of particular concern to the dermatologist. In addition to the relatively large number of drug interactions to be discussed, the 10 most significant drug interactions for the practicing dermatologist are listed (Table VI). The list is based on both potential frequency and risk to the patient. Some well-known interactions (e.g., tetracycline and calcium salts) are not included. Of course, any drug interaction is significant if it involves a patient, especially our patient. All the drug interactions presented are clinically significant and

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Table VI. Ten most significant drug interactions Interacting drugs

Mechanism

Effect

Azathioprine*/Allopurinol

Decreased metabolism

Cyprohepadine/Fluoxetine,* paroxetine*

Serotonin antagonism

Erythromycin*/Warfarin

Decreased metabolism

Erythromycin,* clarithromycin,* troleandomycin*/Astemizole, terfenadine Erythromycin,* clarithromycin,* troleandomycin*/Cisapride Erythromycin,* clarithromycin,* troleandomycin*/Theophylline Ketoconazole,* itraconazole*/ Astemizole, terfenadine Ketoconazole,* itraconazole,* fluconazole*/Cisapride Methotrexate/Sulfonamides*

Decreased metabolism

Increased plasma azathioprine with pancytopenia Decreased antidepressant effect with possible suicide Increased plasma warfarin with increased anticoagulation and hemorrhage Increased plasma astemizole and terfenadine with cardiotoxicity

Tetracycline HCl, doxycycline, minocycline/Digoxin

Decreased metabolism Decreased metabolism Decreased metabolism Decreased metabolism. Methotrexate displaced from protein binding sites Increased absorption of digoxin

Increased plasma cisapride with cardiotoxicity Increased plasma theophylline with seizures Increased plasma astemizole and terfenadine with cardiotoxicity Increased plasma cisapride with cardiotoxicity Increased plasma methotrexate with methotrexate toxicity Increased plasma digoxin with cardiotoxicity

*Red flag drugs.

Table VII. Tetracyclines: Tetracycline hydrochloride, minocycline, and doxycycline may interact with the following: Drug

Significance rating

Digoxina,b,c Methoxyfluranea,b,c Penicillinsa,b,c

1 1 1

Aluminum saltsa,b,c (e.g., Rolaids) Barbituratesc Bismuth saltsa,b,c (e.g., Pepto-Bismol) Calcium saltsa,b,c (e.g., Oscal-500) Carbamazepinec Charcoala,b,c Fooda,b,c (especially dairy products)* Hydantoinsc Iron saltsa,b,c (e.g., Fergon) Magnesium saltsa,b,c (e.g., Riopan, Phillips’ Milk of Magnesia) Rifamycinsc Urinary alkalinizersa,b,c (e.g., Urocit-K) Zinc saltsa,b

Mechanism

Effect

2

Increased GI absorption of digoxin Unknown Decreased bactericidal action of penicillins Decreased GI absorption

Increased digoxin toxicity Increased renal toxicity Decreased therapeutic effect of penicillins Decreased plasma tetracyclines

2 2

Increased metabolism Decreased GI absorption

Decreased plasma doxycycline Decreased plasma tetracyclines

2

Decreased GI absorption

Decreased plasma tetracyclines

2 2 2

Increased metabolism Decreased GI absorption Decreased GI absorption.

Decreased plasma doxycyclines Decreased plasma tetracyclines Decreased plasma tetracyclines.

2 2

Increased metabolism Decreased GI absorption.

Decreased plasma doxycyclines Decreased plasma tetracyclines.

2

Decreased GI absorption

Decreased plasma tetracyclines

2 2

Increased metabolism of doxycycline Increased excretion

Decreased plasma doxycyclines Decreased plasma tetracyclines

2

Decreased GI absorption

Decreased plasma tetracycline HCl and minocycline

GI, Gastrointestinal. Interacting tetracyclines: a, Tetracycline HCl; b, minocycline; c, doxycycline. *Decreased absorption of minocycline and doxycycline is not of clinical importance in most patients. It is still preferable to avoid milk with all tetracycline derivatives.

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Table VIII. Macrolide antibiotics (erythromycin, clarithromycin, troleandomycin) may interact with the following: Significance rating

Drug

Mechanism

Effect

Carbamazepine Cisapride Digoxin Ergot alkaloids Nonsedating antihistamines (astemizole, terfenadine)

1 1 1 1 1

Decreased metabolism Decreased metabolism Increased GI absorption Decreased metabolism Decreased metabolism

Vinblastine Warfarin Benzodiazepine Bromocriptine Cyclosporine Felodipine Food* Methylprednisolone

1 1 2 2 2 2 2 2

Decreased metabolism Decreased metabolism Unknown; may decrease metabolism Unknown; may decrease metabolism Decreased metabolism Decreased metabolism Decreased GI absorption Unknown

Theophylline

2

Decreased metabolism

Increased plasma carbamazepine Increased plasma cisapride Increased plasma digoxin Increased plasma ergotamine Increased plasma level of nonsedating antihistamine with cardiotoxicity Increased plasma vinblastine Increased plasma warfarin Increased plasma benzodiazepine Increased plasma bromocriptine Increased plasma cyclosporine Increased plasma felodipine Decreased plasma erythromycin Increased pharmacologic and toxic effects of methylprednisolone Increased plasma theophylline

GI, Gastrointestinal. *Nonenteric-coated erythromycin base and erythromycin stearate must be given 1 or 2 hours before or after meals. Erythromycin estolate and erythromycin ethylsuccinate may be taken with food. Clarithromycin absorption is increased by food.

Table IX. Cephalosporins (oral) may interact with the following: Drug

Significance rating

Mechanism

Effect

Aminoglycosides (e.g., gentamicin)

2

Unknown

Increased nephrotoxicity

Table X. Penicillins (oral) may interact with the following: Drug

Significance rating

Tetracycline

1

Allopurinol

2

Atenolol

2

Food* 2 Warfarin 2 (e.g., Coumadin) Amiloride 3

Mechanism

Decreased bactericidal action of penicillins Unknown, but allopurinol may increase the risk of drug rash to ampicillin GI absorption impaired by ampicillin

Effect

Decreased therapeutic effect of penicillin Drug eruption

Food decreases absorption of penicillins Increased metabolism

Decreased antihypertensive and antianginal effect of atenolol Decreased therapeutic effect of penicillin Decreased warfarin activity

Decreased absorption of amoxicillin

Decreased therapeutic effort of amoxicillin

GI, Gastrointestinal. *Amoxicillin and penicillin V may be given without regard to meals. All other penicillins should be given 1 hour before or 2 hours after meals.

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Table XI. Quinolones may interact with the following: Drug

Significance rating

Antacidsa,b,c,d,e Didanosinea,b,c,d,e Fooda,d Iron saltsa,b,c,d,e Procainamidee Sucralfatea,b,c,d,e Theophyllinea,b,d Azlocillina Caffeinea,b,d

2 2 2 2 2 2 2 3 3

Mechanism

Effect

Decreased GI absorption Decreased GI absorption Decreased GI absorption Decreased GI absorption Decreased renal clearance Decreased GI absorption Decreased metabolism Decreased renal clearance Decreased metabolism

Decreased plasma quinolones Decreased plasma quinolones Decreased plasma quinolones Decreased plasma quinolones Increased plasma procainamide Decreased plasma quinolones Increased plasma theophylline Increased plasma ciprofloxacin Increased plasma caffeine

GI, Gastrointestinal. Interacting quinolones: a, ciprofloxacin; b, enoxacin; c, lomefloxacin; d, norfloxacin; e, ofloxacin.

Table XII. Rifamycins (rifabutin and rifampin) may interact with the following: Drug

Significance rating

Corticosteroidsb Cyclosporineb Isoniazida Aminosalicylic acida

1 1 1 2

Azole antifungalsb

2

β-Blockersb (bisoprolol, metoprolol, propranolol) Contraceptivesa (oral) Digitoxina Disopyramidea Doxycyclineb Estrogensa Haloperidolb Hydantoinsb Indinavirb

2

2 2 2 2 2 2 2 2

Methadoneb 2 Nifedipinea 2 Quinidine and quinineb 2 Ritonavirb

2

Sulfonylureasa Theophyllinesa Tocainidea Verapamila Warfarina Benzodiazepinesb

2 2 2 2 2 3

Mechanism

Effect

Increased metabolism Increased metabolism Altered metabolism of isoniazid Decreased GI tract absorption with rifampin Increased metabolism of azole antifungals; decreased absorption of rifamycins by ketoconazole Increased metabolism

Decreased plasma corticosteroids Decreased plasma cyclosporine Hepatotoxicity Decreased plasma rifampin

Increased metabolism Increased metabolism Increased metabolism Increased metabolism Increased metabolism Increased metabolism Increased metabolism Increased metabolism of indinavir; decreased metabolism of rifamycin Increased metabolism Increased metabolism Increased metabolism

Decreased plasma oral contraceptives Decreased plasma digitoxin Decreased plasma disopyramide Decreased plasma doxycycline Decreased plasma estrogen Decreased plasma haloperidol Decreased plasma hydantoin Decreased plasma indinavir; increased plasma rifamycin Decreased plasma methadone Decreased plasma nifedipine Decreased plasma quinidine and quinine Decreased plasma ritonavir; increased plasma rifamycins Decreased plasma sulfonylureas Decreased plasma theophyllines Decreased plasma tocainide Decreased plasma verapamil Decreased plasma verapamil Decreased plasma benzodiazepines

Increased metabolism of ritonavir; decreased metabolism of rifamycins Increased metabolism Increased metabolism Increased metabolism Increased metabolism Increased metabolism Increased metabolism

GI, Gastrointestinal. Interacting rifamycins: a, rifampin; b, rifabutin and rifampin.

Decreased plasma azole antifungals and decreased plasma rifamycins Decreased plasma bisoprolol, metoprolol, and propranolol

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604 Barranco Table XIII. Sulfonamides may interact with the following: Drug

Significance rating

Cyclosporine Methotrexate

1 1

Warfarin Hydantoins Sulfonylurea

1 2 2

Mechanism

Effect

Unknown Methotrexate displaced from protein binding sites and decreased renal clearance Decreased metabolism Decreased metabolism Decreased metabolism

Increased nephrotoxicity Increased plasma methotrexate with bone marrow suppression and sulfa-induced megaloblastic anemia Increased plasma warfarin Increased plasma hydantoins Increased plasma sulfonylurea

Table XIV. Dapsone may interact with the following: Drug

Significance rating

Didanosine Trimethoprim

1 2

Mechanism

Effect

Decreased absorption Both drugs may decrease renal clearance of each other

Decreased plasma dapsone Increased plasma dapsone and trimethoprim

Table XV. Griseofulvin may interact with the following: Drug

Significance rating

Barbiturates

2

Contraceptives (oral) Warfarin

Mechanism

Effect

2

Decreased GI absorption and increased metabolism Increased metabolism

Decreased plasma griseofulvin Decreased oral contraceptive effectiveness

2

Unknown

Decreased anticoagulant activity

GI, Gastrointestinal.

pose a threat to the patient. A list of generic and trade names of less familiar drugs is included at the end of the article to assist in the use of the tables (Appendix). CLINICALLY SIGNIFICANT DRUG INTERACTIONS (Tables VII-XXXI)

The drug interactions shown in Tables VII through XXX are all documented or may occur because of the pharmacokinetic similarities of the culprit drug(s) to other drug(s) in the same class. Interactions of the tetracyclines (tetracycline hydrochloride, minocycline, and doxycycline), macrolide antibiotics (erythromycin, clarithromycin, and troleandomycin), oral cephalosporins and penicillins, quinolones, rifamycins (rifabutin and rifampin), sulfonamides, and dapsone are

illustrated in Tables VII through XIV. Tables XV through XXX show various interactions of the following drugs: griseofulvin, the azole group of antifungal agents, colchicine, pentoxifylline, chloroquine, corticosteroids, methotrexate, azathioprine, cyprohepadine, cyclosporine, astemizole and terfenadine, histamine2 antagonists, tricyclic antidepressants, serotonin reuptake inhibitors, spironolactone, and vitamin E. OTHER DRUG INTERACTIONS (Tables XXXIIXXXIV)

Interactions with a significance rating less than 3 but which are controversial or of particular interest to dermatologists This section contains few documented, clinicalText continued on p. 610

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Table XVI. Azole antifungal agents may interact with the following: Drug

Significance rating

Astemizole and terfenadinea,b Cisapridea,b,c Warfarina,b,c Antacidsa Benzodiazepinesa,b (midazolam and triazolam) Corticosteroidsa Cyclosporinea,c Digoxinb Foodb Histamine2 antagonistsa HMG-CoA reductase inhibitorsb Hydantoinsb,c

Mechanism

Effect

1

Decreased metabolism

1 1 2 2

Decreased metabolism Decreased metabolism Decreased GI absorption Decreased metabolism

Increased plasma astemizole and terfenadine with possible cardiotoxicity Increased plasma cisapride Increased plasma warfarin Decreased plasma ketoconazole Increased plasma midazolam and triazolam

2 2 2 2 2

Decreased renal clearance Decreased GI absorption Unknown Increased absorption Decreased GI absorption

Increased plasma corticosteroids Increased plasma cyclosporine Increased plasma digoxin Increased plasma itraconazole Decreased plasma ketoconazole

2

Decreased metabolism

2

Increased plasma HMG-CoA reductase inhibitors with rhabdomyolysis Decreased plasma itraconazoleb and increased plasma hydantoinsc

Increased metabolism of itraconazoleb and decreased metabolism of hydantoinsc Decreased metabolism Increased plasma indinavir Decreased GI absorption Decreased plasma ketoconazole Rifamycins increase azole antifungal Decreased plasma azole antifungals and metabolism; ketoconazole decreases rifamycins absorption of rifamycins Decreased metabolism Increased plasma tacrolimus.

Indinavira Omeprazolea Rifamycinsa,b,c

2 2 2

Tacrolimusb

2

GI, Gastrointestinal. Interacting azole antifungal agents: a, ketoconazole; b, itraconazole; c, fluconazole.

Table XVII. Colchicine may interact with the following: Drug

Significance rating

Mechanism

Cyclosporine

2

Unknown

Effect

Severe GI, hepatic, renal, and neurotoxicity

GI, Gastrointestinal.

Table XVIII. Pentoxifylline may interact with the following: Drug

Significance rating

Mechanism

Effect

Cimetidine

3

Decreased metabolism

Increased plasma pentoxifylline

Table XIX. Chloroquine may interact with the following: Drug

Cimetidine Magnesium salts (e.g., milk of magnesia)

Significance rating

3 3

Mechanism

Decreased metabolism Decreased absorption of chloroquine; effectiveness of magnesium salt decreased

Effect

Increased plasma chloroquine Decreased plasma chloroquine and decreased antacid activity of magnesium salts

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606 Barranco Table XX. Corticosteroids may interact with the following: Significance rating

Drug

Mechanism

Effect

Anticholinesterases

1

Unknown

Rifamycins Aminoglutethimide Barbiturates Bile acid sequestrants (e.g., cholestyramine) Contraceptives (oral) Estrogens Hydantoin

1 2 2 2

Increased metabolism Unknown Increased metabolism Decreased GI absorption

May impair the effect of anticholinesterases Decreased plasma corticosteroids Decreased effect of dexamethasone Decreased plasma corticosteroids Decreased plasma hydrocortisone

2 2 2

Decreased metabolism Decreased metabolism Increased metabolism of corticosteroid; increased metabolism of hydantoins Decreased elimination and clearance Decreased metabolism

Increased plasma corticosteroids Increased plasma corticosteroids Decreased plasma corticosteroids and hydantoins Increased plasma corticosteroids Increased plasma methylprednisolone

Increased metabolism and increased renal excretion

Decreased plasma salicylates

Ketoconazole Macrolide antibiotics (erythromycin and troleandomycin) Salicylates

2 2 2

GI, Gastrointestinal.

Table XXI. Methotrexate may interact with the following: Drug

Significance rating

NSAIDS Probenecid Sulfonamides

1 1 1

Salicylates (e.g., aspirin, Pepto-Bismol) Charcoal Digoxin Hydantoins

1 2 2 2

Mechanism

Effect

Decreased renal clearance Decreased renal clearance Methotrexate displaced from protein binding sites; methotrexate may induce folate deficiency, causing sulfonamideinduced megaloblastic anemia Decreased renal clearance and plasma protein binding

Increased plasma methotrexate Increased plasma methotrexate Increased plasma methotrexate

Decreased GI absorption Decreased GI absorption Decreased absorption or increased metabolism

Decreased plasma methotrexate Decreased plasma digoxin Decreased plasma hydantoins

Increased plasma methotrexate

GI, Gastrointestinal.

Table XXII. Azathioprine may interact with the following: Drug

Significance rating

Allopurinol Nondepolarizing muscle relaxants (e.g., tubocurarine)

1 2

Mechanism

Decreased metabolism Decreased phosphodiesterase in nerves

Effect

Increased plasma azathioprine Decreased effectiveness of nondepolarizing muscle relaxants

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Table XXIII. Cyprohepadine may interact with the following: Significance rating

Drug

Fluoxetine and paroxetine Metyrapone

Mechanism

Effect

2

Serotonin antagonism

Decreased effectiveness of fluoxetine and paroxetine

2

Decreased ACTH secretion

Decreased pituitary-adrenal response

ACTH, Corticotropin.

Table XXIV. Cyclosporine may interact with the following: Significance rating

Drug

Mechanism

Digoxin Foscarnet Hydantoins Lovastatin Rifamycins Sulfonamide

1 1 1 1 1 1

Unknown Added nephrotoxicity Increased metabolism Unknown Increased metabolism Unknown

Amiodarone Androgens Carbamazepine Colchicine Diltiazem Etoposide Fluconazole Grapefruit juice Imipenem/Cilastatin

2 2 2 2 2 2 2 2 2

Ketoconazole Macrolide antibiotic (clarithromycin, erythomycin, troleandomycin) Metoclopramide Nicardipine Terbinafine Verapamil

2 2

Decreased metabolism Decreased metabolism Increased metabolism Unknown Decreased metabolism Decreased renal clearance Decreased metabolism Decreased metabolism Additive CNS toxicity; cilastatin may have protective effect on renal tubular cell Decreased metabolism Decreased metabolism

2 2 2 2

Increased absorption Decreased metabolism Increased metabolism Decreased metabolism

Effect

Increased plasma digoxin Increased risk of renal failure Decreased plasma cyclosporine Severe myopathy or rhabdomyolysis Decreased plasma cyclosporine Decreased cyclosporine effectiveness and increased nephropathy Increased plasma cyclosporine Increased plasma cyclosporine Decreased plasma cyclosporine GI, hepatic, and neuromuscular toxicity Increased plasma cyclosporine Increased plasma etoposide Increased plasma cyclosporine Increased plasma cyclosporine Increased CNS toxicity; decreased cyclosporine-induced nephropathy Increased plasma cyclosporine Increased plasma cyclosporine

Increased plasma cyclosporine Increased plasma cyclosporine Decreased plasma cyclosporine Increased plasma cyclosporine; verapamil given before cyclosporine may be nephroprotective

CNS, Central nervous system; GI, gastrointestinal.

Table XXV. Astemizole and terfenadine may interact with the following: Drug

Significance rating

Azole antifungals (itraconazole and ketoconazole) Indinavir Macrolide antibiotics (erythromycin, clarithromycin, troleandomycin) Quinine Ritonavir Serotonin reuptake inhibitors (fluvoxamine and nefazodone)

Mechanism

Effect

1

Decreased metabolism

Increased plasma terfenadine and astemizole

1 1

Decreased metabolism Decreased metabolism

Increased plasma terfenadine and astemizole Increased plasma terfenadine and astemizole

1 1 1

Decreased metabolism Decreased metabolism Decreased metabolism

Increased plasma terfenadine and astemizole Increased plasma terfenadine and astemizole Increased plasma terfenadine and astemizole

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Table XXVI. Histamine2 antagonists may interact with the following: Significance rating

Drug

Carmustinea Warfarina

β-Blockers (metoprolol and propranolol)a Carbamazepinea Hydantoinsa Ketoconazolea,b,c,d

Mechanism

Effect

1 1

Decreased metabolism Decreased metabolism

Increased plasma carmustine Increased plasma warfarin

2 2 2 2

Decreased metabolism Decreased metabolism Decreased metabolism Decreased absorption from higher gastric pH Decreased metabolism Decreased renal clearance Decreased metabolism Decreased metabolism Decreased renal clearance Decreased metabolism and increased absorption Decreased metabolism Decreased metabolism Decreased metabolism Decreased metabolism Decreased metabolism

Increased plasma metoprolol and propranolol Increased plasma carbamazepine Increased plasma hydantoins Decreased plasma ketoconazole

Lidocainea Metformina Moricizinea Nifedipinea Procainamidea Quinidinea

2 2 2 2 2 2

Theophyllinesa Tricyclic antidepressantsa Benzodiazepinesa Chloroquinea Pentoxifyllinea

2 2 3 3 3

Increased plasma lidocaine Increased plasma metformin Increased plasma moricizine Increased plasma nifedipine Increased plasma procainamide Increased plasma quinidine Increased plasma theophyllines Increased plasma tricyclic antidepressants Increased plasma benzodiazepines Increased plasma chloroquine Increased plasma pentoxifylline

Interacting histamine2 antagonists: a, cimetidine; b, famotidine; c, nizatidine; d, ranitidine.

Table XXVII. Tricyclic antidepressants may interact with the following: Significance rating

Mechanism

Effect

Clonidine

1

Inhibition of α2-adrenergic receptors

Monoamine oxidase inhibitors Carbamazepine

1

Unknown

Loss of blood pressure control including malignant hypertension High fever, convulsion, and death

2

Charcoal

2

Cimetidine Dicumarol Fluoxetine Guanethidine

2 2 2 2

Unknown, possibly change in metabolism Decreased GI absorption and “GI dialysis” Decreased metabolism Decreased metabolism Decreased metabolism Decreased uptake in nerve terminal

Sympathomimetic (e.g., epinephrine)

2

Decrease reuptake of sympathomimetics in the neuron

Valproic acid Barbiturates

2 3

Fenfluramine

3

Decreased metabolism Increased metabolism and possibly synergistic pharmacologic actions Decreased metabolism

Drug

GI, Gastrointestinal.

Increased plasma carbamazepine and decreased plasma tricyclic antidepressants Decreased plasma tricyclic antidepressants Increased plasma tricyclic antidepressants Increased plasma dicumarol Increased plasma tricyclic antidepressants Decreased hypotensive effect of guanethidine The pressor effect of direct-acting sympathomimetics is increased and decreased with the indirect acting forms Increased plasma tricyclic antidepressants Decreased plasma tricyclic antidepressants; CNS and respiratory depression may be additive Increased plasma tricyclic antidepressants

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Table XXVIII. Serotonin reuptake inhibitors (SRIs) may interact with the following: Significance rating

Drug

Astemizole and 1 terfenadineb,c Cisapridec 1 Monoamine oxidase 1 inhibitorsa,b,c,d,e,f 1 Sympathomimeticsa,b,d,e 1 Carbamazepinea Cyproheptadinea,d Hydantoinsa Tricyclic antidepressantsa,e Benzodiazepinesb,c

Mechanism

Effect

Decreased metabolism

Increased plasma astemizole and terfenadine

2 2 2 2

Decreased metabolism Increased plasma cisapride Rapid, excess accumulation of “Serotonin syndrome” (CNS irritability, myoclonus brain serotonin and altered consciousness) Unknown Increased effect of sympathomimetics and increased risk of “serotonin syndrome” Decreased metabolism Increased plasma carbamazepine Serotonin antagonist Decreased effectiveness of SRI Decreased metabolism Increased plasma hydantoins Decreased metabolism Increased plasma tricyclic antidepressants

3

Decreased metabolism

Increased plasma benzodiazepines

CNS, Central nervous system. Interacting SRIs: a, fluoxetine; b, fluvoxamine; c, nefazodone; d, paroxetine; e, sertraline; f, venlafaxine.

Table XXIX. Spironolactone may interact with the following: Drug

Significance rating

Potassium preparations Digoxin

1 2

Salicylates (e.g., PeptoBismol and aspirin)

3

Mechanism

Effect

Decreased renal clearance Decreased positive inotropic effect of digoxin; also decreased renal clearance of digoxin Unknown

Hyperkalemia, even severe Decreased positive inotropic effect and increased plasma level of digoxin Decreased natriuresis

Table XXX. Vitamin E may interact with the following: Drug

Significance rating

Warfarin (e.g., Coumadin)

1

Mechanism

Effect

May interfere with vitamin K–dependent clotting factors

Increased anticoagulation

Table XXXI. Acyclovir may interact with the following: Drug

Significance rating

Mechanism

Effect

Theophyllines

2

Decreased metabolism

Increased plasma theophyllines

Table XXXII. Ketoconazole may interact with the following: Drug

Mechanism

Acyclovir Antidiabetic agents, oral

Unknown Decreased metabolism of oral antidiabetic agents Unknown Increased metabolism of ketoconazole

Contraceptives, oral Phenytoin

Effect

Synergistic antiviral effect Increased plasma level of oral antidiabetic agents Decreased plasma level of oral contraceptives Decreased plasma ketoconazole

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610 Barranco Table XXXIII. Fluconazole may interact with the following: Drug

Antidiabetic agents, oral Cimetidine Estradiol Rifampin Thiazides

Mechanism

Effect

Decreased metabolism of oral antidiabetic agents Unknown, possibly decreased absorption of fluconazole Unknown Increased metabolism of fluconazole Decreased excretion of fluconazole

Increased plasma level of oral antidiabetic agents Decreased plasma fluconazole Decreased plasma estradiol Decreased plasma fluconazole Increased plasma fluconazole

Table XXXIV. Itraconazole may interact with the following: Drug

Calcium channel blockers (especially felodipine and nifedipine) Carbamazepine Cyclosporine H2 antagonists Isoniazid Oral antidiabetic agents Phenobarbital Warfarin

Mechanism

Effect

Decreased metabolism of calcium channel blockers

Increased plasma calcium channel blockers

Increased metabolism of itraconazole Decreased metabolism of cyclosporine Decreased metabolism of itraconazole Increased metabolism of itraconazole Decreased metabolism of oral antidiabetic agents Increased metabolism of itraconazole Decreased metabolism of warfarin

Decreased plasma itraconazole Increased plasma cyclosporine Increased plasma itraconazole Decreased plasma itraconazole Increased plasma level of oral antidiabetic agents Decreased plasma itraconazole Increased plasma warfarin

ly significant drug interactions, but is of great concern to the dermatologist. The drugs discussed are heavily prescribed, extensively discussed in the literature, and shrouded in controversy. These include the antibiotic–oral contraceptive interactions and interactions involving the azole group of antifungal agents. Two significant exceptions in this section are synthetic retinoids and first-generation antihistamines. Tetracycline and minocycline should not be used with synthetic retinoids because of their additive risk of inducing pseudotumor cerebri. Similarly, oral vitamin A has additive toxicity when used together with synthetic retinoids.6 In addition, first-generation antihistamines should be given with great caution to patients who are using alcohol or who are taking other central nervous system depressants. No significant drug interactions could be documented for the following: cetirizine, famciclovir, hydroxyzine, and nicotinamide. Antibiotic–oral contraceptive interactions An interaction involving rifampin and oral con-

traceptives is well established, with a significance rating of 2. The mechanism is an increase in hepatic metabolism by rifampin. Other antibiotics commonly used by the dermatologist, with the exception of griseofulvin (significance rating of 2), have little or no documentation and a significance rating of 4 or less. These antibiotics include the penicillins, metronidazole, tetracycline, cephalexin, dapsone, and erythromycin. They reduce intestinal bacterial flora that are helpful in the absorption of oral contraceptive steroids. Only rarely have these antibiotics been associated with reduced efficacy of oral contraceptives, and a definitive interaction is yet to be proved.7,8 Nevertheless, the controversy continues. Miller, Helms, and Brodell7 have developed “a practical approach” to this problem. They do not believe a second form of birth control is necessary for these antibiotics in most patients. After appropriate counseling and patient education, they recommend that the physician offer the option of a second form of birth control to patients who request it. Finally, a recent report stated that intestinal

Journal of the American Academy of Dermatology Volume 38, Number 4

bacterial resistance to tetracycline occurs in less than 2 weeks. Therefore they recommend a second form of birth control for only 2 weeks.9 Azole antifungal agents Azole antifungal agents have already been discussed under “Clinically Significant Drug Interactions.” They are also included here because several reports and reviews credit them with interactions that I consider less significant (4-5) or insignificant.4,10,11 It seems important to address this issue because of the conflicting data and the current popularity of these drugs. Tables XXXI through XXXIII illustrate the drug interactions with a significance of 4 or less. CONCLUSION

Many significant drug interactions involve drugs routinely prescribed by dermatologists. The concept of “red flag” drugs can be helpful in reducing the possibility of this risk. It is also helpful to have an updated “laundry” list of significant drug interactions. Finally, a complete drug history before prescription of a drug is invaluable.

Barranco 611 REFERENCES 1. Hansten PD, Horn JR, editors. Clinical significance of DDIs. 6th ed. Philadelphia: Lea & Febiger; 1993. 2. Hansten PD, Horn JR, Koda-Kimble MA, editors. Drug interactions and updates quarterly. Vancouver (WA): Applied Therapeutics; 1993. 3. Tatro DS. Drug interaction facts. St. Louis: Facts and Comparisons; 1996. 4. Bickers DR. Antifungal therapy: potential interactions with other classes of drugs. J Am Acad Dermatol 1994;31(Suppl):S87-S90. 5. Belpaire FM, Bogaert MG. Cytochrome P450: genetic polymorphism and drug interactions. Acta Clin Belg 1996;51:254-60. 6. Shalita AR, Cunningham WJ, Leyden JJ, Pochi JE, Strauss JS. Isotretinoin treatment of acne and related disorders: an update. J Am Acad Dermatol 1983;9:629-38. 7. Miller DM, Helms SE, Brodell RT. A practical approach to antibiotic treatment in women taking oral contraceptives. J Am Acad Dermatol 1994;30:1008-11. 8. Fazio A. Oral contraceptive drug interactions: important considerations. South Med J 1991;84:997-1001. 9. Morgan JM, Carmichael AJ. Long-term treatment for acne: interaction with oral contraceptives [letter]. J Dermatol Treat 1995;6:250. 10. Gupta AK, Sauder DN, Shear NH. Antifungal agents: an overview. Part II. J Am Acad Dermatol 1994;30:911-33. 11. Brodell RT, Eleweki BE. Clinical pearl: systemic antifungal drugs and drug interactions. J Am Acad Dermatol 1995;33:259-60.

Appendix. Trade names of less familiar drugs Generic name

Allopurinol Aluminum salts Aminoglutethimide Aminoglycosides (gentamicin) Aminosalicylic acid Amiodarone Amitriptyline Astemizole Atenolol Azathioprine Azlocillin Bismuth salts Bismuth subsalicylate Bisoprolol Bromocriptine Calcium salts Carmustine Cholestyramine Cimetidine Ciprofloxacin Cisapride Clarithromycin Clonidine

Trade name

Zyloprim Rolaids (e.g.)* Cytadren Garamycin PAS Cordarone Elavil (e.g.)* Hismanal Tenormin Imuran Azlin Pepto-Bismol (e.g.)* Pepto-Bismol Zebeta Parlodel Os-Cal 500 (e.g.)* Bicnu Questran Tagamet Cipro Propulsid Biaxin Catapres

Generic name

Cyproheptadine Desipramine Didanosine Digitoxin Digoxin Diltiazem Dipyridamole Disopyramide Enoxacin Etoposide Famotidine Felodipine Fluconazole Fluoxetine Fluvoxamine Foscarnet Gemfibrozil Guanethidine Hydantoin (phenytoin) Imipenem/Cilastatin Indinavir Iron salts Itraconazole

Trade name

Periactin Norpramin Videx Crystodigin Lanoxin Cardizem (e.g.)* Persantine Norpace Penetrex Vepesid Pepcid Plendil Diflucan Prozac Luvox Foscavir Lopid Ismelin Dilantin Primaxin Crixivan Fergon (e.g.)* Sporanox Continued on next page

Journal of the American Academy of Dermatology April 1998

612 Barranco Appendix. Cont’d. Generic name

Ketoconazole Lomefloxacin Lovastatin Magnesium salts MAO inhibitors Isocarboxazid Pargyline Phenelzine Tranylcypromine Methadone Metoclopramide Metoprolol Metronidazole Metyrapone Mexiletine Midazolam Moricizine Nefazodone Nicardipine Nifedipine Nizatidine Norfloxacin Nortriptyline Ofloxacin Omeprazole Paroxetine Pentoxifylline Probenecid

Trade name

Nizoral Maxaquin Mevacor Riopan, milk of magnesia (e.g.)* Marplan Eutonyl Nardil Parnate Dolophine (e.g.)* Reglan (e.g.)* Lopressor (e.g.)* Flagyl (e.g.)* Metopirone Mexitil Versed Ethmozine Serzone Cardene Procardia Axid Noroxin Pamelor Floxin Prilosec Paxil Trental Benemid (e.g.)*

*Trade name given is representative; others are available.

Generic name

Procainamide Propranolol Quinidine Ranitidine Rifabutin Rifampin Ritonavir Sertraline Spironolactone Sucralfate Sulfamethoxazole Sulfonylureas Chlorpropramide Glimepiride Glipizide Glyburide Tacrolimus Terfenadine Theophylline Tocainide Triazolam Trimethoprim Troleandomycin Urinary alkalinizers Venlafaxine Verapamil Warfarin

Trade name

Pronestyl (e.g.)* Inderal Quinaglute (e.g.)* Zantac Mycobutin Rifadin, Rimactane Norvir Zoloft Aldactone Carafate Bactrim (e.g.)* Diabinese Amaryl Glucotrol Diabeta, Glynase, Micronase Prograf Seldane Theo-Dur (e.g.)* Tonocard Halcion Trimpex Tao Urocit-K (e.g.)* Effexor Calan (e.g.)* Coumadin