!U'm~~~~!W'!'!;=7'7~~-~~· ~---~-"-_:_:"' _·_ ::.···
`
`-
`
`-
`
`--- .. -·
`
`-.. -·---- ._._- ----
`
`_ _:: _____ ::·.~
`
`----- - - - - - - - - - - - - - - · - - · - - - - - - - - · - - - - - - ------~
`
`~herapeutics and clinical risk management
`enera1l Collection
`·
`W1 TH171
`v.1,no.4
`2005
`
`1rHIE1RAIPEU1rllCS AND
`
`CJLJNKCAIL RHSK MANAGIEMJENT
`
`VOLUME I NUMBER 4
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`2005
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`PROPERTY OF THE
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`THERAPEUTICS AND CLINICAL RISK MANAGEMENT
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`
`DOVE MEDICAL PRESS
`
`Editor
`Garry Walsh
`garry.walsh@dovepress.com
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`Publisher
`Tim Hill
`publisher@doveprcss.com
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`
`CONTENTS
`Volume I • Number 4 • 2005
`
`EDITORIAL FOREWORD
`Gany Walsh
`
`REVIEWS
`
`Management of oxaliplatin-induced peripheral neuropathy
`M WasifSa(f,' John Reardon
`
`Duloxetine in the treatment of stress urinary incontinence
`Wolfgang H Jost, Parvaneh Marsalek
`
`Management of persistent allergic rhinitis: evidence-based treatment
`with levocetirizine
`Joaquim Mullol, Claus Bachert, Jean Bousquet
`
`Asthma exacerbations: prevention is better than cure
`Dominick E Shaw, Ruth H Green, Peter Bradding
`
`Endogenous opioid analgesia in peripheral tissues and the clinical
`implications for pain control
`Daniel Kapitzke, Irina Vette1; Peter J Cabot
`
`Safety and tolerability of oral antifungal agents in the treatment of
`fungal nail disease: a proven reality
`Bani Elewski, Amir Tavaklwl
`
`OPINION
`
`Antimicrobial biocides in the healthcare environment: efficacy,
`usage, policies, and perceived problems
`Jean- Yves Maillard
`
`ORIGINAL RESEARCH
`
`Changing personnel behavior to promote quality care practices in
`an intensive care unit
`Dominic Coope1; Keith Farnze1y, Martin Johnson, Christine Hwpe1;
`Fiona L Clarke, Philip Holton, Susan Wilson, Paul Rayson, Hugh Bence
`
`Prescribing errors and other problems reported by community pharmacists
`Yen-Fu Chen, Karen E Neil, Anthony J Avery, Michael E Dewey,
`Christine Johnson
`
`247
`
`249
`
`259
`
`265
`
`273
`
`279
`
`299
`
`307
`
`321
`
`333
`
`This materia I was copied
`at the NLM and may be
`~ubject US Copyright Laws
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2098 - 3/12
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`

`
`REVIEW
`
`Safety and tolerability of oral antifungal agents
`in the treatment of fungal nail disease: a proven
`reality
`
`Boni Elewski 1
`Amir Tavakkol 2
`
`'University of Birmingham in
`Alabama, Birmingham, AL, USA;
`2Novartis Pharmaceuticals
`Corporation, East Hanover, NJ, USA
`
`Correspondence: Amir Tavakkol
`US Clinical Development & Medical
`Affairs, Novartis Pharmaceuticals
`Corporation, Building EH70 1-403, East
`Hanover, NJ 07936-1080, USA
`Tel +I 862 778 3554
`Fax+ I 973 781 8430
`Email amir.tavakkol@novartis.com
`
`Abstract: Clinicians now have five oral antifungal therapeutic agents to choose from when
`assessing the risk-benefits associated with a particular treatment for onychomycosis (OM):
`griseofulvin, itraconazole, terbinafine, ketoconazole, and fluconazole. Only the first three are
`approved by the FDA for this indication. Griseofulvin is fungistatic and inhibits nucleic acid
`synthesis, arresting cell division at metaphase, and impairing fungal wall synthesis. Due to its
`low cure rates and high relapse, it is rarely used for treatment of onychomycosis. Itraconazole
`is a broad spectrum drug and is effective against dermatophytes, candida, and some non(cid:173)
`dennatophytic molds. Itraconazole works by inhibiting ergosterol synthesis via cytochrome
`P-450 (CYP450)-dependent demethylation step. This azoic antifungal agent is metabolized
`in the liver by cytochrome P-450 3A4 (CYP3A4), and therefore has the potential to interact
`with drugs metabolized through this pathway. Terbinafine, an allylamine, is fungicidal and
`remains at therapeutic levels in keratinized tissues, but with a short plasma half-life of 36
`hours. Terbinafine has the advantage in that it does not inhibit CYP3A4 isoenzyme during its
`metabolism where some 50% of all commonly prescribed drugs are metabolized. The only
`potentially significant drug interaction with terbinafine is with the cytochrome P-450 2D6
`(CYP2D6) isoenzyme. The lack of widely reported or published clinically relevant drug
`interactions, and extensive experience from a large prospective, surveillance study conducted
`in "real world" setting with no patient exclusions, suggest that this is not a major issue. The
`high cure rates ofterbinafine against dermatophytes, as shown in many studies since its launch
`in the I 990s, together with lack of clinically significant drug interactions and well established
`safety record, indicate the use of continuous oral terbinafine as the top choice for the treatment
`of onychomycosis in most patients.
`Keywords: antifungal, safety, drug interactions, onychomycosis
`
`Introduction
`Onychomycosis is relatively common, with a prevalence of6.5%-6.8% in the general
`population in Canada (Gupta eta! 1997), 8.5% in the general male population in
`Finland (Heikkila and Stubb 1995), and up to 18.5% in the US (Ghannoum eta!
`2004). Some studies suggest that as much as 48% of the population may be atTected
`by the age of70 (Drake et al1998; Scher 1999).
`Balancing patient safety with therapeutic benefit is a prime directive when treating
`onychomycosis. There are several oral antifungal agents to choose from when
`assessing the risk-benefits associated with a particular treatment for onychomycosis;
`griseofulvin, ketoconazole, fluconazole, itraconazole, and terbinafine, although only
`three have been approved by the Food and Dmg Administration (FDA). Fluconazole,
`an azole much like itraconazole, can be used, but it is not approved for onychomycosis.
`Ketoconazole is rarely used due to poor tolerability, low efficacy, and the availability
`
`Therapeutics and Clinical Risk Management 2005: I (4) 299-306
`© 2005 Dove Medical Press Limited. All rights reserved
`
`299
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2098 - 4/12
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`
`Elewski and Tavakkol
`
`Allylamines -Squalene epoxidase
`
`Squalene
`
`2,3-oxidosqualcnc
`
`Accumulation
`of squalene is
`fungicidal
`
`1
`
`~.__A_z_o_le_s _ _jl __. Lanosterol
`/Cl4-a-
`
`dcmethylase
`
`\
`
`Ergosterol
`
`Cholesterol
`
`Deficiency of ergosterol is
`fungistatic
`
`Figure I Mode of action of allylamine and azole antifungal agents.
`
`of new antifungal agents. In this review, we compare the
`mode of action, pharmacokinetics, and potential for drug
`interactions for various oral antifungal agents. However,
`the focus is on the mode of action, pharmokinetics,
`tolerability, and safety of the three FDA approved oral drugs
`griseofulvin, itraconazole, and terbinafine. An increased
`understanding of the metabolism of all the oral antifungal
`agents allows a better appreciation of potential drug-drug
`interactions, impact on safety, and appropriate choice of
`therapy. This is particularly relevant as the number of
`patients on polypharmacy is increasing due to an aging
`population and increased comorbidities. Moreover, the
`widespread use of cholesterol-lowering statins and
`antihypertensive drugs in otherwise healthy individuals may
`put many patients at risk for drug interactions.
`
`Table I Characteristics of oral antifungal agents
`
`Allylamines
`(terbinafine)
`
`Metabolic
`effect
`
`Route of
`incorporation
`into nails
`
`Accumulation of
`Via diffusion from
`squalene (fungicidal);
`nail plate and nail
`depletion of ergosterol matrix
`(fungistatic)
`
`Triazoles (itraconazole,
`fluconazole)
`
`Depletion of ergosterol Via diffusion from nail
`(fungistatic)
`bed and nail matrix
`
`Pharmacokinetics
`Mode of action
`Griseofulvin acts by disrupting the fungal mitotic spindle,
`inhibiting cell wall synthesis, whereas azoles act to block
`ergosterol synthesis, required for assembly of the fungal
`cell wall, by inhibiting C 14a-demethylase, a member of
`the cytochrome P-450 (CYP450) family. Terbinafine works
`much like azoles, with the exception that it blocks ergosterol
`synthesis further upstream by inhibiting squalene epoxidase.
`This results in cells becoming deficient in ergosterol and
`causes accumulation oftoxic squalene, which, in turn, results
`in fungal death. This activity makes terbinafine a fungicidal
`drug compared with azoles which are fungistatic. This step
`does not involve CYP450 enzymes, therefore drug inter(cid:173)
`actions are not typically an issue (Figure 1 ).
`
`Absorption
`Griseofulvin is poorly absorbed, unless micronized, or
`coated with polyethylene glycol, or given with fatty meals
`(Lin et a! 1982). Its absorption decreases with repeated
`administration, possibly due to damage to the mucosal wall
`by unabsorbed griseofulvin (Debruyne and Coquerel200 1 ).
`This agent has therefore largely been superceded by
`compounds with better pharmacokinetics. The bio(cid:173)
`availability of the most effective azole antifungal,
`itraconazole, is increased by coadministration of food, and
`decreased in the presence of agents that reduce gastric
`acidity, eg, antacids, H2 blocker antihistamines, proton
`pump inhibitors, and the anti-HIV agent, oral didanosine.
`The efficacy ofitraconazole may therefore be compromised
`by drug coadministration. The bioavailability ofterbinafine
`is good, with 70%-80% of the ingested dose being absorbed,
`
`Oral
`absorption
`
`Good absorption
`unaffected by food or
`drug coadministration
`
`Spectrum
`of activity
`
`Broad
`
`Absorption improved if Broad
`administered with food;
`absorption decreased if
`coadministered with
`agents that decrease
`gastric acidity
`
`Efficacy
`
`Very high
`
`lntraconazole
`more effective
`than fluconazole
`
`Antibiotics
`(griseofulvin)
`
`Disruption of fungal
`mitotic spindle
`(fungicidal)
`
`Deposited in keratin
`matrix precursor cells
`
`Poorly absorbed but
`improved if
`administered with food
`
`Narrow
`
`Low
`
`300
`
`This material wascopied Therapeutics and Clinical Risk Management 2005: I (4)
`at the N LM and may b,e
`~ubject US Copyright Laws
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2098 - 5/12
`
`

`
`Elewski and Tavakkol
`
`Allylaminos -Squalene cpoxidasc
`
`Squalene
`
`Accumulation
`of squalene is
`fungicidal
`
`2,3-oxidosqualenc
`
`1
`
`c___A_z_o_Ic_s ----'' __. Lanosterol
`
`/CI4-a-
`
`domethylase
`
`\
`
`Ergosterol
`
`Cholesterol
`
`Deficiency of ergosterol is
`fungistatic
`
`Figure I Mode of action of allylamine and azole antifungal agents.
`
`of new antifungal agents. In this review, we compare the
`mode of action, pharmacokinetics, and potential for drug
`interactions for various oral antifungal agents. However,
`the focus is on the mode of action, pharmokinetics,
`tolerability, and safety of the three FDA approved oral dmgs
`griseofulvin, itraconazole, and terbinafine. An increased
`understanding of the metabolism of all the oral antifungal
`agents allows a better appreciation of potential dmg-dmg
`interactions, impact on safety, and appropriate choice of
`therapy. This is particularly relevant as the number of
`patients on polypharmacy is increasing due to an aging
`population and increased comorbidities. Moreover, the
`widespread use of cholesterol-lowering statins and
`antihypertensive drugs in otherwise healthy individuals may
`put many patients at risk for dmg interactions.
`
`Table I Characteristics of oral antifungal agents
`
`Allylamines
`(terbinafine)
`
`Metabolic
`effect
`
`Route of
`incorporation
`into nails
`
`Accumulation of
`Via diffusion from
`squalene (fungicidal);
`nail plate and nail
`depletion of ergosterol matrix
`(fungistatic)
`
`Triazoles (itraconazole,
`fluconazole)
`
`Depletion of ergosterol Via diffusion from nail
`(fungistatic)
`bed and nail matrix
`
`Pharmacokinetics
`Mode of action
`Griseofulvin acts by disrupting the fungal mitotic spindle,
`inhibiting cell wall synthesis, whereas azoles act to block
`ergosterol synthesis, required for assembly of the fungal
`cell wall, by inhibiting C14cx-demethylase, a member of
`the cytochrome P-450 (CYP450) family. Terbinafine works
`much like azoles, with the exception that it blocks ergosterol
`synthesis further upstream by inhibiting squalene epoxidase.
`This results in cells becoming deficient in ergosterol and
`causes accumulation of toxic squalene, which, in turn, results
`in fungal death. This activity makes terbinafine a fungicidal
`drug compared with azoles which are fungistatic. This step
`does not involve CYP450 enzymes, therefore drug inter(cid:173)
`actions are not typically an issue (Figure I).
`
`Absorption
`Griseofulvin is poorly absorbed, unless micronized, or
`coated with polyethylene glycol, or given with fatty meals
`(Lin et a! 1982). Its absorption decreases with repeated
`administration, possibly due to damage to the mucosal wall
`by unabsorbed griseofulvin (Debruyne and Coquere\200 1 ).
`This agent has therefore largely been superceded by
`compounds with better pharmacokinetics. The bio(cid:173)
`availability of the most effective azoic antifungal,
`itraconazole, is increased by coadministration of food, and
`decreased in the presence of agents that reduce gastric
`acidity, eg, antacids, H2 blocker antihistamines, proton
`pump inhibitors, and the anti-I-IIV agent, oral didanosine.
`The efficacy ofitraconazole may therefore be compromised
`by dmg coadministration. The bioavailability ofterbinafine
`is good, with 70%-80% of the ingested dose being absorbed,
`
`Oral
`absorption
`
`Good absorption
`unaffected by food or
`drug coadministration
`
`Spectrum
`of activity
`
`Broad
`
`Absorption improved if Broad
`administered with food;
`absorption decreased if
`coadministered with
`agents that decrease
`gastric acidity
`
`Efficacy
`
`Very high
`
`lntraconazole
`more effective
`than fluconazole
`
`Antibiotics
`(griseofulvin)
`
`Disruption of fungal
`mitotic spindle
`(fungicidal)
`
`Deposited in keratin
`matrix precursor cells
`
`Poorly absorbed but
`improved if
`administered with food
`
`Narrow
`
`Low
`
`300
`
`This matenal was co~Hed
`atthe Ill LM and may be
`~ubject US Copyright Laws
`
`Therapeutics and Clinical Risk Management 2005: I (4)
`
`(
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2098 - 6/12
`
`

`
`and maximal plasma concentrations reached within 8 hours
`(Debruyne and Coqucrcl 2001 ). In aclclition, the absorption
`of terbinafine is unaffected by coadministration of food or
`agents that decrease gastric pH (Table 1 ).
`
`Concentrations in the nails and plasma
`Steady-state plasma levels of terbinafine are reached after
`10-14 days of treatment (De Doncker 1997), and
`itraconazole within 3 weeks (Leyden 1998). Both terbinaflne
`and itraconazole can be measured in the nail by 7 clays after
`the start of treatment, indicating that the route of entry into
`the nail plate is via the nail bed and the matrix (De Doncker
`1997), rather than solely by incorporation into keratin
`precursor cells, as seen with griseofulvin (Debruyne and
`Coquerel 2001 ). Terbinaflne reaches a steady state in the
`nail after I week of treatment, whereas itraconazole may
`require 3-12 weeks; these levels are then sustained in the
`nail plate for several months.
`The older generation of antifungal drugs (eg,
`griseofulvin) had to be used continuously until an entirely
`new nail plate was grown out, which could take up to a
`year. Griseofulvin has low affinity for keratins and drug
`levels decline rapidly with plasma levels (Meinhof 1993).
`Also, the drug persists for only a short duration, for
`approximately two weeks after treatment is discontinued.
`On the other hand, both itraconazole and terbinafine are
`keratinophilic and lipophilic, allowing them to be used for
`only a short period of time. Terbinafine can persist in the
`nails between 24 and 156 days (Debruyne and Coquerel
`2001 ); this allows terbinafine to be used effectively with
`relatively short courses of treatment. Plasma levels of
`terbinafine and itraconazole fall rapidly after the end of
`treatment, and the shorter treatment requirements with both
`drugs further minimize the I ikelihood of systemic side effects
`(Debruyne and Coquerel 200 I).
`
`Drug interactions
`Potential drug interactions that could reduce efficacy or drug
`toxicity must be taken into account when assessing the
`benefits and risks of the different oral antifungal agents.
`The most common hepatic enzyme involved in drug
`metabolism is cytochrome 3A4 (CYP3A4), which is
`required for the clearance of many different therapeutic
`agents.
`
`Griseofulvin
`Griseofulvin is not indicated for those with porphyria and
`hepatocellular failure. Also, patients on warfarin-type
`
`Oral antifungals in treatment of onychomycosis
`
`anticoagulants may need an adjustment of their anti(cid:173)
`coagulant dose (Develoux 2001 ). These may cause
`contraceptive failure especially of! ow dose pills. The major
`drug interactions noted are with phenobarbital, anti(cid:173)
`coagulants, and oral contraceptives.
`
`Azole antifungal agents
`These are metabolized in the liver by CYP3A4, and thus
`have the potential to interact with a long list of clinically
`important agents (Table 2). In particular, concurrent
`administration of azole antifungal agents and the following
`therapeutics are contraindicated: the antidysrhymic and
`antimalarial agent, quinidine; benzodiapines that undergo
`oxidative metabolism (including alprazolam, chlordia(cid:173)
`zepoxide, clonazepam, diazepam, estazolam, flurazepam,
`halazepam, quazepam, and triazolam); dofetilide; the
`antipsychotic, pimozide; and the statins, lovastatin,
`
`Table 2 Drug-drug interactions observed with azole
`antifungal drugs and CYP3A4 metabolizing agents
`
`Agent
`
`Indication
`
`Contraindicated
`Quinidine
`
`Antimalarial prophylaxis
`Arrythym ias
`
`Selected benzodiazapines
`
`Anxiety
`
`Pimozide
`
`Dofetilide
`
`Lovastatin,simvastatin,
`atovastatin
`
`Psychotic symptoms
`
`Arrythmias
`
`High cholesterol, heart disease
`
`Reported drug-drug interactions
`Hypertension
`Nifedipine
`
`Potential for drug-drug interactions
`Phenytoin
`Epilepsy
`
`Astemizole
`
`Midazolam
`
`Allergy
`
`Anxiety
`
`Oral contraceptives
`
`Contraception
`
`Reaglinide, pioglitzone
`
`Diabetes
`
`Cisapride
`
`Didanosine
`
`Ritonavir, saquinavir,
`Amprenavir
`
`Poor gastrointestinal motility
`
`HIV
`
`HIV
`
`Digoxin
`
`Congestive heart failure
`
`H2 receptor blockers
`
`Dyspepsia, stomach ulcer
`
`Isoniazid
`
`Rifampicin
`
`Tacrolimus
`
`Vincristine
`
`Warfarin
`
`Tuberculosis
`
`Tuberculosis
`
`Transplant recipients
`
`Solid tumors
`
`Anticoagulant
`
`Therapeutics and Clinical Risk Management 2005: I (4)
`
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`
`Elewski and Tavakkol
`
`simvastatin, and atovastatin (Katz 1999; Shapiro and Shear
`2002). Peripheral edema resulting from coadministration
`of itraconazole and calcium channel blocker, nifedipine, has
`also been reported (Tailor et al 1996).
`Other commonly used agents that are metabolized by
`CYP3A4 are warfarin, cisapride, and cyclosporine.
`Monitoring of serum levels, and dosage adjustment if
`indicated, should therefore be carried out during treatment
`with itraconazole (Shapiro and Shear 2002). Inhibition of
`CYP3A4 by itraconazole may increase warfarin's anti(cid:173)
`coagulant activity when administered together (Del Rosso
`2004). Similarly, some oral antidiabetic agents, including
`reaglinide and pioglitzone, are metabolized by CYP3A4,
`and concurrent administration may cause hypoglycemia (Del
`Rosso 2004). Any agent that induces CYP3A4, such as
`rifampicin and phenytoin, may increase the metabolism and
`therefore reduce the efficacy of itraconazole (Shear et al
`2000). Itraconazole levels should therefore be monitored in
`the event of coadministration with these agents.
`Azole antifungal agents have also been implicated in
`several hormone-dmg interactions (Venkatakrishnan et al
`2000). Patients with HIV infection undergoing treatment
`with highly active retroviral therapy are also likely to be
`receiving protease inhibitors such as ritonavir, saquinavir,
`or amprenavir that are potent inhibitors of CYP3A4. The
`effects ofketoconazole on amprenavir and saquinavir have
`been documented, and in the event of concurrent treatment
`with azole antifungal agents and protease inhibitors, dose
`reduction of the latter is required.
`
`Terbinafine (allylamine)
`In contrast with azole antifungal agents, the potential of
`terbinafine for drug interaction is generally considered low.
`Side effects associated with CYP3A4 are not observed.
`While terbinafine is metabolized extensively in the liver,
`this occurs via the action of various P-450 enzymes ( eg,
`CYP2C9, CYP1A2, CYP3A4, CYP2C8, and CYP2Cl9)
`(Vickers et al 1999). In addition, metabolism ofterbinafine
`requires less than 5% of the total liver CYP450 capacity
`(Vickers eta! 1999). Clinically significant drug interactions
`are limited to cimetidine and rifampicin, which decrease
`and increase the rate of terbinafine plasma clearance,
`respectively. The rate of clearance ofterbinafine is reduced
`by one-third in the presence of cimetidine, and doubles in
`the presence of rifampicin (Shear et a! 2000). Terbinafine
`inhibits the cytochrome family member, cytochrome P-450
`2D6 (CYP2D6) (Abdel-Rahman et a! 1999), and caution
`may be indicated when administering CYP2D6 substrates,
`
`such as nortriptyline, desipramine, perphenazine,
`metoprolol, encainide, and propafenone (Shear et al 2000;
`Debruyne and Coquerel2001). Concentrations ofwarfarin
`may be altered when coadministered with terbinafine (Shear
`et al2000).
`Terbinafine has a terminal half-life of 16-22 hours
`(Debmyne and Coquerel200 1 ). This is prolonged in patients
`with liver or kidney impairment, and patients with a
`creatinine clearance less than 50 mL/min or semm creatinine
`level of more than 300 f.tmol/L should receive half the normal
`dose. Terbinafine is primarily excreted (>70%) in the urine
`(see Table 3) (Balfour and Faulds 1992).
`
`Liver enzyme elevations
`Despite transient asymptomatic liver enzyme changes seen
`in clinical trials, terbinafine is not listed in the British
`National Formulary as a potential inducer ofliver enzymes.
`While some rare cases of hepatic failure have been reported
`among millions of adults treated for OM (van 't Wout et al
`1994; Boldewijn eta! 1996; Mall at et a! 1997; Shiloah et al
`1997; Vivas et all997; Gupta eta! 1998; Anania and Rabin
`2002), many of these patients were elderly and/or had
`preexisting liver diseases; therefore the causal relationship
`in many such cases has not been unequivocally determined.
`The risk of acute liver injury among 69 830 patients
`treated with oral antifungal agents was determined in a
`cohort study in which patients with prior liver disease were
`excluded (Garcia Rodriguez eta! 1999). The incidence rates
`of acute liver injury were found to be 134.1 per 100 000
`person-months; (95% confidence interval [CI]: 36.8, 488.0)
`for ketoconazole, 10.4 (95% CI: 2.9, 38.1) for itraconazole,
`and 2.5 (95% CI: 0.4, 13.9) for terbinafine. Ketoconazole
`was associated with the highest relative risk with 228.0 (95%
`CI: 33.9, 933.0), when compared with the risk among non(cid:173)
`users, followed by itraconazole (relative risk [RR] 17.7; 95%
`CI: 2.6, 72.6) and terbinafine (RR 4.2; 95% CI: 0.2, 24.9).
`This cohort study confirms the finding that most case reports
`ofliver injury after administration of oral antifungal agents
`occur with ketoconazole and itraconazole, and argues against
`using these agents as initial treatment for uncomplicated
`fungal infections. While the Rodriguez study (Garcia
`Rodriguez et all999) highlights low incidence ofliver injury
`for terbinafine, the higher rates of hepatotoxicity seen with
`azole antifungals has adversely affected the perception of
`terbinafine-induced liver enzyme elevation. The incidence
`ofterbinafine-related hepatobiliary dysfunction in the same
`studies are even lower at 1 in 45 000-120 000 patients (Hay
`1993). To put this finding further into context, the low risk
`
`302
`
`This material wasuJ~i'El:lerapeutics and Clinical Risk Management 2005: I (4)
`at the NLM and may bel!
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`
`Oral antifungals in treatment of onychomycosis
`
`of hepatic injury observed with terbinafine may be
`comparable to that seen with paracetamol, a medication
`widely used for pain relief, and perceived as safe by the
`general population (Friis and Andreasen 1992; Skorepova
`2004).
`The risk of hepatotoxicity with terbinafine should not
`be exaggerated, but should be taken into account, together
`with any other relevant factors. Patients with chronic or
`active liver diseases should not be treated with terbinafine,
`and baseline (pretreatment) liver transaminase testing is
`recommended. While some physicians continue to monitor
`liver enzymes during the course of terbinafine treatment,
`this is no longer recommended by the revised current
`labeling. After many years of experience with terbinafine,
`the FDA subsequently removed the LFT monitoring
`recommendation from the terbinafine label (MedWatch
`2001). This is in line with early safety data reported for
`1508 patients with toenail onychomycosis, with a mean age
`of 50 years, and extensive intractable disease, averaging over
`11 years in duration (Pollak and Billstein 1997). The
`
`incidence of hepatic or biliary disorders was 2.8%, of which
`the most common was abnormal liver function tests (2.4%).
`A recent study of 504 patients, in which patients with
`baseline abnormal liver enzymes were excluded, showed
`no clinically significant alanine aminotransferase (ALT) and
`aspartate aminotransferase (AST) elevation in plasma levels
`when tested 6 weeks into the treatment (250 mg/day) (Pollak
`et a! 2004 ). For griseofulvin, there is a clear dosage(cid:173)
`dependent association with hepatic toxicity, particularly in
`patients with prior liver damage (Skorepova 2004).
`
`Tolerability of oral antifungal
`(adverse drug events)
`Griseofulvin
`Availability of newer antifungal agents terbinafine and
`itraconazole suggest that griseofulvin is no longer the
`treatment of choice for dermatophyte onychomycosis. Side(cid:173)
`effects include nausea and rashes in 8%-15% of patients.
`In adults, it is contraindicated in pregnancy and the
`
`Table 3 Randomized trials with terbinafine 250 mg daily
`
`Trial
`design
`
`Subject
`(n)
`
`Treatment
`duration
`
`Terbinafine 250 mg daily vs placebo
`
`Terbinafine 250 mg daily vs itraconazole
`200mg daily
`
`Continuous terbinafine 250 mg daily
`vs intermittent itraconazole 400 mg daily
`(LION Study)
`
`Terbinafine vs griseofulvin
`
`Terbinafine 250 mg daily
`vs fluconazole ISO mg daily
`
`112
`Ill
`358
`
`195
`372
`
`496
`
`195
`
`180
`
`137
`
`3 months
`3 months
`3 and 6 months
`
`3 months
`3 months
`
`Terbinafine daily for
`3 or 4 months, or
`itraconazole I week
`in every 4, for 3 or
`4 months
`
`24 weeks terbinafine
`vs 24 weeks
`griseofulvin
`12 weeks
`
`3 months terbinafine
`vs 3 or 6 months
`fluconazole
`
`Abbreviations: LION, Jamisil vs itraconazole in onychomycosis.
`
`Mycological
`cure rate
`at study end
`
`Terbinafine
`48%
`59%
`70% and 87%
`
`Terbinafine
`78%
`73%
`
`Reference
`
`Placebo
`13%
`9%
`9%
`
`ltraconazo/e
`61%
`46%
`
`Goodfield et al 1992
`Watson et al 1995
`Drake et al 1997
`
`Brautigam et al 199 5
`De Backer et al 1998
`
`Terbinafine
`76% (3 months)
`and 81%
`(4 months)
`
`ltraconazole
`38% (3 months)
`and 49%
`(4 months)
`
`Evans and
`Sigurgeirsson 1999
`
`Terbinafine
`81%
`
`Griseofulvin
`62%
`
`Hofmann et al 1995
`
`90%
`
`64%
`
`Haneke et al 1995
`
`Terbinafine
`88%
`
`Fluconazole
`51% ( 3 months)
`49% (6 months)
`
`Havu et al 2000
`
`Therapeutics and Clinical Risk Management 2005: I (4)
`
`303
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`

`
`Elewski and Tavakkol
`
`manufacturers caution against men fathering children for
`6 months after therapy.
`
`Terbinafine
`Safety data from four large-scale post-marketing surveys
`investigating safety ofterbinafine in actual clinical practice
`in an uncontrolled setting have been pooled and reported
`(Hallet all997; O'Sullivan 1999). The incidence of adverse
`events was 1 0.5%; the majority involved the gastrointestinal
`system (4.9%) or skin (2.3%); these tended to be mild,
`transient, and reversible. Terbinafine was considered a
`"possible" or "probable" cause of only 11 (0.04%) serious
`adverse events. No drug-drug interactions were reported,
`even in patients taking oral antidiabetic agents (astemizole,
`terfenadine, or cimetidine), nor were any pr