You are on page 1of 11

Teijo I. Saari and Klaus T.


SEDA-33, 541; SEDA-34, 427]
Terbinafine [SED-15, 3316; SEDA-32,
491; SEDA-33, 541; SEDA-34, 427]
Observational studies Serious adverse
events due to systemic terbinafine reported
to the National Danish Adverse Reaction
Database over 10-year period have been
analysed [1R]. During this time 263 patients
(140 women and 123 men) developed an
adverse event that was attributed to terbinafine. Of these 26% (n ¼ 78) were considered serious. The most common serious
adverse events were: skin and subcutaneous tissue disorders (n ¼ 60, 30%), nervous
system disorders (n ¼ 26, 13%), and
hepatobiliary disorders (n ¼ 29, 15%).
The rate of serious adverse events corrected for consumption of terbinafine
(defined daily doses, DDD) during the
study was 4.2 per 1000 DDD (78 serious
adverse events, 18 534 DDD).
Drug–drug interactions Risperidone A 43year-old boy with bipolar schizoaffective
disorder who was taking risperidone was
given terbinafine for onychomycosis; he
had an exacerbation of his psychotic symptoms [2A]. Terbinafine was withdrawn and
he rapidly stabilized within 12 days. Terbinafine is an inhibitor of CYP2D6, which
is the main metabolic pathway of

Side Effects of Drugs, Annual 35
J.K. Aronson (Editor)
ISSN: 0378-6080
# 2014 Elsevier B.V. All rights reserved.

Antifungal drugs

[SED-15, 192;
SEDA-32, 493; SEDA-33, 542; SEDA34, 427]

Amphotericin B Lipid Complex
Nephrotoxicity Amphotericin lipid complex
has been evaluated in the management of
invasive fungal infections in immunocompromised patients in a retrospective review of
observational studies [3R]. Amphotericin
lipid complex was associated with 80% and
60% response rates in patients with confirmed fungal infections and in empirical
treatment respectively. Compared with conventional amphotericin, there is a substantially lower incidence of nephrotoxicity
associated with amphotericin lipid complex.
Intranasal administration used in prophylaxis
of invasive fungal infection may emerge as a
useful treatment strategy in the future.

Liposomal amphotericin (L-AmB)
Observational studies Hepatotoxicity and
nephrotoxicity have been retrospectively
evaluated in 100 consecutive patients
receiving L-AmB [4c]. According to the
inclusion criteria, 75 patients were included.
Based on increases in laboratory values
(bilirubin and aminotransferases), there
was hepatotoxicity in 16 (21%) of the
patients. The analysis revealed no further
correlates to explain this adverse effect.
Nephrotoxicity developed in 42 (56%) of
the patients who received L-AmB, but 31
(74%) of these received intravenous contrast media and 38 (90%) received other

Alitretinoin AUC was reduced by 21% and Cmax by 35% after ketoconazole. • A 71-year-old man with severe coronary artery disease and previous coronary artery bypass grafting received intravenous L-AmB for oral histoplasmosis. Age. and 3 tyrosine kinase inhibitor. Neratinib Neratinib is a low molecular weight. Voriconazole and methadone concentrations were subsequently high. Olkkola Amiodarone A 65-year old Caucasian man with extensive ischemic stroke was given intravenous amiodarone for atrial fibrillation. to 24 healthy . Atazanavir A 56-year old man with HIV and Candida infection was treated successfully using atazanavir during voriconazole therapy [10A]. Coadministration of neratinib with ketoconazole. an inhibitor of CYP3A.484 concurrent nephrotoxins. 497. Nervous system A healthy 38-year-old man received liposomal amphotericin B for cutaneous leishmaniasis and shortly after developed memory difficulties and confusion [6A]. Esomeprazole A 26-year-old woman with acute lymphoblastic leukemia and a history of drug abuse received intravenous voriconazole. atazanavir does not affect voriconazole metabolism by affecting CYP2C19. Chapter 27 Teijo I. but CYP3A inhibition caused by voriconazole should be considered when adjusting atazanavir doses. Two months later he received intravenous itraconazole again and developed hypotension and cardiac arrest. randomized study in 28 healthy subjects there was no clinically significant interaction with fluconazole [13c]. the electrocardiogram normalized. SEDA-34. and oral esomeprazole. anemia. open. SEDA33. and L-AmB was withdrawn [7A]. 545. 2. the dose was increased to 150 mg/day during 1 week and his symptoms resolved. irreversible human epidermal growth factor receptor 1. Coumarin anticoagulants A 67-year-old man who was taking itraconazole was given warfarin for a deep vein thrombosis. he developed severe hypotension after receiving the first dose of itraconazole for candidemia [9A]. Fesoterodine Fesoterodine is an oral antimuscarinic drug. but he developed acute renal damage. and exposure to concomitant nephrotoxins and intravenous contrast media were independently associated with nephrotoxicity.43 on day 10 [11A]. SEDA-32. the plasma concentrations of warfarin started to increase and the INR was 2. Saari and Klaus T. ANTIFUNGAL AZOLES [SED-15. dose escalation. 301. Urinary tract A 36-year-old Chinese man with remitting fever. oral methadone. the plasma concentrations started to fall. orally administered. The symptoms resolved over a few weeks. Resuscitation was successful and itraconazole was changed to caspofungin. Two maintenance doses of 100 mg/day L-AmB were administered subsequently without further symptoms. crossover. 4 days after starting voriconazole she developed ventricular bigeminy without prolongation of the QT interval [12A]. Cardiovascular A hypersensitivity reaction with ST segment elevated myocardial infarction (Kounis syndrome) has been attributed to liposomal amphotericin B [5A]. Logistic regression analysis showed that age was the only significant variable that determined nephrotoxicity. and pancytopenia received liposomal amphotericin 10 mg/day for visceral leishmaniasis. After withdrawal of esomeprazole and reduction of the dose of methadone. 428] Drug–drug interactions with antifungal azoles Alitretinoin The effects of ketoconazole on the pharmacokinetics of alitretinoin have been studied in 54 healthy men [8C]. 1 hour after the start of the infusion he developed a hypersensitivity reaction with subsequent ST elevation. After withdrawal of warfarin. cumulative dose. In a two-way.

430] Nervous system Severe neuropathy and peripheral edema has been attributed to itraconazole [23A]. Vandetanib exposure was increased significantly by about 9% during itraconazole administration. .2 and 2.2 times and AUC by 4. The patient was a carrier of the CYP2C19*2/*2 allele and was a poor metabolizer. there was an unexpected increase in AUC due to reduced clearance of voriconazole [20A]. Voriconazole Concomitant use of fluconazole reduced interindividual variability and increased voriconazole plasma concentrations significantly in healthy subjects [21c]. the clearance decreased further and the AUC increased. which is partly metabolized by CYP3A in vitro.6 and 1.8 times respectively. fluconazole was considered necessary and the patient underwent desensitization. Tacrolimus The extent of the interaction of voriconazole and itraconazole with tacrolimus has been described during 12 months of follow-up [17C]. tmax and half-life were unchanged [16c]. but nevertheless the patient had adverse reactions that could be attributed to an interaction of voriconazole with vincristine. The patient tolerated the therapeutic dose of 200 mg after 2 days. starting with 200 micrograms of oral fluconazole [22A]. 430] Immunology A 29-year-old Hispanic woman with HIV/AIDS developed a hypersensitivity reaction after the first oral dose of 400 mg fluconazole. there were no differences in efficacy or renal toxicity. 1377. Tamsulosin Co-administration of ketoconazole 400 mg/day for 5 days with tamsulosin 0. the Cmax and AUC of panobinostat. Voriconazole was withdrawn 3 days before the second cycle of chemotherapy. 1932.Antifungal drugs Chapter 27 subjects increased neratinib Cmax by 3. 552. Itraconazole [SED-15. SEDA-32. These results suggest that neratinib is a substrate of CYP3A and is susceptible to interactions with CYP3A inhibitors. 504. SEDA-34. Plasma concentration monitoring and CYP2C19 genotyping together with administration of a non-triazole antifungal before chemotherapy may be required to prevent serious vincristine neurotoxicity. The dose was increased gradually every 6 hours until a dose of 200 mg was reached. SEDA-33.8 times compared with neratinib alone [14C]. SEDA-34. The effect was most significant in CYP2C19 extensive metabolizers. Vincristine An obese 41-year-old Caucasian man (BMI 36 kg/m2) with a T-cell lymphoma 485 received intravenous voriconazole 4 mg/kg between chemotherapy cycles. the daily dose of tacrolimus was on average increased by 76% and 64% after itraconazole and voriconazole were withdrawn. dosage adjustments may be needed if neratinib is administered with such compounds. Oxycodone In a retrospective medical record review of nine patients with cancer who took oxycodone during voriconazole treatment there was enhanced analgesia and an increase in the frequency of adverse events [15A]. Thus.4 mg/day to 24 healthy volunteers increased the geometric mean values of Cmax and AUC by 2. Vandetanib In a phase I study of the effects of itraconazole on the pharmacokinetics of vandetanib were studied [19c]. Panobinostat (LBH589) Panobinostat is a histone deacetylase inhibitor. However. but this increase is unlikely to have any clinical consequences. 551. Fluconazole [SED-15. SEDA-33. who took panobinostat 20 mg orally after exposure for 4 days to oral ketoconazole 400 mg/day.8 times [18c]. were increased 1. SEDA-32. The pharmacokinetic changes were not associated with clinically significantly altered pharmacodynamics. Despite a reduction in dose. In a prospective study in 14 patients with metastatic solid tumors. 502.

intravenous magnesium. rifabutin. midazolam. HMG-CoA reductase inhibitors (statins). 553. He was later treated successfully with voriconazole without prolongation of the QT interval. and may contribute to increased serum voriconazole concentrations and prolongation of the QT interval in certain patients. SEDA32. The prolonged QTc interval normalized after voriconazole was withdrawn. There were no further dysrhythmias.8 mmol/l) and hypomagnesemia (0. 2905. Phenytoin. but he gradually recovered during neurorehabilitation. Posaconazole is a potent CYP3A inhibitor. which was successfully terminated with defibrillation. cisapride and quinidine). some antidysrhythmic agents (e.7 mmol/l). Three patients developed prolongation of the QT interval and severe dysrhythmias after taking voriconazole [28A. potassium. and simvastatin were withdrawn. tacrolimus. • A 15-year-old-boy developed a prolonged QTc interval from 380 to 500 ms after taking a loading dose of voriconazole (6 mg/kg intravenously) for fungal endocarditis. Ketoconazole was withdrawn and she gave birth to a healthy boy at 34 weeks. Itraconazole was withdrawn.g. The symptoms resolved after 10 days of hemodialysis. Pregnancy A 26-year-old pregnant woman took ketoconazole (200 mg bd) to treat Cushing’s syndrome. He developed rhabdomyolysis and acute renal failure. 505. SEDA-34. 430] Drug–drug interactions Posaconazole pharmacokinetics and CYP3A-mediated druginteractions have been reviewed [27R]. SEDA-33. Ketoconazole [SED-15. After 6 weeks the patient became bed bound owing to muscle weakness. Musculoskeletal A 64-year-old man took simvastatin and fenofibrate for dyslipidemia and developed hematuria and muscle weakness after an increase in the dose of ketoconazole to treat prostate cancer [25A]. 430] Endocrine The effect of ketoconazole for 3 weeks on the hypothalamic–pituitary– adrenal axis was evaluated in six elderly treatment-resistant depressed patients. and the edema resolved. 554. Posaconazole [SED-15. 3688. which had been diagnosed 9 weeks before the pregnancy [26A]. • A 12-year-old girl with pulmonary aspergillosis was treated with intravenous voriconazole and 11 days later developed ventricular bigeminy and trigeminy. and calcium channel blockers. SEDA- 34. Voriconazole was changed to caspofungin and the QTc interval normalized (430 ms). everolimus. which can be life threatening. after which ketoconazole. fenofibrate. After withdrawal of voriconazole and treatment with lidocaine. Posaconazole increases plasma Teijo I. which is the main route of metabolism of voriconazole. Saari and Klaus T. sirolimus. SEDA-33. can contribute substantially to the wide variability in voriconazole pharmacokinetics. the electrolyte concentrations and QTc interval normalized (QTc 390 ms). SEDA-34. but the peripheral edema persisted and he developed weakness in all four limbs. 1269. • A 70-year-old Japanese man with acute myeloblastic leukemia developed severe dysrhythmias after receiving intravenous voriconazole for a neutropenic fever. Olkkola concentrations of vinca alkaloids. 504. .486 Chapter 27 • A 72-year-old man with severe asthma took itraconazole for Aspergillus fumigatus infection and 1 month later developed progressive bilateral ankle edema. and lidocaine. He developed torsade de pointes. The QTc interval was prolonged to 570 ms and there was hypokalemia (2. there was no major increase in cerebrospinal fluid corticotropin-releasing hormone concentrations [24A]. Voriconazole [SED-15. The dosage was reduced. 431] Cardiovascular Prolongation of the QT interval is a marker for ventricular dysrhythmias. and ciclosporin significantly reduce the Cmax and AUC of posaconazole. and magnesium. but extensive pharmacokinetics studies with posaconazole and putative substrates with extensive first-pass metabolism are lacking. Variant polymorphisms of CYP2C19. Two days later he became febrile again and was rechallenged with voriconazole.29A]. SEDA-32.

differences in liver function were not observed. vesicles. aged 4 and 5 years. voriconazole plasma concentrations varied widely. However. other photosensitizing drugs) Diseases (HIV-AIDS) Figure 1 The EIDOS and DoTS descriptions of voriconazole-induced photosensitivity. The EIDOS and DoTS descriptions of this reaction are shown in Figure 1. vitamin A. The symptoms resolved completely. despite low to normal serum voriconazole concentrations [35A].Antifungal drugs Chapter 27 487 Torsade de pointes recurred and voriconazole was withdrawn. In one case the rash worsened when retinoic acid was added. Extrinsic species (E) Intrinsic species (I) Voriconazole Elements of the skin. Trough voriconazole concentrations were satisfactory after dosage adjustment. after which the liver enzymes started to normalize. Skin Cases of voriconazole-induced photosensitivity continue to be reported. who underwent intensive chemotherapy for malignancies were given voriconazole and developed severe photosensitivity after several months. Hepatotoxicity was evaluated retrospectively in a cohort study in 84 patients taking off-label high-dose voriconazole and 25 controls taking normal doses [33C]. 1 day later he developed a pulseless polymorphous ventricular tachycardia necessitating cardiopulmonary resuscitation. median age 10 years. Liver A 46-year-old woman developed aspergillosis after lung transplantation and asymptomatic progressive cholestatic hepatitis after taking oral voriconazole 200 mg bd for 10 days [32A]. DNA EIDOS Distribution Modifying factors Skin Sunlight (especially UVA) Outcome (the adverse effect) Manifestations (clinical) Erythema. Gastrointestinal A 35-year-old man with acute myelogenous leukemia took voriconazole for invasive pulmonary aspergillosis and after 5 days developed pseudomembranous colitis [31A]. Sensory systems Frequent visual hallucinations and abnormal liver function tests were attributed to voriconazole treatment for fungal retinitis in a 43-year-old Indian woman with Wegener’s granulomatosis. However. . A prolonged QT interval was the only finding at this point. The dosage of voriconazole was adjusted to 100 mg bd. In 30 patients. Multivariate analysis showed that dose and duration of therapy were predictive of hepatotoxicity. another report deals with two boys. Voriconazole was withdrawn and oral metronidazole started. and blisters Pseudoporphyria and porphyria cutanea tarda Risk of skin tumors DoTS Free radical-induced damage Sequela (the adverse reaction) Photosensitivity (?phototoxic) Dose-responsiveness Time-course Susceptibility factors Collateral Early permanent Genetic (?CYP2C19 polymorphisms) Age Physiology (skin type) Drugs (immunosuppressants. in whom 196 voriconazole plasma trough measurements were made during 2135 days of voriconazole therapy. There was a significant relation between plasma concentrations above the usual target range and photosensitivity [34C]. the symptoms started 7 days after the start of treatment and resolved after voriconazole was withdrawn [30A].

and markedly high concentrations have been encountered in some cases. In comparison. Causality is further suggested by fast recovery after voriconazole withdrawal. periosteal reactions (x-ray) Manifestations (clinical) Brittleness. and some reports have suggested that vitamin D with ascorbic acid supplementation could ameliorate fluorosis [40A]. Low vitamin D concentrations are associated with fluorosis. Cause Several etiological explanations may be considered for voriconazole-associated fluorosis. reduced mechanical competence of bone. municipal tap water contains fluoride in a concentration of about 1 mg/l. including osteosclerosis and hyperostotic periostitis. The integration of fluorapatite into bone causes alterations in bone crystal size and structure. have been described. reduced mechanical competence. Ultimately this increases bone density and leads to osteosclerosis. voriconazoleinduced periostitis is strongly associated with a raised alkaline phosphatase and characteristically shows no digital clubbing. Voriconazole-associated periostitis Voriconazole has been reported to have caused periostitis [37A]. and a 400 mg dose contains 65 mg of fluoride [38c]. exostoses. Fluoride intoxication resembles hypertrophic osteoarthropathy and periostitis deformans.488 Chapter 27 Immunologic A 28-month-old boy with autosomal recessive chronic granulomatous disease developed facial lupus-like lesions after taking voriconazole [36A]. which is associated with brittleness. and increased susceptibility to fractures [41c]. Voriconazole contains three fluorine atoms. Plasma fluoride concentrations are typically raised in patients who have taken voriconazole for at least 6 months. In contrast to hypertrophic osteoarthropathy. raised plasma fluorine concentrations. risk of fractures DoTS Teijo I. Voriconazole formulations contain fluoride. pain. and several common features have been observed in skeletal imaging. making these more resistant to resorption. Symmetrical diffuse periosteal reactions. ligamentous calcification. Fluorine is organically bound in Extrinsic species (E) Intrinsic species (I) Voriconazole Apatite in the bone EIDOS Manifestations (test results): Raised alkaline phosphatase. . resulting in daily fluoride exposure of 2–4 mg [39S]. Fluoride integrates as fluorapatite into the bone crystal structure and promotes bone formation by stimulating osteoblasts. Saari and Klaus T. these have been located in various parts of the skeleton. The EIDOS and DoTS descriptions are shown in Figure 2. pain. exostoses. and the mechanism of this adverse reaction has been linked to accumulation of fluoride. osteosclerosis Sequela (the adverse reaction) Periostitis Dose-responsiveness Time-course Susceptibility factors Collateral Late Genetic (CYP2C19 polymorphisms) Drugs (fluoride) Diseases (renal function) Figure 2 The EIDOS and DoTS descriptions of voriconazole-induced periostitis. and periarticular changes. Olkkola Distribution Modifying factors Bone ?Low vitamin D Outcome (the adverse effect) Fluorapatite-induced osteoblast stimulation. together with osteoporosis.

fatigue. renal insufficiency or failure may increase the risk of toxicity during fluorine exposure.7 mmol/l. The plasma fluoride concentration was 24 mmol/l (usual range 1–4 mmol/l.Antifungal drugs Chapter 27 voriconazole. although other coinciding factors are most probably also contributory. Conclusions The mechanisms by which chronic voriconazole treatment predisposes to periostitis seem to involve greatly raised fluorine concentrations. Her symptoms resolved shortly after withdrawal of voriconazole. aspartate aminotransferase. there was some resolution of the radiographic anomalies. 1197. and radiography showed multifocal areas of periostitis without clubbing. SEDA-33. The pain was most intense in the hands. and diffuse musculoskeletal pain. After 6 months he developed hand pain. She had nodular periostitis and focal lamellar periosteal reaction around the radial and pretibial diaphyses. His symptoms improved after withdrawal of voriconazole. since its renal clearance depends on glomerular filtration rate [42H] Reports of periostitis In a case–control study in 20 transplant patients five of the ten who took voriconazole for at least 7 months had clinical manifestations of periostitis and exostoses [38c]. and parathyroid hormone) were also observed. Voriconazole was withdrawn and after 5 days all her symptoms resolved. 507. • A 30-year-old woman with a bilateral lung transplant developed severe diffuse skeletal pain after long-term treatment with voriconazole [48A]. 556. a diffuse periosteal reaction was observed in hand radiographs. Laboratory abnormalities (changes in alkaline phosphatase. and hepatic oxidative metabolism may increase unbound fluoride concentrations after extensive voriconazole administration [38c]. whose fluoride concentrations were in the expected range. Exposures were similar in neonates and infants and comparable to exposures in children receiving similar weight-based dosages and adults . All had complicated hospital courses and four died in hospital. to address secondary hyperparathyroidism [44A]. Secondly. ECHINOCANDINS [SED-15. Five elderly lung transplantation patients developed diffuse periostitis after chronic voriconazole treatment [43A]. and 3 weeks later the pain was absent and the plasma fluoride concentration was 6. disabling. but symptoms improve rapidly after voriconazole withdrawal. • A 16-year-old boy with acute myelogenous leukemia took voriconazole 300 mg bd to treat 489 disseminated Fusarium-species infection [46A]. 507] Observational studies Exposure and adverse reactions to anidulafungin have been evaluated in a prospective study in 15 subjects (8 neonates and 7 infants) [49c] who received intravenous anidulafungin 1. Plasma fluorine concentrations are usually raised after 6 months of voriconazole administration. • A 66-year-old man with a heart transplant took voriconazole for pulmonary aspergillosis for 9 months. The pain started to resolve 1 week after withdrawal of voriconazole. SEDA-34. 434] Anidulafungin [SEDA-32. Two patients with exostoses were followed more closely. axial and appendicular pain after taking oral voriconazole 200 mg bd for 3 years. and their symptoms improved 2 months after withdrawal of voriconazole. All those who took voriconazole had significantly raised plasma fluoride concentrations compared with the controls. proliferative periosteal reactions bilaterally in the posterolateral ribs and in multiple phalanges of the right hand. The pain and laboratory values resolved after voriconazole was withdrawn and calcitriol was started. voriconazole-associated periosteal reactions were seen in the proximal long bones and thoracic ribs [45A]. toxic concentration > 15 mmol/l). after 7 weeks of worsening pain. • A 42-year-old woman developed severe diffuse musculoskeletal pain after taking voriconazole for 4 months for fungal endophthalmitis [47A]. This association has been further supported by other anecdotal observations. especially polymorphisms in CYP2C19 may further alleviate this phenomenon. The symptoms lasted for 5 months. • A 69-year-old multimorbid woman with aspergillosis complicating lung transplantation developed progressive. At the 4-month follow-up. Pharmacogenomic variations. Radiographs showed nodular. Plasma fluoride concentrations were not measured. with severe right hand pain and swelling for 1 month. finger swelling. SEDA-32.5 mg/kg/day for 35 days.

nor were any trends observed with respect to duration of treatment. 394 healthy adults. Of these. and 1386 adult patients). Although 27% of the caspofungin-treated subjects reported serious adverse reactions. II. increased alanine aminotransferase activity (6. Micafungin was withdrawn because of adverse events in seven (2. 435] Observational studies Adverse reactions to micafungin in children have been studied in a retrospective analysis of six global trials Chapter 27 Teijo I. The first compared micafungin (adults 100 mg/day. Caspofungin dose-related toxicity was not observed. nausea (21%). previous fluconazole treatment had been withdrawn because of possible liver toxicity [50A]. but 2 days later he died.0%). Micafungin [SEDA-32. and febrile. There was no age-dependency and the data suggested no apparent dose-related effects. seriousness. In a review of data from 32 studies in 1951 subjects (171 children. [55A] Thrombotic thrombocytopenic purpura has been attributed to micafungin [56A]. Success rates with micafungin were generally similar to those with liposomal amphotericin B and caspofungin. The second compared micafungin (100 or 150 mg/day) with caspofungin (50 mg/day with a 70 mg loading dose) in adults. increased aspartate aminotransferase activity (6. During the studies. diarrhea (22%). There was no clear relation between caspofungin dose and the incidence of adverse effects. Management of adverse drug reactions A 50year-old multimorbid woman with a kidney transplant and invasive candidosis was treated with anidulafungin after the discovery of abnormal liver function tests resulting from multiple causes of liver toxicity. The most common adverse events were vomiting (32%).7% were at least possibly related to micafungin. SEDA-34.4%).490 receiving 100 mg/day. Thrombotic thrombocytopenic purpura was diagnosed and micafungin was withdrawn. Autopsy confirmed the presence of disseminated small vessel thrombi. chills (5. causality. 558. 510. 508. SEDA-33. and there were no differences between patients with and without malignancies. Combination studies Two studies of micafungin in adults and children with confirmed Candida infections have been reported [54C]. Saari and Klaus T.5%). and there were only two events with a probable relationship to caspofungin. only 0. • A 19-year-old previously healthy man had a motor vehicle accident and received micafungin for Candida albicans infection. and increased alkaline phosphatase activity (5. adverse reactions were recorded in 93% of the subjects.2%). oliguric. and outcomes of all adverse events were analysed [52R]. SEDA-34. Hematology A 70-year-old Japanese man receiving micafungin developed pure red cell aplasia. 556. Caspofungin [SEDA-32. and III) in 296 patients [53C].3%).2%). The patients had invasive infections and underlying lifethreatening conditions were common. leading to withdrawal of anidulafungin in one subject. SEDA-33. Mild or moderate adverse events were recorded in 53% of the subjects. and 34% had adverse reactions classified as serious. pyrexia (22%). . Two of these studies (91 patients) were double-blind and randomized. Olkkola (phases I.8% were attributed to caspofungin. 434] Observational studies Caspofungin has been evaluated in a phase II study in 46 patients with invasive aspergillosis [51c]. and hypokalemia (21%). There were no serious drug-related adverse events. children 2 mg/day) with liposomal amphotericin B (3 mg/kg/day) in 489 patients. The frequencies of serious adverse events and withdrawal rates with micafungin were similar to those observed with liposomal amphotericin B and caspofungin in patients with and without malignancies. 4. After a single 100 mg dose he became hypotensive. the most common adverse event was worsening of hyperbilirubinemia. The most common caspofungin-related adverse events were fever (9.

Mazza P. Am J Ther 2011. 91(3): 358–9. Wein M. Rossi G. Concia E. Hara A. [9] Tsimogianni AM. Folkenberg M. Takahashi N. Woo MM. Porro MG. Jumadilova Z. Pharmacokinetic interactions between alitretinoin and ketoconazole or simvastatin or ciclosporin A. Tendas A. Mattheus M. Liposomal amphotericin B-induced hypotension leading to ST segment elevated myocardial infarction. Scholler J. Leikin JB. Fuks L. 5: 333. Li W. Li L. Miura M. Pharmacokinetics of oral neratinib during co-administration of ketoconazole in healthy subjects. Abbas R. Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (LBH589). Cascavilla N. Effects of the moderate CYP3A4 inhibitor. Case report: acute renal injury as a result of liposomal amphotericin B treatment in sodium stibogluconate unresponsive visceral leishmaniasis. Alvey C. Concurrent atazanavir and voriconazole in a patient with [11] [12] [13] [14] [15] [16] [17] [18] multidrug-resistant HIV and a mycetoma. an orally active histone deacetylase inhibitor. Drug interaction of (S)-warfarin. Kemmel V. Okoshi Y. Zacharias S. Sauer J. Muppa M. An evaluation of hepatotoxicity and nephrotoxicity of liposomal amphotericin B (L-AMB). Burns J. Effects . Andrianakis I. Kameoka Y. Clin Chim Acta 2011. fluconazole. Crank CW. methadone and esomeprazole. with itraconazole in a hematopoietic stem cell transplant recipient. Troost J. Shitrit D. Wada T. Amital A. Kramer MR. Kohda Y. Amphotericin B lipid complex in the management of invasive fungal infections in immunocompromised patients. Kato S. Kanno S. Nosari AM. Benedetti F. Betrosian A. [10] Gibson JN. Zhang D. A cytochrome P450 inhibitor in a stable schizophrenic patient: a drug interaction. 33(6): 905–8. Busca A. Br J Clin Pharmacol 2011. van der Biessen D. Clin Exp Dermatol 2011. Roos B. Hamberg P. Chiba S. Zhao L. Momo K. 7(1): 12–5. Murray CK. 68(3): 805–13. 31(5): 670–1. Tagawa H. Effects of voriconazole coadministration on oxycodone-induced adverse events: a case in the retrospective survey. Kablinger A. Ventricular bigeminy associated with voriconazole. de Jonge M. Malhotra B. Herbrecht R. Saitoh H. [8] Schmitt-Hoffmann AH. Duczynski G. Mehlburger L. 36(Suppl 2): 24–8. Patel N. Saunte DM. Clin Transplant 2011. Chen LC. and not (R)-warfarin. Michel MC. 18(5): e157–8. 71(4): 522–7. Hug BA. 412(21–22): 2002–6. Homma M. on the pharmacokinetics of fesoterodine in healthy subjects. [3] Bassetti M. Spickermann J. 25(16): 2054–6. [4] Patel GP. Am J Trop Med Hyg 2011. Am J Trop Med Hyg 2011. Mao Q. Tatami S. Zachariae C. Yoshioka T. Leister C. Sharma S. J Clin Psychopharmacol 2011. [5] Golwala H. Li X. Voriconazole and itraconazole in lung transplant recipients receiving tacrolimus (FK 506): efficacy and drug interaction. Fulco PP. [2] Kumar D. J Med Toxicol 2011. Meyer I. Central nervous system toxicity associated with liposomal amphotericin B therapy for cutaneous leishmaniasis. 84(4): 566–8. Ballerini F. Watanabe M. Br J Clin Pharmacol 2011. Tsuda Y. 25(2): E163–7. 67(8): 859–61. Hengelage T. Gandelman K. J Med Case Rep 2011. Nivoix Y.Antifungal drugs Chapter 27 491 References [1] Bangsgaard N. Cardiac arrest provoked by itraconazole and amiodarone interaction: a case report. Itoh M. Sonnichsen D. Maares J. Clin Drug Investig 2011. [6] Glasser JS. Dickins M. AIDS 2011. Cancer Chemother Pharmacol 2011. Levêque D. 31(11): 745–58. [7] Zhao S. Hirokawa M. Eur J Clin Pharmacol 2011. Douzinas E. Fujishima N. Int J Clin Pharm 2011. Serious adverse events reporting on systemic terbinafine: a Danish register-based study. Sawada K. 85(6): 1035–7. Aversa F. Nara M. Verweij J. Di Raimondo F. Schoetzau A. Lozano P. Acta Derm Venereol 2011. 72(2): 263–9.

López-Plasencia Y. Choi SM. Ileri T. 55(1): 184–9. Fotis M. Jariwala S. Intern Med J 2011. Ann Pharmacother 2011. Successful outcome of pregnancy in a patient with Cushing’s disease under treatment with ketoconazole during the first trimester of gestation. 13(3): 309–11. [32] Belaiche S. Deuschle M. Evaluation of hepatotoxicity with off-label oraltreatment doses of voriconazole for invasive fungal infections. Kim SH. Marrero D. Scheetz MH. . de Vos G. Kendirli T. Atalay S. Tutar E. Landgraf R. Wood N. 72(2): 247–56. Antimicrob Agents Chemother 2011. Komatsu T. Teijo I. Watkins JL. [35] Hansford JR. The effect of treatment with ketoconazole on central CRH systems of depressed patients. Figueras C. Idiosyncratic nature of voriconazole photosensitivity in children undergoing cancer therapy. 11(1): 37–51. Lupus-like lesions in a 28month-old boy with chronic granulomatous disease on long-term voriconazole prophylaxis. Takei N. [36] Geller L. MartínNalda A. Voriconazole toxicity related to polymorphisms in CYP2C19. Mycoses 2011. Booth DR. Wilson WH. 51(10): 1488–90. Schamann Y. Ann Allergy Asthma Immunol 2011. Cole C. Pou L. Gilles M. Murata K. Ince E. Heuser I. Read J. 54(Suppl 1): 32–8. Voriconazole drug monitoring in the management of invasive fungal infection in immunocompromised children: a prospective study. Saint-Raymond C. Kim HJ. Luppa P. Robertson J. [28] Aypar E. Martin P. Leung J. Gottardo NG. Posaconazole: clinical pharmacokinetics and drug interactions. Drugs R D 2011. Fatal dysrhythmia following initiation of lansoprazole during a long-term course of voriconazole. Moriyama B. Itokawa T. 27(9): 675–7. Saari and Klaus T.492 [19] [20] [21] [22] [23] [24] [25] [26] Chapter 27 of strong CYP2D6 and 3A4 inhibitors. Denning DW. Antimicrob Agents Chemother 2011. Gynecol Endocrinol 2011. Karadi RL. on the pharmacokinetics and cardiovascular safety of tamsulosin. J Antimicrob Chemother 2012. 26(1): 35–40. Oliver S. Paslakis G. Yonsei Med J 2011. Higaki T. Atkinson BJ. [29] Tsubokura M. 67(7): 1807–9. 106 (6): 542–3. Stewart GJ. Pharmacokinetic drug interactions with vandetanib during coadministration with rifampicin or itraconazole. Voriconazoleinduced QT interval prolongation and torsades de pointes. Barber M. Mycoses 2011. Rhabdomyolysis in a rostate cancer patient taking ketoconazole and simvastatin: case report and review of the literature. Falade-Nwulia O. Raciti PM. Kang MK. A case of pseudomembranous colitis after voriconazole therapy. Kennedy SJ. O’Connor K. Lecei O. O’Driscoll RB. A novel method of desensitization for fluconazole hypersensitivity in a patient with AIDS. [30] Suan D. JjFWeingo C. J Cutan Pathol 2011. Prolonged half-life of voriconazole in a CYP2C19 homozygous poor metabolizer receiving vincristine chemotherapy: avoiding a serious adverse drug interaction. 54(6): e877–9. Blyth CC. Nóvoa FJ. Lanaspa M. Frick MA. Liddle C. 53(5): 761–3. Bedouch P. Duvauchelle T. 38(8): 677–8. Kellett M. 5: 140. J Antimicrob Chemother 2012. Trifilio S. 55(11): 5172–7. Mercer SE. [33] Gorski E. Miura Y. paroxetine and ketoconazole. Phelps RG. Roustit M. Varma MV. Olkkola [27] Lipp HP. Pagliaro LC. 52(5): 863–5. Transpl Infect Dis 2011. Min WS. Roselló E. Vernon N. Quetant S. Hamann B. Br J Clin Pharmacol 2011. 41(4): 364–5. J Med Case Rep 2011. Damle B. Murashige N. Lee DG. Itraconazole associated quadriparesis and edema: a case report. Pediatr Int 2011. [31] Kwon JC. 67(3): 700–6. [34] Soler-Palacín P. Huang X. Pison C Management of voriconazole hepatotoxicity in a lung transplant patient. Gow D. Uhr M. Ciftçi E. Penzak SR. Stalla GK. Hum Psychopharmacol 2011. 45(2): e9. Pharmacokinetics of voriconazole administered concomitantly with fluconazole and population-based simulation for sequential use. Kami M. Postelnick M. Henning SA. Boronat M. J Clin Pharmacol 2011. Walsh TJ. de Heredia CD. Esterly JS.

Imel EA. Stucker F. Public Health Service report on fluoride benefits and risks. Lehrnbecher T. Multifocal nodular periostitis associated with prolonged voriconazole therapy in a lung transplant recipient. Di Perri G. Periostitis secondary to prolonged voriconazole therapy in lung transplant recipients. Hum Exp Toxicol 2000. AubryRozier B. Anidulafungin treatment in a kidney transplant recipient with hepatic damage. Scharschmidt TJ. Yoshida-Hiroi M. Vehreschild MJ. 40(2): 143–8. 55 (12): 5798–803. Voriconazole-induced periostitis. Safety of micafungin in pediatric clinical trials. Verma RJ. [39] Centers for Disease Control. Hope WW. Antimicrob Agents Chemother 2011. Mulligan ME. Moran C. Hallek M. Hulbert ML. [45] Wise SM. Fluoride excess and periostitis in transplant patients receiving long-term voriconazole therapy. Marty FM. Mycoses 2011. Eshaghian P. Wilson MA. Clin Pharmacol Ther 2011. 30(6): e97–e102. Medication-induced periostitis in lung transplant patients: periostitis deformans revisited. Weigt SS. Lupinacci RJ. Kashuba AD. Belperio JA. Cohen-Wolkowiez M. Hiroi N. Saggar R. N Engl J Med 1990. [41] Lindsay R. Kenney CV. Cornely OA. Whitford GM. Schwartz S. 8(1): 5–14. Benjamin DK Jr. Groll AH. De Rosa FG. Saggar R. Koizumi M. Clin Nucl Med 2011.Antifungal drugs Chapter 27 [37] Wang TF. Int J Antimicrob Agents 2011. Ullmann AJ. Vehreschild JJ. Heussel CP. Christenson JC. Safety and pharmacokinetics of multiple-dose anidulafungin in infants and neonates. 19(11): 632–4. Assaly R. Clin Infect Dis 2011. JP. Würthwein G. 34 (11): e793–6. 322 (12): 845–6. Messina M. Piper L. [47] Rossier C. Fluoride and bone—quantity versus quality. 39(2): 375–6. Arrieta AC. Pappas PG. Marchetti O. Skeletal Radiol 2011. 17(2): 73–5. JAMA 1991. Liu P. Farowski F. Adv Dent Res 1994. [43] Chen L. Moyer TP. Muzaffar M. Wilkens A. McKiernan FE. Aram J. Cheifetz IM. Mycoses 2011. Ullmann AJ. Altman R. 266(1061–1062): 1066–7. Segoloni GP. Orthopedics 2011. Kremers WK. Mahne M. Safi F. Groll AH. [48] Lustenberger DP. 29(32): e779–82. Arenz D. Micafungin-induced thrombotic thrombocytopenic purpura: a case report and review of the literature. Intake and metabolism of fluoride. Franklin J. Phase II dose escalation study of caspofungin for invasive aspergillosis. 9(12): 2845–50. Ross DJ. Bourque MR. Capparelli E. Lynch 3rd. Smith PB. [38] Wermers RA. First case report of acquired pure red cell aplasia associated with micafungin. Mitsuda A. Amelioration of fluoride-induced hypocalcaemia by vitamins. [42] Whitford GM. Bell JE. Ranghino A. Raviolo S. Kubak B. . Ngai AL. Efficacy and safety of micafungin for treatment of serious Candida infections in patients with or without malignant disease. Karthaus M. [44] Ayub A. J Clin Oncol 2011. Walsh TJ. Strohmaier KM. Manzione NA. A case of periostitis secondary to voriconazole therapy in a heart transplant recipient. Boubaker A. Intern Med 2011. Periostitis secondary to 493 [49] [50] [51] [52] [53] [54] [55] [56] prolonged voriconazole therapy in a lung transplant recipient. 54(6): e838–47. Nazzal M. Oka R. 52(5): 604–11. Kartsonis NA. Harnischmacher U. Nazzal M. Am J Ther 2011. Gregson A. Arma F. Silling G. Deziel PJ. 38(6): 540–4. J Clin Rheumatol 2011. 18: e258–60. Overview of safety experience with caspofungin in clinical trials conducted over the first 15 years: a brief report. Cooper K. Dunet V. Pediatr Infect Dis J 2011. Granata JD. Wang T. 36(3): 242–4. Maddison P. Tissot F. [40] Guna Sherlin DM. Ottobrelli A. Razonable RR. Cornely OA. 50(9): 1051–4. Eur J Nucl Med Mol Imaging 2012. Fluorosis because of prolonged voriconazole therapy in a teenager with acute myelogenous leukemia. [46] Skiles JL. 54(Suppl 4): 12–5. Am J Transplant 2009. 89(5): 702–7.