The subject of drug-drug interactions has continued to expand in terms of understanding mechanisms, predicting potentially significant interactions based on advances in evaluating metabolic pathways and enhanced recognition of the importance of pharmacogenomics.1-3 Within dermatology, the clinical significance of drug interactions has been made evident by the withdrawal from the marketplace of the “nonsedating” antihistamines, terfenadine (Seldane) and astemizole (Hismanal), due to the increased propensity for prolongation of the QTc interval with subsequent ventricular arrhythmia when these agents were coadministered with erythromycin, ketoconazole (Nizoral) or itraconazole (Sporanox).3-8 This “hallmark interaction” is directly related to inhibition of the cytochrome (CYP) 3A4 metabolic pathway by several macrolide antibiotics and azole antifungal agents. Due to the predominant role of CYP 3A4 in the metabolism of approximately half of drugs currently available on the market, the potential for widespread impact related to CYP 3A4 inhibition, as well as other less predominant CYP metabolic isoenzymes, has received significant notoriety. The importance of drug interactions has also been respected by industry. In the United States, between 1987 and 1991, 98 drugs received approval for use with 32 inclusive of drug interaction studies. Between 1992 and 1997, although the number of approved drugs increased by two-fold, the number of associated drug interaction studies increased by slightly more than three-fold. Several warnings and contraindications have emerged related to drug interactions including recommendations to avoid coadministration of some macrolide antibiotics or azole antifungal agents with HMG-CoA reductase inhibitors (cholesterol-lowering agents), some benzodiazepines and some cardiac drugs, including digoxin (Lanoxin) and quinidine.1-9 Considering the widespread prevalence of superficial mycotic infections and associated oral antifungal use, it is rational to periodically revisit the subject of potential drug interactions and oral antifungal agents. Due to variations in metabolic pathways, significant differences in the potential for interactions have been established when comparing griseofulvin (GrisPEG, Grifulvin V), terbinafine (Lamisil), ketoconazole (Nizoral) and the triazoles, itraconazole (Sporanox) and fluconazole (Diflucan). Overall, as compared to other oral antifungal agents, terbinafine is associated with the most favorable safety profile with regard to clinically significant drug interactions.2-8,10 Through the use of illustrative case studies encountered in clinical practice, this article provides an overview and update on potential drug interactions related to the selection of specific oral antifungal agents. Emphasis will be placed on supportive data, clinical significance and management suggestions for the clinician when selecting oral antifungal therapy for onychomycosis and other superficial mycotic infections. Major Drug Interaction Mechanisms The majority of clinically significant drug interactions involve either alterations in gastrointestinal absorption or hepatic metabolism. Clinical examples are used to illustrate underlying drug interaction mechanisms. Absorption. In cases involving gastrointestinal absorption, interaction occurs when absorption of itraconazole (capsules) or ketoconazole (tablets) is impaired by concurrent administration of a second drug or compound that decreases gastric acidity.1-3,5-8 Decreased gastric acidity may be caused by ingestion of antacids, H-2 blocker antihistamines such as cimetidine (Tagamet) and ranitidine (Zantac), proton pump inhibitors such as omeprazole (Prilosec), rabeprazole (Aciphex), pantoprazole (Protonix), esomeprazole (Nexium) and lansoprazole (Prevacid) and oral didanosine (Videx). Metabolism. Metabolic interactions occur through either enzyme inhibition or enzyme induction (see figure above). Enzyme inhibition occurs when the hepatic metabolism of one drug is decreased by a second drug that the patient is ingesting.2,3 The most common hepatic enzyme associated with drug metabolism is cytochrome 3A4 (CYP 3A4). Other enzymes with lesser degrees of involvement, but still with important roles in the metabolism of specific drugs include CYP 2C9, CYP 2D6 and CYP 1A2. A major example of enzyme inhibition is the decreased metabolism of certain HMG CoA reductase inhibitors such as simvastatin (Zocor), lovostatin (Mevacor) and atorvastatin (Lipitor) which are cholesterol-lowering agents metabolized by CYP 3A4, caused by itraconazole, an inhibitor of CYP 3A4.1-3,7-9 The inhibition of CYP 3A4 by itraconazole results in increased serum levels of simvastatin, lovastatin or atorvastatin, ultimately placing the patient at increased risk of severe myopathy and rhabodomyolysis (see figure 2 on below). Other inhibitors of CYP 3A4, such as ketoconazole, may also produce the same interaction effect. Another example of enzyme inhibition is decreased metabolism of phenytoin (Dilantin), a drug metabolized by CYP 2C9, caused by fluconazole, an inhibitor of CYP 2C9.2,3,7,8 As a result, significantly increased phenytoin serum levels have been documented during concomitant administration of fluconazole, leading to clinically evident phenytoin toxicity. Enzyme induction occurs when an administered drug increases the metabolic activity of an enzyme responsible for the metabolism of another drug.2,3 A clinically relevant example is the coadministration of phenytoin (Dilantin) and itraconazole.2,3,6-8,11 Phenytoin increases the hepatic metabolism of itraconazole resulting in its accelerated clearance. The possible outcome of this interaction is inadequate antifungal response to itraconazole as less is systemically available. Treatment failure related to induction of itraconazole metabolism by phenytoin has been reported. With this background information in mind, consider the following cases of drug interactions with antifungal agents and how they might have been avoided. Case #1 History. A 53-year-old Hispanic male presented with a 6-year history of onychomycosis of both large toenails and multiple smaller toenails. Fungal culture obtained from the right large toenail confirms the presence of Trichophyton rubrum. Bilateral plantar tinea pedis is also noted on examination. The patient has a history of diabetes, hypertension and anxiety with difficulty sleeping. Past medical history and recent evaluation within the last month of a serum chemistry panel are otherwise unremarkable. The patient is highly motivated regarding his interest in treating onychomycosis and is very embarrassed by the condition. Medication History. Current daily systemic medications used by the patient are hydrochlorothiazide and nifedipine (Procardia) for hypertension, metformin (Glucophage) and glipizide (Glucotrol) for diabetes and alprazolam (Xanax) as a sedative-hypnotic agent. The clinician is considering oral antifungal treatment in combination with large toenail debridement. What potentially significant drug interactions may be identified prior to initiation of therapy? Drug Interaction Case Summary. This case illustrates potentially significant drug interactions between certain oral antifungal agents and calcium channel blockers, oral hypoglycemic agents and benzodiazepine sedative-hypnotic agents. Calcium Channel Blockers. As with many other calcium channel blockers, nifedipine is metabolized in the liver by CYP 3A4. Clearance of nifedipine is decreased by itraconazole or ketoconazole due to enzyme inhibition of CYP 3A4.1-3,7-8,12-14 Other calcium channel blockers that may be affected in a similar fashion are felodipine (Plendil), isradipine (DynacCirc) and verapamil (Isoptin, Verelan, Covera) (see figure 3 below). Consequences of the interaction between itraconazole or ketoconazole with nifedipine (or other similarly metabolized calcium channel blockers) include marked peripheral edema and decrease in blood pressure. Cautious concurrent use or avoidance of coadministration with itraconazole or ketoconazole are recommended. Due to inhibition of CYP 3A4, fluconazole, especially at higher doses (>200 mg daily), may potentially cause the same interaction effect as itraconazole and ketoconazole.6-8 As terbinafine does not affect CYP 3A4, interaction with nifedipine or other similarly metabolized calcium channel blockers is not expected. There are no reports of interaction of terbinafine with calcium channel blockers.2,3,7 In vivo studies support the absence of interaction between terbinafine and nifedipine.10 There are no apparent interactions between griseofulvin and calcium channel blockers. Hypoglycemic Agents. Interaction between terbinafine and any of the currently available agents used to treat diabetes, including insulin and oral hypoglycemic agents, have not been reported.4-8,10,15 Drug interactions with terbinafine are not anticipated after consideration of what is known regarding involved pathways of metabolism. Based on routes of metabolism and available data, itraconazole and ketoconazole do not appear to interact with insulin, metformin (Glucophage), oral sulfonylureas such as glyburide (DiaBeta, Glynase, Micronase) and glipizide (Glucotrol), rosiglitazone (Avandia) and nateglinide (Starlix).1-3,6-8,15 As repaglinide (Prandin) and pioglitazone (Actos) are metabolized by CYP 3A4, potential for hypoglycemia due to interaction with itraconazole and ketoconazole exists.2,3,6-8,15 Fluconazole, especially at higher doses, is also capable of inhibiting CYP 3A4 with potential to produce interactions similar to those associated with itraconazole and ketoconazole.2,3,6-8,15 Interaction between fluconazole and several oral hypoglycemic agents, such as sulfonylureas (ie, glipizide, glyburide), rosiglitazone and netaglinide may occur due to inhibition of the metabolic enzyme CYP 2C9.2,3,6-8,15 The potential clinical outcome of these agents interacting with fluconazole is enhanced risk of hypoglycemia. There are no apparent interactions between hypoglycemic agents and griseofulvin.2,3 Sedative-Hypnotic Agents. Patients treated with benzodiazepine sedative-hypnotic agents metabolized by CYP 3A4, specifically triazolam (Halcion), midazolam (Versed) and alprazolam (Xanax), should not co-ingest itraconazole, ketoconazole, and probably fluconazole at doses >200 mg daily.2,3,6-8,15 The CYP 3A4 inhibition associated with itraconazole or ketoconazole results in elevated serum levels of the aforementioned benzodiazepines, ultimately enhancing sedation and somnolence. Similar interaction does not occur with coadministration of terbinafine due to absence of CYP 3A4 inhibition.2-4,6-8,10,15 Griseofulvin does not appear to interact with benzodiazepine sedative-hypnotic agents.2,3 Management Suggestions. From the perspective of potential drug interaction risk, and based on the confirmed diagnosis of dermatophyte onychomycosis, oral terbinafine is the optimal choice for treatment in this patient.2,3,6,7,16 Although griseofulvin is approved for the treatment of onychomycosis, it would not be considered to be a viable option due to its poor efficacy and the availability of newer more effective oral antifungal agents. The combined use of oral antifungal therapy and debridement is likely to optimize the response to therapy by reducing physical factors that promote treatment failure, such as extensive onycholysis, lateral plate involvement, marked nail plate thickening and dermatophyoma.17,18 Case #2 History: A 52-year-old Caucasian female presented with unilateral right plantar tinea pedis and onychomycosis of multiple toenails, including both large toenails. Independently performed potassium hydroxide preparations from the right large toenail and affected plantar surface demonstrate multiple long branched hyphae. Fungal culture from the right large toenail identified Trichophyton rubrum as the causative pathogen. Baseline liver function testing and complete blood cell count are unremarkable. Intermittent pruritis of the right sole is noted. The patient also reports a sense of “pressure” and discomfort of her toenails when wearing certain shoes. Medication History. Current daily systemic medications used by the patient are digoxin and quinidine for atrial fibrillation and sertraline for clinical depression. The patient also mentions that her internist may be starting her on warfarin (Coumadin) in the near future due to atrial fibrillation. The clinician is considering oral antifungal treatment. What potentially significant drug interactions may be identified prior to initiation of therapy? Drug Interaction Case Summary. This case illustrates potentially significant drug interactions between some oral antifungal agents and digoxin, quinidine and certain antidepressant drugs. Consideration is also given to potential interactions with warfarin should this medication be started based on the patient history. Digoxin. Concurrent administration of itraconazole with digoxin may cause a significant increase in digoxin serum levels.1-3,19,20 Documented cases of digoxin toxicity have been reported in association with itraconazole coadministration. The literature also reports rare cases of increased serum levels of digoxin related to concurrent use of ketoconazole.7 The development of digoxin toxicity after concurrent use of itraconazole may be related to inhibition of p-glycoprotein, a membrane transport protein found in intestinal mucosa and renal tubules.7,15 It has been suggested that inhibition of p-glycoprotein by itraconazole impairs the renal pump mechanism responsible for tubular secretion of digoxin into the urine. Terbinafine, fluconazole and griseofulvin can be safely administered to patients utilizing digoxin.4-8,10,15 Quinidine. Concurrent administration of itraconazole is contraindicated in patients taking quinidine; itraconazole increases plasma concentrations of quinidine with cases of toxicity reported.1-3,21 The clinical onset of the interaction often manifests as tinnitus, and serious cardiovascular reactions may occur.1 Transient increase in quinidine plasma levels has also been reported with concurrent use of ketoconazole.22 Interaction with quinidine has not been reported with terbinafine and is not anticipated based on current understanding of metabolic pathways.4-8,10,15 Interaction between griseofulvin or fluconazole with quinidine also does not appear to occur.2,3 Antidepressants. The hepatic metabolism of the antidepressant agents, including tricyclic derivatives and selective serotonin reuptake inhibitors (SSRIs), is dependent on the specific agent prescribed.1-3,15,23 Older antidepressants, such as desipramine (Norpramin), nortriptyline (Aventyl), imipramine and amitriptyline are metabolized by CYP 2D6. Of the SSRIs, fluoxetine (Prozac) is metabolized by CYP 2D6 and paroxetine (Paxil) is metabolized by CYP 2D6 and CYP 3A4; both are also potent inhibitors of CYP 2D6.23 Many SSRIs share their metabolism among multiple CYP enzymatic pathways.23 For example, sertraline (Zoloft) is metabolized by CYP 3A4, CYP 2D6 and CYP 2C19. Shared enzymatic metabolism allows for potential shunting of the antidepressant drug to a different “available metabolic enzyme” should one of the enzymes responsible for the metabolism of the antidepressant be inhibited by another co-ingested drug. Of the available SSRIs, sertraline (Zoloft) and escitalopram (Lexapro) share their metabolism among three metabolic enzymes (CYP 3A4, CYP 2D6, CYP 2C19) and are reported to have a low potential for drug interactions.23 Terbinafine is an inhibitor of CYP 2D6.1,7,15 Examples of drugs that are metabolized by CYP 2D6 include older antidepressants (ie. amitriptyline, desipramine, nortriptyline), the SSRIs fluoxetine (Prozac) and paroxetine (Paxil), and some older beta-blockers such as metoprolol (Lopressor) and propranolol (Inderal).7,15,23 As a result, cautious coadministration with terbinafine is suggested.1,7,15 Nortriptyline toxicity associated with terbinafine coadministration has been reported and interaction has been suggested with desipramine and imipramine.2,7,8 Itraconazole, ketoconazole and fluconazole (at doses > 200 mg daily) may inhibit the metabolism of the SSRI, citalopram (Celexa), potentially resulting in prolongation of central nervous system side effects.7 Warfarin.Warfarin (Coumadin), a commonly used anticoagulant, is potentially sensitive to interaction with many classes of drugs, including antibiotic agents.2,3 All of the five currently available oral antifungal agents have been reported to potentially interact with warfarin, although the degree of risk is unclear.2,3,6-8 Griseofulvin may decrease the anticoagulant activity of warfarin. Itraconazole, ketoconazole, and fluconazole may increase the anticoagulant effect of warfarin; careful monitoring of anticoagulation parameters (ie, international normalized ratio, prothrombin time) is recommended. Premarketing and pharmacosurveillance studies suggested no interaction of terbinafine with warfarin.10 Literature review indicates two interaction reports with contradictory effects.3,7,8 As with the use of other oral antifungal agents in patients taking warfarin, monitoring of anticoagulation parameters is suggested. Management Suggestions. Based on the current medication history, terbinafine may be used safely in patients treated with digoxin and quinidine. Due to shared hepatic metabolism, interaction of terbinafine with sertraline is unlikely. Itraconazole is contraindicated in patients utilizing quinidine and may also cause significant increases in serum digoxin levels. Fluconazole is a potential option in this case for treatment of dermatophyte onychomycosis, however, a longer duration of therapy is required. Due to limited efficacy for onychomycosis, ketoconazole and griseofulvin are not considered to be viable therapeutic options. Although the risk for significant interaction appears to be less than with itraconazole, ketoconazole may alter serum levels of quinidine and digoxin. Case # 3 History. A 32-year-old Fillipino male presented with multiple hypopigmented patches located diffusely on the lateral neck, chest, back, shoulders and upper arms. The eruption has been present for 1 year and has progressively worsened. Fine scaling is noted, which is accentuated by light scratching of affected skin with a tongue blade (“positive scratch sign”). The clinical diagnosis of tinea versicolor is supported by a potassium hydroxide preparation demonstrating multiple short hyphae with clusters of round spores (“spaghetti and meatballs” pattern). Medication History. Current daily systemic medications used by the patient are lansoprazole (Prevacid) and intermittent use of calcium carbonate (Tums) as needed for gastroesophageal reflux disease (GERD) and loratadine (Claritin) for seasonal rhinitis. The clinician is interested in prescribing oral antifungal treatment for tinea versicolor in this patient due to extensive body surface area involvement. What potentially significant drug interactions may be identified prior to initiation of therapy? Drug Interaction Case Summary. This case illustrates potentially significant drug interactions between specific oral antifungal agents and medications or ingestants that reduce gastric acidity. Proton Pump Inhibitors / H-2 Blocker Antihistamines / Antacids. Dissolution and subsequent gastrointestinal absorption of itraconazole from its capsule formulation and ketoconazole from its tablet formulation require gastric acidity. Proton pump inhibitors such as omeprazole (Prilosec), lansoprazole (Prevacid), rabeprazole (Aciphex), pantoprazole (Protonix), esomeprazole (Nexium), H-2 blocker antihistamines, such as cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), and antacids (calcium carbonate, aluminum hydroxide, magnesium hydroxide) reduce gastric acidity resulting in decreased absorption of itraconazole or ketoconazole from the intestinal tract.1-3,6-8 Although concurrent ingestion of a cola beverage has been suggested as a method to enhance gastric acidity and overcome the effect of the interaction, there is no evidence that ingestion of a cola beverage or citrus juice along with itraconazole or ketoconazole provides enough gastric acidity to counteract the marked increase in alkalinity caused by a proton pump inhibitor.2 Interestingly, grapefruit juice has been shown to decrease the absorption and bioavailability of itraconazole.14 Gastrointestinal absorption of terbinafine and fluconazole are not significantly impacted by gastric pH or contents.2-8 Although it has been noted that the absorption of griseofulvin may be enhanced by ingestion with a fatty meal, the clinical significance of this suggestion is not clear. Management Suggestions. Of the currently available oral antifungal agents, ketoconazole, fluconazole and itraconazole have demonstrated efficacy for the treatment of tinea versicolor. Both ketoconazole (400 mg) and fluconazole (300 mg to 400 mg) may be used as single dose therapy for tinea versicolor; efficacy may be enhanced by repeating single dose treatment one week later. In this case, due to use by the patient of a proton pump inhibitor (lansoprazole) and antacid (calcium carbonate), the effectiveness of either ketoconazole or itraconazole is likely to be diminished. Fluconazole absorption is not impacted by reduced gastric acidity, favoring the use of this agent for oral treatment of tinea versicolor in this case. Points to Keep in Mind • A complete medication history is very important prior to choosing an oral antifungal agent in order to proactively identify potentially deleterious drug interactions. • In almost all cases, a viable and safe oral antifungal alternative exists, which allows for treatment of the patient without exposure to the risk of a harmful drug interaction. • Due to differences in absorption and metabolism, terbinafine can be safely used in the majority of clinical situations where a potential interaction with an azole antifungal agent is identified. • Despite the theoretical potential for interactions via CYP 2D6 inhibition, there has been a conspicuous paucity of drug interactions reported in association with terbinafine use based on pharmacosurveillance and literature review. • Review of published literature supports that clinically significant interactions associated with terbinafine use are rare.
Avoiding Drug Interactions with Antifungal Agents
The subject of drug-drug interactions has continued to expand in terms of understanding mechanisms, predicting potentially significant interactions based on advances in evaluating metabolic pathways and enhanced recognition of the importance of pharmacogenomics.1-3 Within dermatology, the clinical significance of drug interactions has been made evident by the withdrawal from the marketplace of the “nonsedating” antihistamines, terfenadine (Seldane) and astemizole (Hismanal), due to the increased propensity for prolongation of the QTc interval with subsequent ventricular arrhythmia when these agents were coadministered with erythromycin, ketoconazole (Nizoral) or itraconazole (Sporanox).3-8 This “hallmark interaction” is directly related to inhibition of the cytochrome (CYP) 3A4 metabolic pathway by several macrolide antibiotics and azole antifungal agents. Due to the predominant role of CYP 3A4 in the metabolism of approximately half of drugs currently available on the market, the potential for widespread impact related to CYP 3A4 inhibition, as well as other less predominant CYP metabolic isoenzymes, has received significant notoriety. The importance of drug interactions has also been respected by industry. In the United States, between 1987 and 1991, 98 drugs received approval for use with 32 inclusive of drug interaction studies. Between 1992 and 1997, although the number of approved drugs increased by two-fold, the number of associated drug interaction studies increased by slightly more than three-fold. Several warnings and contraindications have emerged related to drug interactions including recommendations to avoid coadministration of some macrolide antibiotics or azole antifungal agents with HMG-CoA reductase inhibitors (cholesterol-lowering agents), some benzodiazepines and some cardiac drugs, including digoxin (Lanoxin) and quinidine.1-9 Considering the widespread prevalence of superficial mycotic infections and associated oral antifungal use, it is rational to periodically revisit the subject of potential drug interactions and oral antifungal agents. Due to variations in metabolic pathways, significant differences in the potential for interactions have been established when comparing griseofulvin (GrisPEG, Grifulvin V), terbinafine (Lamisil), ketoconazole (Nizoral) and the triazoles, itraconazole (Sporanox) and fluconazole (Diflucan). Overall, as compared to other oral antifungal agents, terbinafine is associated with the most favorable safety profile with regard to clinically significant drug interactions.2-8,10 Through the use of illustrative case studies encountered in clinical practice, this article provides an overview and update on potential drug interactions related to the selection of specific oral antifungal agents. Emphasis will be placed on supportive data, clinical significance and management suggestions for the clinician when selecting oral antifungal therapy for onychomycosis and other superficial mycotic infections. Major Drug Interaction Mechanisms The majority of clinically significant drug interactions involve either alterations in gastrointestinal absorption or hepatic metabolism. Clinical examples are used to illustrate underlying drug interaction mechanisms. Absorption. In cases involving gastrointestinal absorption, interaction occurs when absorption of itraconazole (capsules) or ketoconazole (tablets) is impaired by concurrent administration of a second drug or compound that decreases gastric acidity.1-3,5-8 Decreased gastric acidity may be caused by ingestion of antacids, H-2 blocker antihistamines such as cimetidine (Tagamet) and ranitidine (Zantac), proton pump inhibitors such as omeprazole (Prilosec), rabeprazole (Aciphex), pantoprazole (Protonix), esomeprazole (Nexium) and lansoprazole (Prevacid) and oral didanosine (Videx). Metabolism. Metabolic interactions occur through either enzyme inhibition or enzyme induction (see figure above). Enzyme inhibition occurs when the hepatic metabolism of one drug is decreased by a second drug that the patient is ingesting.2,3 The most common hepatic enzyme associated with drug metabolism is cytochrome 3A4 (CYP 3A4). Other enzymes with lesser degrees of involvement, but still with important roles in the metabolism of specific drugs include CYP 2C9, CYP 2D6 and CYP 1A2. A major example of enzyme inhibition is the decreased metabolism of certain HMG CoA reductase inhibitors such as simvastatin (Zocor), lovostatin (Mevacor) and atorvastatin (Lipitor) which are cholesterol-lowering agents metabolized by CYP 3A4, caused by itraconazole, an inhibitor of CYP 3A4.1-3,7-9 The inhibition of CYP 3A4 by itraconazole results in increased serum levels of simvastatin, lovastatin or atorvastatin, ultimately placing the patient at increased risk of severe myopathy and rhabodomyolysis (see figure 2 on below). Other inhibitors of CYP 3A4, such as ketoconazole, may also produce the same interaction effect. Another example of enzyme inhibition is decreased metabolism of phenytoin (Dilantin), a drug metabolized by CYP 2C9, caused by fluconazole, an inhibitor of CYP 2C9.2,3,7,8 As a result, significantly increased phenytoin serum levels have been documented during concomitant administration of fluconazole, leading to clinically evident phenytoin toxicity. Enzyme induction occurs when an administered drug increases the metabolic activity of an enzyme responsible for the metabolism of another drug.2,3 A clinically relevant example is the coadministration of phenytoin (Dilantin) and itraconazole.2,3,6-8,11 Phenytoin increases the hepatic metabolism of itraconazole resulting in its accelerated clearance. The possible outcome of this interaction is inadequate antifungal response to itraconazole as less is systemically available. Treatment failure related to induction of itraconazole metabolism by phenytoin has been reported. With this background information in mind, consider the following cases of drug interactions with antifungal agents and how they might have been avoided. Case #1 History. A 53-year-old Hispanic male presented with a 6-year history of onychomycosis of both large toenails and multiple smaller toenails. Fungal culture obtained from the right large toenail confirms the presence of Trichophyton rubrum. Bilateral plantar tinea pedis is also noted on examination. The patient has a history of diabetes, hypertension and anxiety with difficulty sleeping. Past medical history and recent evaluation within the last month of a serum chemistry panel are otherwise unremarkable. The patient is highly motivated regarding his interest in treating onychomycosis and is very embarrassed by the condition. Medication History. Current daily systemic medications used by the patient are hydrochlorothiazide and nifedipine (Procardia) for hypertension, metformin (Glucophage) and glipizide (Glucotrol) for diabetes and alprazolam (Xanax) as a sedative-hypnotic agent. The clinician is considering oral antifungal treatment in combination with large toenail debridement. What potentially significant drug interactions may be identified prior to initiation of therapy? Drug Interaction Case Summary. This case illustrates potentially significant drug interactions between certain oral antifungal agents and calcium channel blockers, oral hypoglycemic agents and benzodiazepine sedative-hypnotic agents. Calcium Channel Blockers. As with many other calcium channel blockers, nifedipine is metabolized in the liver by CYP 3A4. Clearance of nifedipine is decreased by itraconazole or ketoconazole due to enzyme inhibition of CYP 3A4.1-3,7-8,12-14 Other calcium channel blockers that may be affected in a similar fashion are felodipine (Plendil), isradipine (DynacCirc) and verapamil (Isoptin, Verelan, Covera) (see figure 3 below). Consequences of the interaction between itraconazole or ketoconazole with nifedipine (or other similarly metabolized calcium channel blockers) include marked peripheral edema and decrease in blood pressure. Cautious concurrent use or avoidance of coadministration with itraconazole or ketoconazole are recommended. Due to inhibition of CYP 3A4, fluconazole, especially at higher doses (>200 mg daily), may potentially cause the same interaction effect as itraconazole and ketoconazole.6-8 As terbinafine does not affect CYP 3A4, interaction with nifedipine or other similarly metabolized calcium channel blockers is not expected. There are no reports of interaction of terbinafine with calcium channel blockers.2,3,7 In vivo studies support the absence of interaction between terbinafine and nifedipine.10 There are no apparent interactions between griseofulvin and calcium channel blockers. Hypoglycemic Agents. Interaction between terbinafine and any of the currently available agents used to treat diabetes, including insulin and oral hypoglycemic agents, have not been reported.4-8,10,15 Drug interactions with terbinafine are not anticipated after consideration of what is known regarding involved pathways of metabolism. Based on routes of metabolism and available data, itraconazole and ketoconazole do not appear to interact with insulin, metformin (Glucophage), oral sulfonylureas such as glyburide (DiaBeta, Glynase, Micronase) and glipizide (Glucotrol), rosiglitazone (Avandia) and nateglinide (Starlix).1-3,6-8,15 As repaglinide (Prandin) and pioglitazone (Actos) are metabolized by CYP 3A4, potential for hypoglycemia due to interaction with itraconazole and ketoconazole exists.2,3,6-8,15 Fluconazole, especially at higher doses, is also capable of inhibiting CYP 3A4 with potential to produce interactions similar to those associated with itraconazole and ketoconazole.2,3,6-8,15 Interaction between fluconazole and several oral hypoglycemic agents, such as sulfonylureas (ie, glipizide, glyburide), rosiglitazone and netaglinide may occur due to inhibition of the metabolic enzyme CYP 2C9.2,3,6-8,15 The potential clinical outcome of these agents interacting with fluconazole is enhanced risk of hypoglycemia. There are no apparent interactions between hypoglycemic agents and griseofulvin.2,3 Sedative-Hypnotic Agents. Patients treated with benzodiazepine sedative-hypnotic agents metabolized by CYP 3A4, specifically triazolam (Halcion), midazolam (Versed) and alprazolam (Xanax), should not co-ingest itraconazole, ketoconazole, and probably fluconazole at doses >200 mg daily.2,3,6-8,15 The CYP 3A4 inhibition associated with itraconazole or ketoconazole results in elevated serum levels of the aforementioned benzodiazepines, ultimately enhancing sedation and somnolence. Similar interaction does not occur with coadministration of terbinafine due to absence of CYP 3A4 inhibition.2-4,6-8,10,15 Griseofulvin does not appear to interact with benzodiazepine sedative-hypnotic agents.2,3 Management Suggestions. From the perspective of potential drug interaction risk, and based on the confirmed diagnosis of dermatophyte onychomycosis, oral terbinafine is the optimal choice for treatment in this patient.2,3,6,7,16 Although griseofulvin is approved for the treatment of onychomycosis, it would not be considered to be a viable option due to its poor efficacy and the availability of newer more effective oral antifungal agents. The combined use of oral antifungal therapy and debridement is likely to optimize the response to therapy by reducing physical factors that promote treatment failure, such as extensive onycholysis, lateral plate involvement, marked nail plate thickening and dermatophyoma.17,18 Case #2 History: A 52-year-old Caucasian female presented with unilateral right plantar tinea pedis and onychomycosis of multiple toenails, including both large toenails. Independently performed potassium hydroxide preparations from the right large toenail and affected plantar surface demonstrate multiple long branched hyphae. Fungal culture from the right large toenail identified Trichophyton rubrum as the causative pathogen. Baseline liver function testing and complete blood cell count are unremarkable. Intermittent pruritis of the right sole is noted. The patient also reports a sense of “pressure” and discomfort of her toenails when wearing certain shoes. Medication History. Current daily systemic medications used by the patient are digoxin and quinidine for atrial fibrillation and sertraline for clinical depression. The patient also mentions that her internist may be starting her on warfarin (Coumadin) in the near future due to atrial fibrillation. The clinician is considering oral antifungal treatment. What potentially significant drug interactions may be identified prior to initiation of therapy? Drug Interaction Case Summary. This case illustrates potentially significant drug interactions between some oral antifungal agents and digoxin, quinidine and certain antidepressant drugs. Consideration is also given to potential interactions with warfarin should this medication be started based on the patient history. Digoxin. Concurrent administration of itraconazole with digoxin may cause a significant increase in digoxin serum levels.1-3,19,20 Documented cases of digoxin toxicity have been reported in association with itraconazole coadministration. The literature also reports rare cases of increased serum levels of digoxin related to concurrent use of ketoconazole.7 The development of digoxin toxicity after concurrent use of itraconazole may be related to inhibition of p-glycoprotein, a membrane transport protein found in intestinal mucosa and renal tubules.7,15 It has been suggested that inhibition of p-glycoprotein by itraconazole impairs the renal pump mechanism responsible for tubular secretion of digoxin into the urine. Terbinafine, fluconazole and griseofulvin can be safely administered to patients utilizing digoxin.4-8,10,15 Quinidine. Concurrent administration of itraconazole is contraindicated in patients taking quinidine; itraconazole increases plasma concentrations of quinidine with cases of toxicity reported.1-3,21 The clinical onset of the interaction often manifests as tinnitus, and serious cardiovascular reactions may occur.1 Transient increase in quinidine plasma levels has also been reported with concurrent use of ketoconazole.22 Interaction with quinidine has not been reported with terbinafine and is not anticipated based on current understanding of metabolic pathways.4-8,10,15 Interaction between griseofulvin or fluconazole with quinidine also does not appear to occur.2,3 Antidepressants. The hepatic metabolism of the antidepressant agents, including tricyclic derivatives and selective serotonin reuptake inhibitors (SSRIs), is dependent on the specific agent prescribed.1-3,15,23 Older antidepressants, such as desipramine (Norpramin), nortriptyline (Aventyl), imipramine and amitriptyline are metabolized by CYP 2D6. Of the SSRIs, fluoxetine (Prozac) is metabolized by CYP 2D6 and paroxetine (Paxil) is metabolized by CYP 2D6 and CYP 3A4; both are also potent inhibitors of CYP 2D6.23 Many SSRIs share their metabolism among multiple CYP enzymatic pathways.23 For example, sertraline (Zoloft) is metabolized by CYP 3A4, CYP 2D6 and CYP 2C19. Shared enzymatic metabolism allows for potential shunting of the antidepressant drug to a different “available metabolic enzyme” should one of the enzymes responsible for the metabolism of the antidepressant be inhibited by another co-ingested drug. Of the available SSRIs, sertraline (Zoloft) and escitalopram (Lexapro) share their metabolism among three metabolic enzymes (CYP 3A4, CYP 2D6, CYP 2C19) and are reported to have a low potential for drug interactions.23 Terbinafine is an inhibitor of CYP 2D6.1,7,15 Examples of drugs that are metabolized by CYP 2D6 include older antidepressants (ie. amitriptyline, desipramine, nortriptyline), the SSRIs fluoxetine (Prozac) and paroxetine (Paxil), and some older beta-blockers such as metoprolol (Lopressor) and propranolol (Inderal).7,15,23 As a result, cautious coadministration with terbinafine is suggested.1,7,15 Nortriptyline toxicity associated with terbinafine coadministration has been reported and interaction has been suggested with desipramine and imipramine.2,7,8 Itraconazole, ketoconazole and fluconazole (at doses > 200 mg daily) may inhibit the metabolism of the SSRI, citalopram (Celexa), potentially resulting in prolongation of central nervous system side effects.7 Warfarin.Warfarin (Coumadin), a commonly used anticoagulant, is potentially sensitive to interaction with many classes of drugs, including antibiotic agents.2,3 All of the five currently available oral antifungal agents have been reported to potentially interact with warfarin, although the degree of risk is unclear.2,3,6-8 Griseofulvin may decrease the anticoagulant activity of warfarin. Itraconazole, ketoconazole, and fluconazole may increase the anticoagulant effect of warfarin; careful monitoring of anticoagulation parameters (ie, international normalized ratio, prothrombin time) is recommended. Premarketing and pharmacosurveillance studies suggested no interaction of terbinafine with warfarin.10 Literature review indicates two interaction reports with contradictory effects.3,7,8 As with the use of other oral antifungal agents in patients taking warfarin, monitoring of anticoagulation parameters is suggested. Management Suggestions. Based on the current medication history, terbinafine may be used safely in patients treated with digoxin and quinidine. Due to shared hepatic metabolism, interaction of terbinafine with sertraline is unlikely. Itraconazole is contraindicated in patients utilizing quinidine and may also cause significant increases in serum digoxin levels. Fluconazole is a potential option in this case for treatment of dermatophyte onychomycosis, however, a longer duration of therapy is required. Due to limited efficacy for onychomycosis, ketoconazole and griseofulvin are not considered to be viable therapeutic options. Although the risk for significant interaction appears to be less than with itraconazole, ketoconazole may alter serum levels of quinidine and digoxin. Case # 3 History. A 32-year-old Fillipino male presented with multiple hypopigmented patches located diffusely on the lateral neck, chest, back, shoulders and upper arms. The eruption has been present for 1 year and has progressively worsened. Fine scaling is noted, which is accentuated by light scratching of affected skin with a tongue blade (“positive scratch sign”). The clinical diagnosis of tinea versicolor is supported by a potassium hydroxide preparation demonstrating multiple short hyphae with clusters of round spores (“spaghetti and meatballs” pattern). Medication History. Current daily systemic medications used by the patient are lansoprazole (Prevacid) and intermittent use of calcium carbonate (Tums) as needed for gastroesophageal reflux disease (GERD) and loratadine (Claritin) for seasonal rhinitis. The clinician is interested in prescribing oral antifungal treatment for tinea versicolor in this patient due to extensive body surface area involvement. What potentially significant drug interactions may be identified prior to initiation of therapy? Drug Interaction Case Summary. This case illustrates potentially significant drug interactions between specific oral antifungal agents and medications or ingestants that reduce gastric acidity. Proton Pump Inhibitors / H-2 Blocker Antihistamines / Antacids. Dissolution and subsequent gastrointestinal absorption of itraconazole from its capsule formulation and ketoconazole from its tablet formulation require gastric acidity. Proton pump inhibitors such as omeprazole (Prilosec), lansoprazole (Prevacid), rabeprazole (Aciphex), pantoprazole (Protonix), esomeprazole (Nexium), H-2 blocker antihistamines, such as cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), and antacids (calcium carbonate, aluminum hydroxide, magnesium hydroxide) reduce gastric acidity resulting in decreased absorption of itraconazole or ketoconazole from the intestinal tract.1-3,6-8 Although concurrent ingestion of a cola beverage has been suggested as a method to enhance gastric acidity and overcome the effect of the interaction, there is no evidence that ingestion of a cola beverage or citrus juice along with itraconazole or ketoconazole provides enough gastric acidity to counteract the marked increase in alkalinity caused by a proton pump inhibitor.2 Interestingly, grapefruit juice has been shown to decrease the absorption and bioavailability of itraconazole.14 Gastrointestinal absorption of terbinafine and fluconazole are not significantly impacted by gastric pH or contents.2-8 Although it has been noted that the absorption of griseofulvin may be enhanced by ingestion with a fatty meal, the clinical significance of this suggestion is not clear. Management Suggestions. Of the currently available oral antifungal agents, ketoconazole, fluconazole and itraconazole have demonstrated efficacy for the treatment of tinea versicolor. Both ketoconazole (400 mg) and fluconazole (300 mg to 400 mg) may be used as single dose therapy for tinea versicolor; efficacy may be enhanced by repeating single dose treatment one week later. In this case, due to use by the patient of a proton pump inhibitor (lansoprazole) and antacid (calcium carbonate), the effectiveness of either ketoconazole or itraconazole is likely to be diminished. Fluconazole absorption is not impacted by reduced gastric acidity, favoring the use of this agent for oral treatment of tinea versicolor in this case. Points to Keep in Mind • A complete medication history is very important prior to choosing an oral antifungal agent in order to proactively identify potentially deleterious drug interactions. • In almost all cases, a viable and safe oral antifungal alternative exists, which allows for treatment of the patient without exposure to the risk of a harmful drug interaction. • Due to differences in absorption and metabolism, terbinafine can be safely used in the majority of clinical situations where a potential interaction with an azole antifungal agent is identified. • Despite the theoretical potential for interactions via CYP 2D6 inhibition, there has been a conspicuous paucity of drug interactions reported in association with terbinafine use based on pharmacosurveillance and literature review. • Review of published literature supports that clinically significant interactions associated with terbinafine use are rare.
The subject of drug-drug interactions has continued to expand in terms of understanding mechanisms, predicting potentially significant interactions based on advances in evaluating metabolic pathways and enhanced recognition of the importance of pharmacogenomics.1-3 Within dermatology, the clinical significance of drug interactions has been made evident by the withdrawal from the marketplace of the “nonsedating” antihistamines, terfenadine (Seldane) and astemizole (Hismanal), due to the increased propensity for prolongation of the QTc interval with subsequent ventricular arrhythmia when these agents were coadministered with erythromycin, ketoconazole (Nizoral) or itraconazole (Sporanox).3-8 This “hallmark interaction” is directly related to inhibition of the cytochrome (CYP) 3A4 metabolic pathway by several macrolide antibiotics and azole antifungal agents. Due to the predominant role of CYP 3A4 in the metabolism of approximately half of drugs currently available on the market, the potential for widespread impact related to CYP 3A4 inhibition, as well as other less predominant CYP metabolic isoenzymes, has received significant notoriety. The importance of drug interactions has also been respected by industry. In the United States, between 1987 and 1991, 98 drugs received approval for use with 32 inclusive of drug interaction studies. Between 1992 and 1997, although the number of approved drugs increased by two-fold, the number of associated drug interaction studies increased by slightly more than three-fold. Several warnings and contraindications have emerged related to drug interactions including recommendations to avoid coadministration of some macrolide antibiotics or azole antifungal agents with HMG-CoA reductase inhibitors (cholesterol-lowering agents), some benzodiazepines and some cardiac drugs, including digoxin (Lanoxin) and quinidine.1-9 Considering the widespread prevalence of superficial mycotic infections and associated oral antifungal use, it is rational to periodically revisit the subject of potential drug interactions and oral antifungal agents. Due to variations in metabolic pathways, significant differences in the potential for interactions have been established when comparing griseofulvin (GrisPEG, Grifulvin V), terbinafine (Lamisil), ketoconazole (Nizoral) and the triazoles, itraconazole (Sporanox) and fluconazole (Diflucan). Overall, as compared to other oral antifungal agents, terbinafine is associated with the most favorable safety profile with regard to clinically significant drug interactions.2-8,10 Through the use of illustrative case studies encountered in clinical practice, this article provides an overview and update on potential drug interactions related to the selection of specific oral antifungal agents. Emphasis will be placed on supportive data, clinical significance and management suggestions for the clinician when selecting oral antifungal therapy for onychomycosis and other superficial mycotic infections. Major Drug Interaction Mechanisms The majority of clinically significant drug interactions involve either alterations in gastrointestinal absorption or hepatic metabolism. Clinical examples are used to illustrate underlying drug interaction mechanisms. Absorption. In cases involving gastrointestinal absorption, interaction occurs when absorption of itraconazole (capsules) or ketoconazole (tablets) is impaired by concurrent administration of a second drug or compound that decreases gastric acidity.1-3,5-8 Decreased gastric acidity may be caused by ingestion of antacids, H-2 blocker antihistamines such as cimetidine (Tagamet) and ranitidine (Zantac), proton pump inhibitors such as omeprazole (Prilosec), rabeprazole (Aciphex), pantoprazole (Protonix), esomeprazole (Nexium) and lansoprazole (Prevacid) and oral didanosine (Videx). Metabolism. Metabolic interactions occur through either enzyme inhibition or enzyme induction (see figure above). Enzyme inhibition occurs when the hepatic metabolism of one drug is decreased by a second drug that the patient is ingesting.2,3 The most common hepatic enzyme associated with drug metabolism is cytochrome 3A4 (CYP 3A4). Other enzymes with lesser degrees of involvement, but still with important roles in the metabolism of specific drugs include CYP 2C9, CYP 2D6 and CYP 1A2. A major example of enzyme inhibition is the decreased metabolism of certain HMG CoA reductase inhibitors such as simvastatin (Zocor), lovostatin (Mevacor) and atorvastatin (Lipitor) which are cholesterol-lowering agents metabolized by CYP 3A4, caused by itraconazole, an inhibitor of CYP 3A4.1-3,7-9 The inhibition of CYP 3A4 by itraconazole results in increased serum levels of simvastatin, lovastatin or atorvastatin, ultimately placing the patient at increased risk of severe myopathy and rhabodomyolysis (see figure 2 on below). Other inhibitors of CYP 3A4, such as ketoconazole, may also produce the same interaction effect. Another example of enzyme inhibition is decreased metabolism of phenytoin (Dilantin), a drug metabolized by CYP 2C9, caused by fluconazole, an inhibitor of CYP 2C9.2,3,7,8 As a result, significantly increased phenytoin serum levels have been documented during concomitant administration of fluconazole, leading to clinically evident phenytoin toxicity. Enzyme induction occurs when an administered drug increases the metabolic activity of an enzyme responsible for the metabolism of another drug.2,3 A clinically relevant example is the coadministration of phenytoin (Dilantin) and itraconazole.2,3,6-8,11 Phenytoin increases the hepatic metabolism of itraconazole resulting in its accelerated clearance. The possible outcome of this interaction is inadequate antifungal response to itraconazole as less is systemically available. Treatment failure related to induction of itraconazole metabolism by phenytoin has been reported. With this background information in mind, consider the following cases of drug interactions with antifungal agents and how they might have been avoided. Case #1 History. A 53-year-old Hispanic male presented with a 6-year history of onychomycosis of both large toenails and multiple smaller toenails. Fungal culture obtained from the right large toenail confirms the presence of Trichophyton rubrum. Bilateral plantar tinea pedis is also noted on examination. The patient has a history of diabetes, hypertension and anxiety with difficulty sleeping. Past medical history and recent evaluation within the last month of a serum chemistry panel are otherwise unremarkable. The patient is highly motivated regarding his interest in treating onychomycosis and is very embarrassed by the condition. Medication History. Current daily systemic medications used by the patient are hydrochlorothiazide and nifedipine (Procardia) for hypertension, metformin (Glucophage) and glipizide (Glucotrol) for diabetes and alprazolam (Xanax) as a sedative-hypnotic agent. The clinician is considering oral antifungal treatment in combination with large toenail debridement. What potentially significant drug interactions may be identified prior to initiation of therapy? Drug Interaction Case Summary. This case illustrates potentially significant drug interactions between certain oral antifungal agents and calcium channel blockers, oral hypoglycemic agents and benzodiazepine sedative-hypnotic agents. Calcium Channel Blockers. As with many other calcium channel blockers, nifedipine is metabolized in the liver by CYP 3A4. Clearance of nifedipine is decreased by itraconazole or ketoconazole due to enzyme inhibition of CYP 3A4.1-3,7-8,12-14 Other calcium channel blockers that may be affected in a similar fashion are felodipine (Plendil), isradipine (DynacCirc) and verapamil (Isoptin, Verelan, Covera) (see figure 3 below). Consequences of the interaction between itraconazole or ketoconazole with nifedipine (or other similarly metabolized calcium channel blockers) include marked peripheral edema and decrease in blood pressure. Cautious concurrent use or avoidance of coadministration with itraconazole or ketoconazole are recommended. Due to inhibition of CYP 3A4, fluconazole, especially at higher doses (>200 mg daily), may potentially cause the same interaction effect as itraconazole and ketoconazole.6-8 As terbinafine does not affect CYP 3A4, interaction with nifedipine or other similarly metabolized calcium channel blockers is not expected. There are no reports of interaction of terbinafine with calcium channel blockers.2,3,7 In vivo studies support the absence of interaction between terbinafine and nifedipine.10 There are no apparent interactions between griseofulvin and calcium channel blockers. Hypoglycemic Agents. Interaction between terbinafine and any of the currently available agents used to treat diabetes, including insulin and oral hypoglycemic agents, have not been reported.4-8,10,15 Drug interactions with terbinafine are not anticipated after consideration of what is known regarding involved pathways of metabolism. Based on routes of metabolism and available data, itraconazole and ketoconazole do not appear to interact with insulin, metformin (Glucophage), oral sulfonylureas such as glyburide (DiaBeta, Glynase, Micronase) and glipizide (Glucotrol), rosiglitazone (Avandia) and nateglinide (Starlix).1-3,6-8,15 As repaglinide (Prandin) and pioglitazone (Actos) are metabolized by CYP 3A4, potential for hypoglycemia due to interaction with itraconazole and ketoconazole exists.2,3,6-8,15 Fluconazole, especially at higher doses, is also capable of inhibiting CYP 3A4 with potential to produce interactions similar to those associated with itraconazole and ketoconazole.2,3,6-8,15 Interaction between fluconazole and several oral hypoglycemic agents, such as sulfonylureas (ie, glipizide, glyburide), rosiglitazone and netaglinide may occur due to inhibition of the metabolic enzyme CYP 2C9.2,3,6-8,15 The potential clinical outcome of these agents interacting with fluconazole is enhanced risk of hypoglycemia. There are no apparent interactions between hypoglycemic agents and griseofulvin.2,3 Sedative-Hypnotic Agents. Patients treated with benzodiazepine sedative-hypnotic agents metabolized by CYP 3A4, specifically triazolam (Halcion), midazolam (Versed) and alprazolam (Xanax), should not co-ingest itraconazole, ketoconazole, and probably fluconazole at doses >200 mg daily.2,3,6-8,15 The CYP 3A4 inhibition associated with itraconazole or ketoconazole results in elevated serum levels of the aforementioned benzodiazepines, ultimately enhancing sedation and somnolence. Similar interaction does not occur with coadministration of terbinafine due to absence of CYP 3A4 inhibition.2-4,6-8,10,15 Griseofulvin does not appear to interact with benzodiazepine sedative-hypnotic agents.2,3 Management Suggestions. From the perspective of potential drug interaction risk, and based on the confirmed diagnosis of dermatophyte onychomycosis, oral terbinafine is the optimal choice for treatment in this patient.2,3,6,7,16 Although griseofulvin is approved for the treatment of onychomycosis, it would not be considered to be a viable option due to its poor efficacy and the availability of newer more effective oral antifungal agents. The combined use of oral antifungal therapy and debridement is likely to optimize the response to therapy by reducing physical factors that promote treatment failure, such as extensive onycholysis, lateral plate involvement, marked nail plate thickening and dermatophyoma.17,18 Case #2 History: A 52-year-old Caucasian female presented with unilateral right plantar tinea pedis and onychomycosis of multiple toenails, including both large toenails. Independently performed potassium hydroxide preparations from the right large toenail and affected plantar surface demonstrate multiple long branched hyphae. Fungal culture from the right large toenail identified Trichophyton rubrum as the causative pathogen. Baseline liver function testing and complete blood cell count are unremarkable. Intermittent pruritis of the right sole is noted. The patient also reports a sense of “pressure” and discomfort of her toenails when wearing certain shoes. Medication History. Current daily systemic medications used by the patient are digoxin and quinidine for atrial fibrillation and sertraline for clinical depression. The patient also mentions that her internist may be starting her on warfarin (Coumadin) in the near future due to atrial fibrillation. The clinician is considering oral antifungal treatment. What potentially significant drug interactions may be identified prior to initiation of therapy? Drug Interaction Case Summary. This case illustrates potentially significant drug interactions between some oral antifungal agents and digoxin, quinidine and certain antidepressant drugs. Consideration is also given to potential interactions with warfarin should this medication be started based on the patient history. Digoxin. Concurrent administration of itraconazole with digoxin may cause a significant increase in digoxin serum levels.1-3,19,20 Documented cases of digoxin toxicity have been reported in association with itraconazole coadministration. The literature also reports rare cases of increased serum levels of digoxin related to concurrent use of ketoconazole.7 The development of digoxin toxicity after concurrent use of itraconazole may be related to inhibition of p-glycoprotein, a membrane transport protein found in intestinal mucosa and renal tubules.7,15 It has been suggested that inhibition of p-glycoprotein by itraconazole impairs the renal pump mechanism responsible for tubular secretion of digoxin into the urine. Terbinafine, fluconazole and griseofulvin can be safely administered to patients utilizing digoxin.4-8,10,15 Quinidine. Concurrent administration of itraconazole is contraindicated in patients taking quinidine; itraconazole increases plasma concentrations of quinidine with cases of toxicity reported.1-3,21 The clinical onset of the interaction often manifests as tinnitus, and serious cardiovascular reactions may occur.1 Transient increase in quinidine plasma levels has also been reported with concurrent use of ketoconazole.22 Interaction with quinidine has not been reported with terbinafine and is not anticipated based on current understanding of metabolic pathways.4-8,10,15 Interaction between griseofulvin or fluconazole with quinidine also does not appear to occur.2,3 Antidepressants. The hepatic metabolism of the antidepressant agents, including tricyclic derivatives and selective serotonin reuptake inhibitors (SSRIs), is dependent on the specific agent prescribed.1-3,15,23 Older antidepressants, such as desipramine (Norpramin), nortriptyline (Aventyl), imipramine and amitriptyline are metabolized by CYP 2D6. Of the SSRIs, fluoxetine (Prozac) is metabolized by CYP 2D6 and paroxetine (Paxil) is metabolized by CYP 2D6 and CYP 3A4; both are also potent inhibitors of CYP 2D6.23 Many SSRIs share their metabolism among multiple CYP enzymatic pathways.23 For example, sertraline (Zoloft) is metabolized by CYP 3A4, CYP 2D6 and CYP 2C19. Shared enzymatic metabolism allows for potential shunting of the antidepressant drug to a different “available metabolic enzyme” should one of the enzymes responsible for the metabolism of the antidepressant be inhibited by another co-ingested drug. Of the available SSRIs, sertraline (Zoloft) and escitalopram (Lexapro) share their metabolism among three metabolic enzymes (CYP 3A4, CYP 2D6, CYP 2C19) and are reported to have a low potential for drug interactions.23 Terbinafine is an inhibitor of CYP 2D6.1,7,15 Examples of drugs that are metabolized by CYP 2D6 include older antidepressants (ie. amitriptyline, desipramine, nortriptyline), the SSRIs fluoxetine (Prozac) and paroxetine (Paxil), and some older beta-blockers such as metoprolol (Lopressor) and propranolol (Inderal).7,15,23 As a result, cautious coadministration with terbinafine is suggested.1,7,15 Nortriptyline toxicity associated with terbinafine coadministration has been reported and interaction has been suggested with desipramine and imipramine.2,7,8 Itraconazole, ketoconazole and fluconazole (at doses > 200 mg daily) may inhibit the metabolism of the SSRI, citalopram (Celexa), potentially resulting in prolongation of central nervous system side effects.7 Warfarin.Warfarin (Coumadin), a commonly used anticoagulant, is potentially sensitive to interaction with many classes of drugs, including antibiotic agents.2,3 All of the five currently available oral antifungal agents have been reported to potentially interact with warfarin, although the degree of risk is unclear.2,3,6-8 Griseofulvin may decrease the anticoagulant activity of warfarin. Itraconazole, ketoconazole, and fluconazole may increase the anticoagulant effect of warfarin; careful monitoring of anticoagulation parameters (ie, international normalized ratio, prothrombin time) is recommended. Premarketing and pharmacosurveillance studies suggested no interaction of terbinafine with warfarin.10 Literature review indicates two interaction reports with contradictory effects.3,7,8 As with the use of other oral antifungal agents in patients taking warfarin, monitoring of anticoagulation parameters is suggested. Management Suggestions. Based on the current medication history, terbinafine may be used safely in patients treated with digoxin and quinidine. Due to shared hepatic metabolism, interaction of terbinafine with sertraline is unlikely. Itraconazole is contraindicated in patients utilizing quinidine and may also cause significant increases in serum digoxin levels. Fluconazole is a potential option in this case for treatment of dermatophyte onychomycosis, however, a longer duration of therapy is required. Due to limited efficacy for onychomycosis, ketoconazole and griseofulvin are not considered to be viable therapeutic options. Although the risk for significant interaction appears to be less than with itraconazole, ketoconazole may alter serum levels of quinidine and digoxin. Case # 3 History. A 32-year-old Fillipino male presented with multiple hypopigmented patches located diffusely on the lateral neck, chest, back, shoulders and upper arms. The eruption has been present for 1 year and has progressively worsened. Fine scaling is noted, which is accentuated by light scratching of affected skin with a tongue blade (“positive scratch sign”). The clinical diagnosis of tinea versicolor is supported by a potassium hydroxide preparation demonstrating multiple short hyphae with clusters of round spores (“spaghetti and meatballs” pattern). Medication History. Current daily systemic medications used by the patient are lansoprazole (Prevacid) and intermittent use of calcium carbonate (Tums) as needed for gastroesophageal reflux disease (GERD) and loratadine (Claritin) for seasonal rhinitis. The clinician is interested in prescribing oral antifungal treatment for tinea versicolor in this patient due to extensive body surface area involvement. What potentially significant drug interactions may be identified prior to initiation of therapy? Drug Interaction Case Summary. This case illustrates potentially significant drug interactions between specific oral antifungal agents and medications or ingestants that reduce gastric acidity. Proton Pump Inhibitors / H-2 Blocker Antihistamines / Antacids. Dissolution and subsequent gastrointestinal absorption of itraconazole from its capsule formulation and ketoconazole from its tablet formulation require gastric acidity. Proton pump inhibitors such as omeprazole (Prilosec), lansoprazole (Prevacid), rabeprazole (Aciphex), pantoprazole (Protonix), esomeprazole (Nexium), H-2 blocker antihistamines, such as cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), and antacids (calcium carbonate, aluminum hydroxide, magnesium hydroxide) reduce gastric acidity resulting in decreased absorption of itraconazole or ketoconazole from the intestinal tract.1-3,6-8 Although concurrent ingestion of a cola beverage has been suggested as a method to enhance gastric acidity and overcome the effect of the interaction, there is no evidence that ingestion of a cola beverage or citrus juice along with itraconazole or ketoconazole provides enough gastric acidity to counteract the marked increase in alkalinity caused by a proton pump inhibitor.2 Interestingly, grapefruit juice has been shown to decrease the absorption and bioavailability of itraconazole.14 Gastrointestinal absorption of terbinafine and fluconazole are not significantly impacted by gastric pH or contents.2-8 Although it has been noted that the absorption of griseofulvin may be enhanced by ingestion with a fatty meal, the clinical significance of this suggestion is not clear. Management Suggestions. Of the currently available oral antifungal agents, ketoconazole, fluconazole and itraconazole have demonstrated efficacy for the treatment of tinea versicolor. Both ketoconazole (400 mg) and fluconazole (300 mg to 400 mg) may be used as single dose therapy for tinea versicolor; efficacy may be enhanced by repeating single dose treatment one week later. In this case, due to use by the patient of a proton pump inhibitor (lansoprazole) and antacid (calcium carbonate), the effectiveness of either ketoconazole or itraconazole is likely to be diminished. Fluconazole absorption is not impacted by reduced gastric acidity, favoring the use of this agent for oral treatment of tinea versicolor in this case. Points to Keep in Mind • A complete medication history is very important prior to choosing an oral antifungal agent in order to proactively identify potentially deleterious drug interactions. • In almost all cases, a viable and safe oral antifungal alternative exists, which allows for treatment of the patient without exposure to the risk of a harmful drug interaction. • Due to differences in absorption and metabolism, terbinafine can be safely used in the majority of clinical situations where a potential interaction with an azole antifungal agent is identified. • Despite the theoretical potential for interactions via CYP 2D6 inhibition, there has been a conspicuous paucity of drug interactions reported in association with terbinafine use based on pharmacosurveillance and literature review. • Review of published literature supports that clinically significant interactions associated with terbinafine use are rare.
