- Email: [email protected]
Antifungal drugs
C H A P T E R
25 Antifungal drugs Dayna S. McManus, PharmD1, Sunish Shah, PharmD Department of Pharmacy Services, Yale-New Haven Hospital, New Haven, CT, United States 1 Corresponding author: [email protected]
ALLYLAMINES
candidiasis. Following the initiation of fluconazole, the patient shortly developed acute liver failure. Following cessation of fluconazole, the patient’s hepatic failure resolved [3A].
Terbinafine Skin A case of widespread pruritic eruption was seen in a 59-year-old woman who had received oral terbinafine for a dermatophyte infection of the groin for 2 days. Physical exam revealed 2–3 mm, non-follicular pustules and erythema on the neck, axilla, chest, trunk, and extremities. Skin biopsy identified prominent dermal eosinophilia. The patient also had peripheral leukocytosis 13.6 103 WBC/mm3 with neutrophil predominance. Terbinafine was discontinued and the patient was cured following a systemic steroid taper over 2 weeks [1A].
ANTIFUNGAL AZOLES [SEDA-35, 484; SEDA-36, 382; SEDA-37, 307; SEDA-38, 245; SEDA-39, 245; SEDA-40, 327] Fluconazole Skin A cohort of 97 patients with coccidioidomycosis were surveyed to identify cutaneous effects of fluconazole. Patients receiving fluconazole reported significantly more severe cutaneous effects, including dry lips (74.2% [46/62] vs 23.5% [8/34]; P < 0.001), dry skin (45.8% [27/59] vs 22.9% [8/35]; P ¼ 0.03), and alopecia (31.1% [19/61] vs 11.4% [4/35]; P ¼ 0.004), compared to untreated patients. The median duration of treatment in patients receiving fluconazole was 6 months [2c]. Hepatic A case of fluconazole induced liver injury was reported in a 45-year-old African-American male with no history of liver disease. The patient was being receiving fluconazole for the treatment of superficial Side Effects of Drugs Annual, Volume 41 ISSN: 0378-6080 https://doi.org/10.1016/bs.seda.2019.09.002
Systemic A report of long-term adverse reactions was reported following fluconazole and ketoconazole treatment in a 56-year-old man with a 40 years history of pesticide and petrochemical exposure. The patient received ketoconazole 200 mg by mouth twice daily concomitantly with topical 0.5% fluconazole cream for fungal infections of his ears and penis. Soon after therapy, he developed hypotension and shortness of breath which was diagnosed as a disulfiram reaction. By age 57, many substances caused the patient to experience adverse effects such as hypotension, headaches, dizziness and anaphylactic symptoms. Agents listed in this report include ethanol, pesticides, chlorine, gasoline, diesel fuel, artificial fragrances, fertilizers/lime, fresh paint, and formaldehyde containing products. These symptoms would subside within minutes when the patient was treated with sauna and IV glutathione [4A]. Observational studies A randomized, open-label, clinical trial of 36 neonates was conducted to determine the pharmacokinetics and safety profile of fluconazole and micafungin for the treatment of systemic candidiasis. During therapy, the most frequent adverse event in both arms were anemia [fluconazole 6/20 (30%) and micafungin 8/21 (38%)], staphylococcal infection [fluconazole 5/20 (25%) and micafungin 2/21 (10%)] and thrombocytopenia [fluconazole 3/20 (15%) and micafungin 3/21 (14%)]. It is important to recognize that no adverse events led to drug discontinuation nor were any considered to be directly related to therapy [5c].
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Drug interactions A case report highlighted the effect of fluconazole on the pharmokinetics of everolimus and tacrolimus in a heart transplant recipient. Upon discontinuation of fluconazole, the patient experienced a 2.8- and 4.7-fold increase in drug clearance for everolimus and tacrolimus, respectively. This resulted in a 3.5-fold increase in the everolimus dose and a 3.0-fold increase in the tacrolimus dose [6A]. A case series highlighted a drug interaction in three allogeneic stem cell transplant patients who discontinued fluconazole while on therapy with sirolimus. Following the discontinuation of fluconazole, a 70%, 30% and 28% decrease in sirolimus trough levels were identified in the first, second and third patient, respectively. In order to maintain a therapeutic sirolimus level upon the discontinuation of fluconazole, an increase in the sirolimus dose by 267%, 243% and 200% was required in the first, second and third patient, respectively [7c].
ITRACONAZOLE Observational studies A non-blinded, randomized trial of 123 patients was conducted to compare the efficacy and safety of itraconazole and prednisolone for the treatment of allergic bronchopulmonary aspergillosis. No patients in either arm required a discontinuation of therapy due to an adverse event. However, transient liver function test abnormalities occurred in 9 (15%) of patients in the itraconazole group compared to 0% of patients in the prednisolone group (P ¼ 0.001) [8c].
Drug interactions A case of severe neuropsychiatric adverse reaction was reported in a male patient in his mid-40s with Human Immunodeficiency Virus (HIV) and cerebral histoplasmosis. The patient presented with seizures, sensory disorders and chronic weight loss over the past 6 months. A lumbar puncture was performed and positive CSF Histoplasma capsulatum PCR confirmed the diagnosis of cerebral histoplasmosis. The patient was treated with liposomal amphotericin B (6 mg/kg) and itraconazole oral suspension (300 mg q8h followed by 200 mg q12). After 6 weeks of therapy, the patient developed renal impairment. Amphotericin B was subsequently discontinued and the patient’s HIV regimen of efavirenz/emtricitabine/tenofovir disoproxil fumarate was switched to darunavir/ritonavir, abacavir/lamivudine and maraviroc (600/100 mg q12h, 600/300 mg q24h and 150 mg q12h, respectively). The patient’s mentality subsequently declined and the patient experienced confusion,
drowsiness and severe diarrhea. In the particular case of Histoplasma meningitis, the target of the active sum of itraconazole and hydroxy-itraconazole plasma Cmin should be at least 2000 lg/L. In this case, the active Cmin of itraconazole at day 7 was four- to sixfold higher, whereas darunavir Cmin was twofold higher than in healthy adult volunteers, showing reciprocal drug–drug enzymatic inhibitions. Darunavir/ritonavir was replaced by dolutegravir and after 3 months, itraconazole was discontinued. One month later, Cmin serum concentration of itraconazole was found to be 1030 μg/L and the drug was resumed. After 4 months of itraconazole, a follow-up CSF Histoplasma capsulatum PCR was negative and the patient was deemed clinically cured. Therefore, it was suspected that the drug–drug interaction lead to this adverse event [9A]. A case of severe neurotoxicity was reported in a 4-year-old male on maintenance therapy for acute lymphocytic leukemia. Each cycle of maintenance therapy consisted of 6-mercaptopurine, methotrexate, vindesine (3 mg/m2 every 4 weeks) and two doses of intrathecal chemotherapy (methotrexate, cytarabine and dexamethasone). Following the second cycle, the child developed a pulmonary fungal infection and was initiated on 2.5 mg/kg of oral itraconazole. Following clinical improvement, the patient received vindesine concomitantly with itraconazole. Five days after therapy with vindesine, the patient experience severe abdominal pain, pancytopenia and paralysis of the extremities. Trismus and syndrome of inappropriate anti-diuretic hormone (SIADH) occurred after 7 days of therapy with vindesine. Itraconazole was discontinued and intravenous caspofungin with inhaled amphotericin B was administered as an alternative. One week later, the patient’s neurologic function recovered. Again, the neurotoxicity side effect was a result of an important drug–drug interaction [10A].
ISAVUCONAZOLE Observational studies In a post-hoc analysis of the VITAL study, safety data were obtained for isavuconazole for the treatment of rare invasive fungal diseases. This analysis included 26 patients with infections caused by uncommon molds, non-Candida yeasts and unidentified molds. All patients in this analysis experienced at least 1 treatment-emergent adverse event (TEAE). The most common TEAEs were gastrointestinal effects (23.1%), peripheral edema (19.2%), respiratory failure (19.2%), pyrexia (15.4%) and urinary tract infections (15.4%). Four patients (15.4%) experienced TEAEs that required discontinuation of isavuconazole. One patient required discontinuation
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of isavuconazole due to severe nausea and vomiting. The other three patients discontinued isavuconazole due to a worsening brain abscess, a stroke and breakthrough aspergillosis [11c]. A randomized, double-blind, multicenter, noninferiority study compared isavuconazole to caspofungin for candidemia and candidiasis. One objective of this study was to identify the safety of both therapies. There were 220 patients randomized to isavuconazole and 220 patients randomized to caspofungin. Study drug related TEAE leading to discontinuation occurred in 5% of patients in both treatment arms. More patients in the isavuconazole arm had infusion site pain (2.3% vs 0%), while serum alkaline phosphatase was increased more often in the caspofungin arm (2.7% vs 0.9%) [12C].
significance of isavuconazole on tacrolimus and sirolimus concentration/dose (C/D) ratios. Patients were eligible for inclusion if they received >10 days of combination therapy with isavuconazole and tacrolimus and/or sirolimus. No patients received dose reductions of tacrolimus or sirolimus at the time of isavuconazole administration nor were CYP3A4 inhibitors or inducers concomitantly administered. Of the 22 patients who received tacrolimus, the mean C/D ratio was increased from baseline by 1.42-fold for week 1 (P ¼ 0.002). Of the 18 patients who received sirolimus for 2 weeks, the mean C/D ratio was increased from baseline by 1.56-fold during week 2 (P ¼ 0.002). While consideration should be given to the small sample size of this study, the remaining time points did not achieve a statistically significantly different C/D from baseline for either tacrolimus or sirolimus [15c].
Cardiovascular A multicenter, observational study of 26 adult patients was conducted to assess changes in the QTc interval caused by isavuconazole use. Twenty-five patients received isavuconazole for the treatment of invasive fungal infection and one patient was administered isavuconazole for prophylaxis. A baseline electrocardiogram (ECG) was performed before isavuconazole therapy was administered and a follow-up ECG was performed a median of 10 days (range 1–46) later. QTc shortening occurred in 24 (92.3%) patients. Patients who experienced QTc shortening had a mean QTc interval decrease of 7.4 + 5.8% (36.5 + 38.8 milliseconds; P ¼ 0.004). One patient had an extended follow-up of 110 days in which the QTc interval further decreased [13c].
Drug interactions A case of subtherapeutic tacrolimus levels following isavuconazole was reported in a 47-year-old African American female who underwent allogeneic stem cell transplantation (alloHSCT) for acute lymphoblastic leukemia. Following transplantation, the patient was started on immunosuppressive therapy with tacrolimus and antifungal prophylaxis with posaconazole. However, the patient had experienced significant QTc prolongation upon initiating these agents. Posaconazole was subsequently switched to micafungin; however, the patient’s QTc was still prolonged from baseline. The decision was made to discontinue micafungin and initiate isavuconazole. Although, tacrolimus was empirically dose reduced by 40%, trough concentrations subsequently declined. Tacrolimus doses were steadily increased until a therapeutic trough concentration was achieved 14 days after initiating isavuconazole. Her QTc subsequently returned to baseline [14A]. A retrospective study of 42 alloHSCT patients was conducted to determine the
KETOCONAZOLE Drug interactions The effect of CYP3A4 inhibition of ketoconazole was further studied in a vivo mouse model analyzing cyclophosphamide metabolism. Ketoconazole doses were administered at 10, 20 and 40mg/kg while cyclophosphamide was administered at 10 mg/kg. Pharmacokinetic data from this study demonstrated that concomitant use of cyclophosphamide demonstrated a ketoconazole dose dependent increase in Cmax, Tmax and AUC [16E]. In an analysis of open-label phase III studies, the potential for drug interaction was studied between ketoconazole and rolapitant, a CYP3A4 substrate used for the prevention of chemotherapy-induced nausea and vomiting. Co-administration of ketoconazole and rolapitant did not affect rolapitant maximum concentration and only resulted in a 20% increase in the area under the concentration time curve. However, concurrent therapy with rifampin, a CYP3A4 inducer, and rolapitant resulted in a 33% decrease rolapitant concentration and 87% decrease in the area under the concentration time curve [17E].
POSACONAZOLE Observational studies The safety and efficacy of voriconazole and posaconazole were compared for prophylaxis against invasive fungal infections in patients with hematologic malignancies. There were 81 patients who received posaconazole while 83 patients received voriconazole. While the rate of breakthrough antifungal therapy did not differ between the posaconazole and voriconazole groups, drug related
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adverse events occurred more frequently in the voriconazole group (1 vs 11 patients, P ¼ 0.003). One patient had a gastrointestinal reaction related to posaconazole use. Of the 11 patients who experienced an adverse event to voriconazole, 8 patients experienced liver dysfunction and 3 patients experienced hallucinations [18c]. A retrospective study of 77 patients was performed to assess the safety of posaconazole and voriconazole as antifungal prophylaxis during induction therapy for acute myelogenous leukemia or myelodysplastic syndrome. The primary outcome was the rate of discontinuation of either agent. In the posaconazole group 13/43 (30%) patients discontinued therapy for any reason compared to 12/34 (35%) of patients who received voriconazole (P ¼ 0.64). However, a higher rate of discontinuation due to adverse drug events was reported in the voriconazole group (18% (6/34) vs 2% (1/43), P ¼ 0.04). Posaconazole was discontinued due to a dermatologic reaction. Of the six patients who discontinue voriconazole due to an adverse drug reaction, three patients experienced elevated liver enzymes and three patients experienced hallucinations. No breakthrough invasive fungal infections were reported in this cohort [19c]. A single-arm prospective, observational study evaluated the safety profile and concentration–toxicity relationship of posaconazole tablets in 60 neutropenic patients with hematologic malignancies. There were 18 patients (30%) who experienced an adverse event attributable to posaconazole. The most frequent adverse event was abnormal liver function tests which occurred in 12 patients (20%). During follow-up, 28.6% of patients had at least one posaconazole concentration <0.7 μg/mL, and 35.7% had at least one concentration >2 μg/mL. Rates of adverse events by quartile of trough were not statistically different [20c].
Drug interactions An observational, pharmacokinetic study of 30 subjects assessed the drug interaction between ranolazine, a CYP3A4 substrate, and posaconazole in healthy obese and non-obese subjects. Ranolazine was administered (500 mg tablet) on study days 1, 15, 18, 22, 25 and 29. On study day 2, posaconazole was administered at 300 mg tablet twice daily and on study days 3–15, posaconazole was administered at 300 mg daily. Although it was not statistically significant, trough steady-state posaconazole concentrations on day 15 were 3071 1422 ng/mL in normal-weight subjects and 2258 952 ng/mL in obese subjects. In the non-obese group, a statistically significant increase in ranolazine Cmax was observed from baseline on day 15 (1429 666 ng/mL), day 18 (1188 469ng/mL), day 22 (974 400 ng/mL) and day 25 (928 482ng/mL). In the obese group, a statistically significant increase
in ranolazine Cmax was also observed from baseline on day 15 (1177 512 ng/mL), day 18 (1096 502 ng/mL), day 22 (1063 508 ng/mL) and day 25 (976 487 ng/mL). Electrocardiography data identified a statistically significant increase in QTc by an average of 12.9 16 milliseconds in non-obese subjects on day 30 compared to day 1 [21c]. An analysis of two open-label trials was conducted to assess the pharmacokinetics and clinical sequelae of the concomitant use of posaconazole, voriconazole and letermovir—a cytomegalovirus (CMV) terminase complex inhibitor recently approved for CMV prophylaxis in hematopoietic stem cell transplant. Both trials included healthy female subjects between 18 and 55 years old. In the first trial, 16 subjects were included. Posaconazole (300 mg once) was administered alone, followed by a 7-day washout before letermovir (480 mg once daily) was administered for 14 days with posaconazole (300 mg once) concomitantly administered on day 14. In the second trial, 14 subjects were included. On day 1 voriconazole 400 mg was given every 12 h. Voriconazole 200 mg was given every 12 h was given on days 2 and 3 while 200 mg of voriconazole was given on day 4. On days 5–8, letermovir 480 mg was given once daily. Days 9–12 mimicked the voriconazole regimen on days 1–4 coadministered with letermovir 480 mg once daily. While posaconazole pharmacokinetic remained minimally effects by letermovir, voriconazole steady-state plasma area under the curve and Cmax was decreased by 44% and 39%, respectively, when given concomitantly with letermovir vs administered alone. The most common adverse event in both trials was nausea. It is hypothesized that this interaction is mediated by induction through CYP2C9 and CYP2C19. No serious adverse events or adverse events that led to discontinuation were reported in either study [22c]. A retrospective chart-review of 66 adult patients withhaematologic malignancies on posaconazole prophylaxis aimed to determine clinical features associated with subtherapeutic concentrations of posaconazole (0.7 μg/mL). On day 1, an initial posaconazole tablet loading dose of 300 mg every 12 h and continued in the subsequent days with a maintenance dose of 300 mg tablets once daily. Therapeutic drug monitoring was performed at steady state which was after day 4. Subtherapeutic levels were observed at least once in 33.3% of patients. In a multivariate model, use of proton pump inhibitors (P ¼ 0.008), male gender (P ¼ 0.025) and use of high-dose steroids were significantly associated with subtherapeutic troughs [23c]. An observational study, multicenter study of 59 patients with lung transplantation aimed to assess drug interactions and drug exposure in patients receiving posaconazole. The tacrolimus trough concentration to dose ratio (C/D) without posaconazole was 1.4 0.6 (n ¼ 19).
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However, with posaconazole tablets the tacrolimus C/D was 7.4 4.4. The posaconazole plasma concentration was not significantly different regardless of concomitant PPI use: 1.49 1.07 mg/L in patients not receiving a PPI (n ¼ 6) vs 1.33 1.17 mg/L in patients receiving a PPI (n ¼ 19) (P ¼ 0.4134) [24c]. There was a case of atrial fibrillation with slow ventricular response with transformation in polymorphic ventricular tachycardia that was thought to have occurred from concomitant use of posaconazole and digoxin. The patient was a 72-year-old female with a history of atrial fibrillation, cerebrovascular accident, heart failure with preserved ejection fraction and acute myeloid leukemia was admitted for neutropenic fever. Her home medication list consisted of torsemide (20 mg by mouth daily), allopurinol (300 mg by mouth daily), escitalopram (10 mg by mouth daily), and digoxin (0.25 mg by mouth daily, Monday through Friday). On day 3 of hospitalization, a CT scan was performed to determine the source of infection. Pulmonary nodules were identified, and the patient was started on posaconazole 300 mg by mouth daily. Five days after posaconazole initiation, a therapeutic level was observed at 1.8 μg/mL. On hospital day 10, the patient experienced severe bradycardia at 42 beats per minute. The digoxin level was noted to be 3.1 ng/mL and the drug was held. Later that day, the patient developed polymorphic ventricular tachycardia and posaconazole was transitioned to micafungin. The patient received 200 mg of digoxin immune fab twice. The digoxin level immediately post digoxin immune fab was 2.4 ng/mL. The digoxin level became undetectable 11 days later [25A]. The drug interaction between posaconazole and lurasidone, an antipsychotic metabolized by CYP3A enzymes, was studied in an observational study of 13 obese and 11 normal weight volunteers. Subjects received single doses of lurasidone (20 mg tablet) on days 1, 14, 20, 23, 26 and 30. On day 4, subjects received 300 mg twice daily of posaconazole followed by 300 mg daily on days 5–17. In normal weight patients, there was a significantly higher lurasidone area under the concentration time curve on day 14 (356 25 ng/mL), day 20 (272 32 ng/mL), day 23 (272 32 ng/mL), day 26 (148 27 ng/mL) and day 30 (129 20 ng/mL) compared to baseline (63.1 6.4 ng/mL). Similarly, in obese patients, there was a significantly higher lurasidone area under the concentration time curve on day 14 (227 20 ng/mL), day 20 (219 19 ng/mL), day 23 (170 17 ng/mL), day 26 (151 19 ng/mL) and day 30 (150 17 ng/mL) compared to baseline (60.6 10.9 ng/mL). These findings suggest the posaconazole and lurasidone drug interaction persists despite posaconazole discontinuation [26c]. There was a case of severe neuropathic pain attributed to the concomitant administration of posaconazole and vincristine, a CYP3A substrate commonly used as a chemotherapeutic agent for the treatment of acute
lymphoblastic leukemia (ALL). The patient was a 5-year-old female with pre-B-cell acute lymphoblastic leukemia who was started on induction chemotherapy with vincristine, dexamethasone, daunorubicin and PEG-asparaginase. Vincristine was dosed at 1.5 mg/m2 throughout her course. She achieved remission, but consolidation therapy was complicated by febrile neutropenia. She developed a lung nodule which was biopsied, and histology was consistent with mucromycosis. The patient was started on liposomal amphotericin B and oral posoconazole 18 mg/kg/day before undergoing lung resection. The patient then received maintenance chemotherapy with one dose of vincristine and one dose of methotrexate while on posaconazole and amphotericin B. Five days later the patient experienced new severe pain in the right arm, chest, and jaw. The patient also developed foot drop and constipation. Posaconazole was discontinued but restarted after 6 weeks of amphotericin B. The child later continued posaconazole for mucormycosis prophylaxis but was instructed to hold posaconazole 48 h before and on the day of administration of vincristine. Subsequent complications of this drug interaction were not reported [27A].
VORICONAZOLE Skin A multicenter, international, retrospective study aimed to evaluate the risk of voriconazole on squamous cell carcinoma (SCC) in lung transplant recipients. Of the 900 patients included, 55 patients developed SCC. The median time from lung transplant to diagnosis of SCC was 3.3 years (IQR 1.8–4.2 years). In the univariate model, exposure to voriconazole alone was correlated with an increased risk for SCC compared to unexposed patients (hazard ratio 2.55, 95% CI 1.42–4.60). It was also noted that patients with medium and high sunlight exposure were more likely to develop SCC compared to those with low sunlight exposure [28C].
Occular A case report suggests a correlation with voriconazole therapy and macular toxicity with blind spot enlargement. The patient was a 77-year-old man who was receiving voriconazole for pulmonary aspergillosis. On day 3 of therapy, the patient reported incomplete color blindness and ocular hallucination. The Lanthony 15-Hue Desaturated test revealed dyschromatopsia in the left eye and the Goldman visual field examination revealed a blind spot in both eyes. The voriconazole dose was adjusted for supratherapeutic plasma concentrations; however,
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no improvement was noted. The drug was then switched to itraconazole and visual hallucinations resolved [29A].
Observational studies One retrospective, multicenter study aimed to identify the safety of voriconazole in patients with Child-Pugh class C cirrhosis. Patients received voriconazole 200 mg daily in one or two divided doses. Of the 34 patients included, eight patients (23.5%) experienced an adverse event. Of these patients, two patients experienced encephalopathy, two patients developed a rash, one patient experienced tremor, one patient experienced dizziness, one patient reported hallucinations and the final patient was reported to have consciousness disturbance. The mean voriconazole trough level of these eight patients was 5.96 mg/L [30c]. Similarly, the safety profile of voriconazole was studied in a retrospective study of 78 patients with class B and C cirrhosis. Patients were stratified by dosing regimen. Group A patients received the recommended dose regimen based on the voriconazole package insert or a fixed dose of 200 mg twice daily orally or intravenously. Group B patients received a loading dose of 200 mg twice daily on day 1, followed by 100 mg twice daily orally or intravenously. The incidence of adverse events was 26.5% (9/34) in group A and 15.9% (7/44) in group B, P ¼ 0.25. This trend of higher adverse events in group A was suggested to be a consequence of higher voriconazole trough levels compared to group B (6.95 3.42 vs 4.02 2.00, P < 0.001) The most common adverse events were neurologic disturbances (n ¼ 11), including encephalopathy (n ¼ 2). In a multivariate model, factors associated with an elevated voriconazole trough included elevations in international normalized ratio (P ¼ 0.003) and CYP2C19 inhibitor use (P ¼ 0.041) [31c]. The safety of prophylactic voriconazole was studied in a retrospective cohort of 429 courses among 249 with hematologic malignancies. The median number of voriconazole courses per patient was 1.7, whereas the median voriconazole dose was 7 mg/kg every 12 h. Adverse events occurred in 70 courses (16.3%). Of these adverse events, 50% were because of elevated liver enzymes, 24.3% were from hypokalemia, 14.3% were from ophthalmologic disorders, 5.7% were from nausea, 2.8% were from edema, 1.4% were from rash and 1.4% was from keratitis [32C].
Drug interactions A case report attributed sulfonylurea toxicity to concomitant gliclazide and voriconazole use. The patient was a 56-year-old man with a past medical history of type 2 diabetes mellitus and bone marrow transplantation 8 months prior for myelofibrosis. The reported
medications include metformin 2500 mg by mouth in divided doses, gliclazide modified release 90 mg by mouth daily, insulin lispro 6 units subcutaneously with meals and insulin glargine 18 units subcutaneously at night, prednisone 5 mg by mouth daily and was recently started on antifungal therapy prior to admission. The patient was started on voriconazole for suspicion of fungal pneumonia. Six days later the patient developed hallucinations and was transitioned to fluconazole. Of note, on voriconazole therapy, the patient had not required any short acting insulin due to low glucose readings 54–72 mg/dL. The day after transition to fluconazole, the patient presented to the emergency department for confusion and lethargy. He was found to have a blood glucose of 25 mg/dL. He was treated for hypoglycemia and gliclazide was permanently discontinued given the concern of an azole mediated drug interaction [33A].
MICONAZOLE Drug interactions A retrospective analysis of registry data from the United Kingdom was performed to identify significant drug interactions with warfarin. There were 175 patients who had received a combination of miconazole oral gel and warfarin. Prior to miconazole prescription documentation, the mean INR (95% CI) was 2.48 (2.44–2.52). After documentation of miconazole oral gel prescription, the mean INR (95% CI) was 5.83 (5.31–6.36). The mean time between recorded INRs was 19 days [34C]. Acenocoumarol, like warfarin, is an anticoagulant that functions as a vitamin K antagonist. A retrospective analysis was performed to identify the significance of the drug interaction between acenocoumarol and warfarin. A total of 29 patients were included in the study. Patients had received at least 7 days of acenocoumarol, followed by 7 days of a combination of acenocoumarol targeted to an INR of 2.5 with 62 mg of miconazole oral gel. The day before administration of miconazole, the mean INR was 2.2. However, on day 7 of miconazole with warfarin, the mean INR was 4.5 [35c]. An open-label, randomized, cross-over study was conducted to evaluate the drug interaction between three vaginal miconazole nitrate formulations on a vaginal ring containing segesterone acetate and ethinyl estradiol. The study was conducted over three menstrual cycles in healthy women with regular menses. Twenty-nine participants completed the study. While concomitant administration of miconazole cream did not affect hormone levels, the maximum ethinyl estradiol geometric ratio for AUC was elevated at 1.67 (1.51–1.86) with a single-dose of miconazole suppositories. However, no serious treatment adverse events were reported [36c].
REFERENCES
AMPHOTERICIN Observational study A randomized trial assessed different the safety and efficacy of different induction treatment regimens for cryptococcal meningitis in HIV infected adults. Patients were randomized to receive to receive an oral regimen of fluconazole plus flucytosine for 2 weeks, 1 week of amphotericin B, or 2 weeks of amphotericin B. Each patient assigned to receive amphotericin B was also randomly assigned to receive fluconazole or flucytosine as a partner drug. A total of 721 patients were included. Amphotericin B was dosed at 1 mg/kg/day, flucytosine was dosed at 100 mg/kg/day and fluconazole was dosed at 1200 mg/day. Grade 4 anemia occurred in 8.8% of patients who were randomized to 2 weeks of amphotericin B, 4.9% of patients who were randomized to receive 1 week of amphotericin B and in 0.9% of patients who did not receive amphotericin B. A grade 3 or 4 increase in the serum creatinine level developed in 4.9% of patients who did not receive amphotericin B, 6.2% of patients in the 1-week amphotericin B groups, and 8.8% of patients in the 2-week amphotericin B groups [37MC].
PYRIMADINE ANALOGUES Flucytosine See Section ‘Observational study’.
ECHINOCANDINS Anidulafungin An open-label, single-arm, prospective study was performed to assess the safety of anidulafungin for invasive candidiasis including candidemia in patients between the ages of 2 and 18 years old. Forty-nine patients were eligible for inclusion and at least one treatment emergent adverse effect was reported in all patients. Diarrhea, vomiting and pyrexia were most frequent and occurred in 22.4%, 24.5% and 18.4% of patients respectively. There were 4 patients who discontinued treatment due to an adverse event that was deemed to be related to anidulafungin. These adverse events include increased transaminases, increased alanine/aspartate aminotransferases, vomiting and pruritis [38c].
References [1] Ross CL, Shevchenko A, Mollanazar NK, et al. Acute generalized exanthematous pustulosis due to terbinafine. Dermatol Ther. 2018;31(4)e12617 [A].
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[2] Brewer AC, Huber JT, Girardo ME, et al. Cutaneous effects associated with fluconazole in patients treated for coccidioidomycosis. Int J Dermatol. 2019;58(2):250–3 [c]. [3] Gayam V, Khalid M, Dahal S, et al. Hyperacute liver injury following intravenous fluconazole: a rare case of dose-independent hepatotoxicity. J Family Med Prim Care. 2018;7(2):451–4 [A]. [4] Lieberman A, Curtis L. Severe adverse reactions following ketoconazole, fluconazole, and environmental exposures: a case report. Drug Saf Case Rep. 2018;5:18 [A]. [5] Leroux S, Jacqz-Aigrain E, Elie V, et al. Pharmacokinetics and safety of fluconazole and micafungin in neonates with systemic candidiasis: a randomized, open-label clinical trial. Br J Clin Pharmacol. 2018;84(9):1989–99 [c]. [6] Nakagita K, Wada K, Terada Y, et al. Effect of fluconazole on the pharmacokinetics of everolimus and tacrolimus in a heart transplant recipient: case report. Int J Clin Pharmacol Ther. 2018;56(6):270–6 [A]. [7] Nwaroh E, Jupp J, Jadusingh E, et al. Clinical impact and management of fluconazole discontinuation on sirolimus levels in bone marrow transplant patients. J Oncol Pharm Pract. 2018;24(3):235–8 [c]. [8] Agarwal R, Dhooria S, Singh Sehgal I, et al. A randomized trial of itraconazole vs prednisolone in acute-stage allergic bronchopulmonary aspergillosis complicating asthma. Chest. 2018;153(3):656–64 [c]. [9] Le Meur L, Tantet C, L^e MP, et al. Serious neuropsychiatric adverse effects related to interaction between itraconazole and darunavir/ ritonavir in an HIV-infected patient with cerebral histoplasmosis. J Antimicrob Chemother. 2018;73(4):1108–10 [A]. [10] Zhou H, Li L, Zhou Y, et al. Syndrome of inappropriate antidiuretic hormone secretion from concomitant use of itraconazole and vindesine. J Clin Pharm Ther. 2018;43(1):137–40 [A]. [11] Cornely OA, Mullane KM, Ostrosky-Zeichner L, et al. Isavuconazole for treatment of rare invasive fungal diseases. Mycoses. 2018;61(8):518–33 [c]. [12] Kullberg BJ, Viscoli C, Pappas PG, et al. Isavuconazole versus caspofungin in the treatment of candidemia and other invasive candida infections: the ACTIVE trial. Clin Infect Dis. 2018;68:1981–9 [C]. [13] Mellinghoff SC, Bassetti M, D€ orfel D, et al. Isavuconazole shortens the QTc interval. Mycoses. 2018;61(4):256–60 [c]. [14] Kufel WD, Armistead PM, Daniels LM, et al. Drug-drug interaction between isavuconazole and tacrolimus: is empiric dose adjustment necessary? J Pharm Pract. 2018. https://doi.org/ 10.1177/0897190018790688. [A]. [15] Kieu V, Jhangiani K, Dadwal S, et al. Effect of isavuconazole on tacrolimus and sirolimus serum concentrations in allogeneic hematopoietic stem cell transplant patients: a drug-drug interaction study. Transpl Infect Dis. 2018;21:e13007 [c]. [16] Yang L, Yan C, Zhang F. Effects of ketoconazole on cyclophosphamide metabolism: evaluation of CYP3A4 inhibition effect using the in vitro and in vivo models. Exp Anim. 2018;67(1):71–82 [E]. [17] Wang X, Wang J, Arora S, et al. Pharmacokinetic interactions of rolapitant with cytochrome P450 3A substrates in healthy subjects. J Clin Pharmacol. 2018;59:488–99 [E]. [18] Tang L, Yang XF, Qiao M, et al. Posaconazole vs. voriconazole in the prevention of invasive fungal diseases in patients with haematological malignancies: a retrospective study. J Mycol Med. 2018;28(2):379–83 [c]. [19] Phillips K, Cirrone F, Ahuja T, et al. Posaconazole versus voriconazole as antifungal prophylaxis during induction therapy for acute myelogenous leukemia or myelodysplastic syndrome. J Oncol Pharm Pract. 2018;25:398–403 1078155218806975. [c]. [20] Boglione-Kerrien C, Picard S, Tron C, et al. Safety study and therapeutic drug monitoring of the oral tablet formulation of
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posaconazole in patients with haematological malignancies. J Cancer Res Clin Oncol. 2018;144(1):127–34 [c]. Chow CR, Harmatz JS, Ryan MJ, et al. Persistence of a posaconazole-mediated drug-drug interaction with ranolazine after cessation of posaconazole administration: impact of obesity and implications for patient safety. J Clin Pharmacol. 2018;58(11):1436–42 [c]. Marshall WL, McCrea JB, Macha S, et al. Pharmacokinetics and tolerability of letermovir coadministered with azole antifungals (posaconazole or voriconazole) in healthy subjects. J Clin Pharmacol. 2018;58(7):897–904 [c]. Cojutti PG, Candoni A, Lazzarotto D, et al. Co-administration of proton pump inhibitors and/or of steroids may be a risk factor for low trough concentrations of posaconazole delayed-released tablets in adult patients with haematological malignancies. Br J Clin Pharmacol. 2018;84(11):2544–50 [c]. Launay M, Roux A, Beaumont L, et al. Posaconazole tablets in reallife lung transplantation: impact on exposure, drug-drug interactions, and drug management in lung transplant patients, including those with cystic fibrosis. Antimicrob Agents Chemother. 2018;62(3) [c]. Shumaker AC, Bullard HM, Churpek J, et al. Posaconazoledigoxin drug-drug interaction mediated by inhibition of P-glycoprotein. J Oncol Pharm Pract. 2018;25:1758–61 1078155218801055. [A]. Greenblatt DJ, Harmatz JS, Ryan MJ, et al. Sustained impairment of lurasidone clearance after discontinuation of posaconazole: impact of obesity, and implications for patient safety. J Clin Psychopharmacol. 2018;38(4):289–95 [c]. Lin M, Paul M, Kuo D. Severe neuropathic pain with concomitant administration of vincristine and posaconazole. J Pediatr Pharmacol Ther. 2018;23(5):417–20 [A]. Hamandi B, Fegbeutel C, Silveira FP, et al. Voriconazole and squamous cell carcinoma after lung transplantation: a multicenter study. Am J Transplant. 2018;18(1):113–24 [C].
[29] Mounier A, Agard E, Douma I, et al. Macular toxicity and blind spot enlargement during a treatment by voriconazole: a case report. Eur J Ophthalmol. 2018;28(4):NP11–4 [A]. [30] Wang T, Yan M, Tang D, et al. A retrospective, multicenter study of voriconazole trough concentrations and safety in patients with Child-Pugh class C cirrhosis. J Clin Pharm Ther. 2018;43(6):849–54 [c]. [31] Wang T, Yan M, Tang D, et al. Therapeutic drug monitoring and safety of voriconazole therapy in patients with Child-Pugh class B and C cirrhosis: a multicenter study. Int J Infect Dis. 2018;72:49–54 [c]. [32] Pana Z, Kourti M, Vikelouda K, et al. Voriconazole antifungal prophylaxis in children with malignancies: a nationwide study. J Pediatr Hematol Oncol. 2018;40:22–6 [C]. [33] Gunaratne K, Austin E, Wu P. Unintentional sulfonylurea toxicity due to a drug–drug interaction: a case report. BMC Res Notes. 2018;11:331 [A]. [34] Martín-Perez M, Gaist D, de Abajo FJ, et al. Population impact of drug interactions with warfarin: a real-world data approach. Thromb Haemost. 2018;118(3):461–70 [C]. [35] Lozano R, Frutos A. Time course of the drug-drug interaction of acenocoumarol-miconazole. Int J Clin Pharmacol Ther. 2018;56(1):28–30 [c]. [36] Simmons KB, Kumar N, Plagianos M, et al. Effects of concurrent vaginal miconazole treatment on the absorption and exposure of Nestorone® (segesterone acetate) and ethinyl estradiol delivered from a contraceptive vaginal ring: a randomized, crossover drug-drug interaction study. Contraception. 2018;97(3):270–6 [c]. [37] Molloy SF, Kanyama C, Heyderman RS, et al. Antifungal combinations for treatment of cryptococcal meningitis in Africa. N Engl J Med. 2018;378(11):1004–17 [MC]. [38] Roilides E, Carlesse F, Leister-Tebbe H, et al. A prospective, openlabel study to assess the safety, tolerability, and efficacy of anidulafungin in the treatment of invasive candidiasis in children 2 to <18 years of age. Pediatr Infect Dis J. 2018;38:275–9 [c].
25 Antifungal drugs Dayna S. McManus, PharmD1, Sunish Shah, PharmD Department of Pharmacy Services, Yale-New Haven Hospital, New Haven, CT, United States 1 Corresponding author: [email protected]
ALLYLAMINES
candidiasis. Following the initiation of fluconazole, the patient shortly developed acute liver failure. Following cessation of fluconazole, the patient’s hepatic failure resolved [3A].
Terbinafine Skin A case of widespread pruritic eruption was seen in a 59-year-old woman who had received oral terbinafine for a dermatophyte infection of the groin for 2 days. Physical exam revealed 2–3 mm, non-follicular pustules and erythema on the neck, axilla, chest, trunk, and extremities. Skin biopsy identified prominent dermal eosinophilia. The patient also had peripheral leukocytosis 13.6 103 WBC/mm3 with neutrophil predominance. Terbinafine was discontinued and the patient was cured following a systemic steroid taper over 2 weeks [1A].
ANTIFUNGAL AZOLES [SEDA-35, 484; SEDA-36, 382; SEDA-37, 307; SEDA-38, 245; SEDA-39, 245; SEDA-40, 327] Fluconazole Skin A cohort of 97 patients with coccidioidomycosis were surveyed to identify cutaneous effects of fluconazole. Patients receiving fluconazole reported significantly more severe cutaneous effects, including dry lips (74.2% [46/62] vs 23.5% [8/34]; P < 0.001), dry skin (45.8% [27/59] vs 22.9% [8/35]; P ¼ 0.03), and alopecia (31.1% [19/61] vs 11.4% [4/35]; P ¼ 0.004), compared to untreated patients. The median duration of treatment in patients receiving fluconazole was 6 months [2c]. Hepatic A case of fluconazole induced liver injury was reported in a 45-year-old African-American male with no history of liver disease. The patient was being receiving fluconazole for the treatment of superficial Side Effects of Drugs Annual, Volume 41 ISSN: 0378-6080 https://doi.org/10.1016/bs.seda.2019.09.002
Systemic A report of long-term adverse reactions was reported following fluconazole and ketoconazole treatment in a 56-year-old man with a 40 years history of pesticide and petrochemical exposure. The patient received ketoconazole 200 mg by mouth twice daily concomitantly with topical 0.5% fluconazole cream for fungal infections of his ears and penis. Soon after therapy, he developed hypotension and shortness of breath which was diagnosed as a disulfiram reaction. By age 57, many substances caused the patient to experience adverse effects such as hypotension, headaches, dizziness and anaphylactic symptoms. Agents listed in this report include ethanol, pesticides, chlorine, gasoline, diesel fuel, artificial fragrances, fertilizers/lime, fresh paint, and formaldehyde containing products. These symptoms would subside within minutes when the patient was treated with sauna and IV glutathione [4A]. Observational studies A randomized, open-label, clinical trial of 36 neonates was conducted to determine the pharmacokinetics and safety profile of fluconazole and micafungin for the treatment of systemic candidiasis. During therapy, the most frequent adverse event in both arms were anemia [fluconazole 6/20 (30%) and micafungin 8/21 (38%)], staphylococcal infection [fluconazole 5/20 (25%) and micafungin 2/21 (10%)] and thrombocytopenia [fluconazole 3/20 (15%) and micafungin 3/21 (14%)]. It is important to recognize that no adverse events led to drug discontinuation nor were any considered to be directly related to therapy [5c].
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Drug interactions A case report highlighted the effect of fluconazole on the pharmokinetics of everolimus and tacrolimus in a heart transplant recipient. Upon discontinuation of fluconazole, the patient experienced a 2.8- and 4.7-fold increase in drug clearance for everolimus and tacrolimus, respectively. This resulted in a 3.5-fold increase in the everolimus dose and a 3.0-fold increase in the tacrolimus dose [6A]. A case series highlighted a drug interaction in three allogeneic stem cell transplant patients who discontinued fluconazole while on therapy with sirolimus. Following the discontinuation of fluconazole, a 70%, 30% and 28% decrease in sirolimus trough levels were identified in the first, second and third patient, respectively. In order to maintain a therapeutic sirolimus level upon the discontinuation of fluconazole, an increase in the sirolimus dose by 267%, 243% and 200% was required in the first, second and third patient, respectively [7c].
ITRACONAZOLE Observational studies A non-blinded, randomized trial of 123 patients was conducted to compare the efficacy and safety of itraconazole and prednisolone for the treatment of allergic bronchopulmonary aspergillosis. No patients in either arm required a discontinuation of therapy due to an adverse event. However, transient liver function test abnormalities occurred in 9 (15%) of patients in the itraconazole group compared to 0% of patients in the prednisolone group (P ¼ 0.001) [8c].
Drug interactions A case of severe neuropsychiatric adverse reaction was reported in a male patient in his mid-40s with Human Immunodeficiency Virus (HIV) and cerebral histoplasmosis. The patient presented with seizures, sensory disorders and chronic weight loss over the past 6 months. A lumbar puncture was performed and positive CSF Histoplasma capsulatum PCR confirmed the diagnosis of cerebral histoplasmosis. The patient was treated with liposomal amphotericin B (6 mg/kg) and itraconazole oral suspension (300 mg q8h followed by 200 mg q12). After 6 weeks of therapy, the patient developed renal impairment. Amphotericin B was subsequently discontinued and the patient’s HIV regimen of efavirenz/emtricitabine/tenofovir disoproxil fumarate was switched to darunavir/ritonavir, abacavir/lamivudine and maraviroc (600/100 mg q12h, 600/300 mg q24h and 150 mg q12h, respectively). The patient’s mentality subsequently declined and the patient experienced confusion,
drowsiness and severe diarrhea. In the particular case of Histoplasma meningitis, the target of the active sum of itraconazole and hydroxy-itraconazole plasma Cmin should be at least 2000 lg/L. In this case, the active Cmin of itraconazole at day 7 was four- to sixfold higher, whereas darunavir Cmin was twofold higher than in healthy adult volunteers, showing reciprocal drug–drug enzymatic inhibitions. Darunavir/ritonavir was replaced by dolutegravir and after 3 months, itraconazole was discontinued. One month later, Cmin serum concentration of itraconazole was found to be 1030 μg/L and the drug was resumed. After 4 months of itraconazole, a follow-up CSF Histoplasma capsulatum PCR was negative and the patient was deemed clinically cured. Therefore, it was suspected that the drug–drug interaction lead to this adverse event [9A]. A case of severe neurotoxicity was reported in a 4-year-old male on maintenance therapy for acute lymphocytic leukemia. Each cycle of maintenance therapy consisted of 6-mercaptopurine, methotrexate, vindesine (3 mg/m2 every 4 weeks) and two doses of intrathecal chemotherapy (methotrexate, cytarabine and dexamethasone). Following the second cycle, the child developed a pulmonary fungal infection and was initiated on 2.5 mg/kg of oral itraconazole. Following clinical improvement, the patient received vindesine concomitantly with itraconazole. Five days after therapy with vindesine, the patient experience severe abdominal pain, pancytopenia and paralysis of the extremities. Trismus and syndrome of inappropriate anti-diuretic hormone (SIADH) occurred after 7 days of therapy with vindesine. Itraconazole was discontinued and intravenous caspofungin with inhaled amphotericin B was administered as an alternative. One week later, the patient’s neurologic function recovered. Again, the neurotoxicity side effect was a result of an important drug–drug interaction [10A].
ISAVUCONAZOLE Observational studies In a post-hoc analysis of the VITAL study, safety data were obtained for isavuconazole for the treatment of rare invasive fungal diseases. This analysis included 26 patients with infections caused by uncommon molds, non-Candida yeasts and unidentified molds. All patients in this analysis experienced at least 1 treatment-emergent adverse event (TEAE). The most common TEAEs were gastrointestinal effects (23.1%), peripheral edema (19.2%), respiratory failure (19.2%), pyrexia (15.4%) and urinary tract infections (15.4%). Four patients (15.4%) experienced TEAEs that required discontinuation of isavuconazole. One patient required discontinuation
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of isavuconazole due to severe nausea and vomiting. The other three patients discontinued isavuconazole due to a worsening brain abscess, a stroke and breakthrough aspergillosis [11c]. A randomized, double-blind, multicenter, noninferiority study compared isavuconazole to caspofungin for candidemia and candidiasis. One objective of this study was to identify the safety of both therapies. There were 220 patients randomized to isavuconazole and 220 patients randomized to caspofungin. Study drug related TEAE leading to discontinuation occurred in 5% of patients in both treatment arms. More patients in the isavuconazole arm had infusion site pain (2.3% vs 0%), while serum alkaline phosphatase was increased more often in the caspofungin arm (2.7% vs 0.9%) [12C].
significance of isavuconazole on tacrolimus and sirolimus concentration/dose (C/D) ratios. Patients were eligible for inclusion if they received >10 days of combination therapy with isavuconazole and tacrolimus and/or sirolimus. No patients received dose reductions of tacrolimus or sirolimus at the time of isavuconazole administration nor were CYP3A4 inhibitors or inducers concomitantly administered. Of the 22 patients who received tacrolimus, the mean C/D ratio was increased from baseline by 1.42-fold for week 1 (P ¼ 0.002). Of the 18 patients who received sirolimus for 2 weeks, the mean C/D ratio was increased from baseline by 1.56-fold during week 2 (P ¼ 0.002). While consideration should be given to the small sample size of this study, the remaining time points did not achieve a statistically significantly different C/D from baseline for either tacrolimus or sirolimus [15c].
Cardiovascular A multicenter, observational study of 26 adult patients was conducted to assess changes in the QTc interval caused by isavuconazole use. Twenty-five patients received isavuconazole for the treatment of invasive fungal infection and one patient was administered isavuconazole for prophylaxis. A baseline electrocardiogram (ECG) was performed before isavuconazole therapy was administered and a follow-up ECG was performed a median of 10 days (range 1–46) later. QTc shortening occurred in 24 (92.3%) patients. Patients who experienced QTc shortening had a mean QTc interval decrease of 7.4 + 5.8% (36.5 + 38.8 milliseconds; P ¼ 0.004). One patient had an extended follow-up of 110 days in which the QTc interval further decreased [13c].
Drug interactions A case of subtherapeutic tacrolimus levels following isavuconazole was reported in a 47-year-old African American female who underwent allogeneic stem cell transplantation (alloHSCT) for acute lymphoblastic leukemia. Following transplantation, the patient was started on immunosuppressive therapy with tacrolimus and antifungal prophylaxis with posaconazole. However, the patient had experienced significant QTc prolongation upon initiating these agents. Posaconazole was subsequently switched to micafungin; however, the patient’s QTc was still prolonged from baseline. The decision was made to discontinue micafungin and initiate isavuconazole. Although, tacrolimus was empirically dose reduced by 40%, trough concentrations subsequently declined. Tacrolimus doses were steadily increased until a therapeutic trough concentration was achieved 14 days after initiating isavuconazole. Her QTc subsequently returned to baseline [14A]. A retrospective study of 42 alloHSCT patients was conducted to determine the
KETOCONAZOLE Drug interactions The effect of CYP3A4 inhibition of ketoconazole was further studied in a vivo mouse model analyzing cyclophosphamide metabolism. Ketoconazole doses were administered at 10, 20 and 40mg/kg while cyclophosphamide was administered at 10 mg/kg. Pharmacokinetic data from this study demonstrated that concomitant use of cyclophosphamide demonstrated a ketoconazole dose dependent increase in Cmax, Tmax and AUC [16E]. In an analysis of open-label phase III studies, the potential for drug interaction was studied between ketoconazole and rolapitant, a CYP3A4 substrate used for the prevention of chemotherapy-induced nausea and vomiting. Co-administration of ketoconazole and rolapitant did not affect rolapitant maximum concentration and only resulted in a 20% increase in the area under the concentration time curve. However, concurrent therapy with rifampin, a CYP3A4 inducer, and rolapitant resulted in a 33% decrease rolapitant concentration and 87% decrease in the area under the concentration time curve [17E].
POSACONAZOLE Observational studies The safety and efficacy of voriconazole and posaconazole were compared for prophylaxis against invasive fungal infections in patients with hematologic malignancies. There were 81 patients who received posaconazole while 83 patients received voriconazole. While the rate of breakthrough antifungal therapy did not differ between the posaconazole and voriconazole groups, drug related
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adverse events occurred more frequently in the voriconazole group (1 vs 11 patients, P ¼ 0.003). One patient had a gastrointestinal reaction related to posaconazole use. Of the 11 patients who experienced an adverse event to voriconazole, 8 patients experienced liver dysfunction and 3 patients experienced hallucinations [18c]. A retrospective study of 77 patients was performed to assess the safety of posaconazole and voriconazole as antifungal prophylaxis during induction therapy for acute myelogenous leukemia or myelodysplastic syndrome. The primary outcome was the rate of discontinuation of either agent. In the posaconazole group 13/43 (30%) patients discontinued therapy for any reason compared to 12/34 (35%) of patients who received voriconazole (P ¼ 0.64). However, a higher rate of discontinuation due to adverse drug events was reported in the voriconazole group (18% (6/34) vs 2% (1/43), P ¼ 0.04). Posaconazole was discontinued due to a dermatologic reaction. Of the six patients who discontinue voriconazole due to an adverse drug reaction, three patients experienced elevated liver enzymes and three patients experienced hallucinations. No breakthrough invasive fungal infections were reported in this cohort [19c]. A single-arm prospective, observational study evaluated the safety profile and concentration–toxicity relationship of posaconazole tablets in 60 neutropenic patients with hematologic malignancies. There were 18 patients (30%) who experienced an adverse event attributable to posaconazole. The most frequent adverse event was abnormal liver function tests which occurred in 12 patients (20%). During follow-up, 28.6% of patients had at least one posaconazole concentration <0.7 μg/mL, and 35.7% had at least one concentration >2 μg/mL. Rates of adverse events by quartile of trough were not statistically different [20c].
Drug interactions An observational, pharmacokinetic study of 30 subjects assessed the drug interaction between ranolazine, a CYP3A4 substrate, and posaconazole in healthy obese and non-obese subjects. Ranolazine was administered (500 mg tablet) on study days 1, 15, 18, 22, 25 and 29. On study day 2, posaconazole was administered at 300 mg tablet twice daily and on study days 3–15, posaconazole was administered at 300 mg daily. Although it was not statistically significant, trough steady-state posaconazole concentrations on day 15 were 3071 1422 ng/mL in normal-weight subjects and 2258 952 ng/mL in obese subjects. In the non-obese group, a statistically significant increase in ranolazine Cmax was observed from baseline on day 15 (1429 666 ng/mL), day 18 (1188 469ng/mL), day 22 (974 400 ng/mL) and day 25 (928 482ng/mL). In the obese group, a statistically significant increase
in ranolazine Cmax was also observed from baseline on day 15 (1177 512 ng/mL), day 18 (1096 502 ng/mL), day 22 (1063 508 ng/mL) and day 25 (976 487 ng/mL). Electrocardiography data identified a statistically significant increase in QTc by an average of 12.9 16 milliseconds in non-obese subjects on day 30 compared to day 1 [21c]. An analysis of two open-label trials was conducted to assess the pharmacokinetics and clinical sequelae of the concomitant use of posaconazole, voriconazole and letermovir—a cytomegalovirus (CMV) terminase complex inhibitor recently approved for CMV prophylaxis in hematopoietic stem cell transplant. Both trials included healthy female subjects between 18 and 55 years old. In the first trial, 16 subjects were included. Posaconazole (300 mg once) was administered alone, followed by a 7-day washout before letermovir (480 mg once daily) was administered for 14 days with posaconazole (300 mg once) concomitantly administered on day 14. In the second trial, 14 subjects were included. On day 1 voriconazole 400 mg was given every 12 h. Voriconazole 200 mg was given every 12 h was given on days 2 and 3 while 200 mg of voriconazole was given on day 4. On days 5–8, letermovir 480 mg was given once daily. Days 9–12 mimicked the voriconazole regimen on days 1–4 coadministered with letermovir 480 mg once daily. While posaconazole pharmacokinetic remained minimally effects by letermovir, voriconazole steady-state plasma area under the curve and Cmax was decreased by 44% and 39%, respectively, when given concomitantly with letermovir vs administered alone. The most common adverse event in both trials was nausea. It is hypothesized that this interaction is mediated by induction through CYP2C9 and CYP2C19. No serious adverse events or adverse events that led to discontinuation were reported in either study [22c]. A retrospective chart-review of 66 adult patients withhaematologic malignancies on posaconazole prophylaxis aimed to determine clinical features associated with subtherapeutic concentrations of posaconazole (0.7 μg/mL). On day 1, an initial posaconazole tablet loading dose of 300 mg every 12 h and continued in the subsequent days with a maintenance dose of 300 mg tablets once daily. Therapeutic drug monitoring was performed at steady state which was after day 4. Subtherapeutic levels were observed at least once in 33.3% of patients. In a multivariate model, use of proton pump inhibitors (P ¼ 0.008), male gender (P ¼ 0.025) and use of high-dose steroids were significantly associated with subtherapeutic troughs [23c]. An observational study, multicenter study of 59 patients with lung transplantation aimed to assess drug interactions and drug exposure in patients receiving posaconazole. The tacrolimus trough concentration to dose ratio (C/D) without posaconazole was 1.4 0.6 (n ¼ 19).
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However, with posaconazole tablets the tacrolimus C/D was 7.4 4.4. The posaconazole plasma concentration was not significantly different regardless of concomitant PPI use: 1.49 1.07 mg/L in patients not receiving a PPI (n ¼ 6) vs 1.33 1.17 mg/L in patients receiving a PPI (n ¼ 19) (P ¼ 0.4134) [24c]. There was a case of atrial fibrillation with slow ventricular response with transformation in polymorphic ventricular tachycardia that was thought to have occurred from concomitant use of posaconazole and digoxin. The patient was a 72-year-old female with a history of atrial fibrillation, cerebrovascular accident, heart failure with preserved ejection fraction and acute myeloid leukemia was admitted for neutropenic fever. Her home medication list consisted of torsemide (20 mg by mouth daily), allopurinol (300 mg by mouth daily), escitalopram (10 mg by mouth daily), and digoxin (0.25 mg by mouth daily, Monday through Friday). On day 3 of hospitalization, a CT scan was performed to determine the source of infection. Pulmonary nodules were identified, and the patient was started on posaconazole 300 mg by mouth daily. Five days after posaconazole initiation, a therapeutic level was observed at 1.8 μg/mL. On hospital day 10, the patient experienced severe bradycardia at 42 beats per minute. The digoxin level was noted to be 3.1 ng/mL and the drug was held. Later that day, the patient developed polymorphic ventricular tachycardia and posaconazole was transitioned to micafungin. The patient received 200 mg of digoxin immune fab twice. The digoxin level immediately post digoxin immune fab was 2.4 ng/mL. The digoxin level became undetectable 11 days later [25A]. The drug interaction between posaconazole and lurasidone, an antipsychotic metabolized by CYP3A enzymes, was studied in an observational study of 13 obese and 11 normal weight volunteers. Subjects received single doses of lurasidone (20 mg tablet) on days 1, 14, 20, 23, 26 and 30. On day 4, subjects received 300 mg twice daily of posaconazole followed by 300 mg daily on days 5–17. In normal weight patients, there was a significantly higher lurasidone area under the concentration time curve on day 14 (356 25 ng/mL), day 20 (272 32 ng/mL), day 23 (272 32 ng/mL), day 26 (148 27 ng/mL) and day 30 (129 20 ng/mL) compared to baseline (63.1 6.4 ng/mL). Similarly, in obese patients, there was a significantly higher lurasidone area under the concentration time curve on day 14 (227 20 ng/mL), day 20 (219 19 ng/mL), day 23 (170 17 ng/mL), day 26 (151 19 ng/mL) and day 30 (150 17 ng/mL) compared to baseline (60.6 10.9 ng/mL). These findings suggest the posaconazole and lurasidone drug interaction persists despite posaconazole discontinuation [26c]. There was a case of severe neuropathic pain attributed to the concomitant administration of posaconazole and vincristine, a CYP3A substrate commonly used as a chemotherapeutic agent for the treatment of acute
lymphoblastic leukemia (ALL). The patient was a 5-year-old female with pre-B-cell acute lymphoblastic leukemia who was started on induction chemotherapy with vincristine, dexamethasone, daunorubicin and PEG-asparaginase. Vincristine was dosed at 1.5 mg/m2 throughout her course. She achieved remission, but consolidation therapy was complicated by febrile neutropenia. She developed a lung nodule which was biopsied, and histology was consistent with mucromycosis. The patient was started on liposomal amphotericin B and oral posoconazole 18 mg/kg/day before undergoing lung resection. The patient then received maintenance chemotherapy with one dose of vincristine and one dose of methotrexate while on posaconazole and amphotericin B. Five days later the patient experienced new severe pain in the right arm, chest, and jaw. The patient also developed foot drop and constipation. Posaconazole was discontinued but restarted after 6 weeks of amphotericin B. The child later continued posaconazole for mucormycosis prophylaxis but was instructed to hold posaconazole 48 h before and on the day of administration of vincristine. Subsequent complications of this drug interaction were not reported [27A].
VORICONAZOLE Skin A multicenter, international, retrospective study aimed to evaluate the risk of voriconazole on squamous cell carcinoma (SCC) in lung transplant recipients. Of the 900 patients included, 55 patients developed SCC. The median time from lung transplant to diagnosis of SCC was 3.3 years (IQR 1.8–4.2 years). In the univariate model, exposure to voriconazole alone was correlated with an increased risk for SCC compared to unexposed patients (hazard ratio 2.55, 95% CI 1.42–4.60). It was also noted that patients with medium and high sunlight exposure were more likely to develop SCC compared to those with low sunlight exposure [28C].
Occular A case report suggests a correlation with voriconazole therapy and macular toxicity with blind spot enlargement. The patient was a 77-year-old man who was receiving voriconazole for pulmonary aspergillosis. On day 3 of therapy, the patient reported incomplete color blindness and ocular hallucination. The Lanthony 15-Hue Desaturated test revealed dyschromatopsia in the left eye and the Goldman visual field examination revealed a blind spot in both eyes. The voriconazole dose was adjusted for supratherapeutic plasma concentrations; however,
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no improvement was noted. The drug was then switched to itraconazole and visual hallucinations resolved [29A].
Observational studies One retrospective, multicenter study aimed to identify the safety of voriconazole in patients with Child-Pugh class C cirrhosis. Patients received voriconazole 200 mg daily in one or two divided doses. Of the 34 patients included, eight patients (23.5%) experienced an adverse event. Of these patients, two patients experienced encephalopathy, two patients developed a rash, one patient experienced tremor, one patient experienced dizziness, one patient reported hallucinations and the final patient was reported to have consciousness disturbance. The mean voriconazole trough level of these eight patients was 5.96 mg/L [30c]. Similarly, the safety profile of voriconazole was studied in a retrospective study of 78 patients with class B and C cirrhosis. Patients were stratified by dosing regimen. Group A patients received the recommended dose regimen based on the voriconazole package insert or a fixed dose of 200 mg twice daily orally or intravenously. Group B patients received a loading dose of 200 mg twice daily on day 1, followed by 100 mg twice daily orally or intravenously. The incidence of adverse events was 26.5% (9/34) in group A and 15.9% (7/44) in group B, P ¼ 0.25. This trend of higher adverse events in group A was suggested to be a consequence of higher voriconazole trough levels compared to group B (6.95 3.42 vs 4.02 2.00, P < 0.001) The most common adverse events were neurologic disturbances (n ¼ 11), including encephalopathy (n ¼ 2). In a multivariate model, factors associated with an elevated voriconazole trough included elevations in international normalized ratio (P ¼ 0.003) and CYP2C19 inhibitor use (P ¼ 0.041) [31c]. The safety of prophylactic voriconazole was studied in a retrospective cohort of 429 courses among 249 with hematologic malignancies. The median number of voriconazole courses per patient was 1.7, whereas the median voriconazole dose was 7 mg/kg every 12 h. Adverse events occurred in 70 courses (16.3%). Of these adverse events, 50% were because of elevated liver enzymes, 24.3% were from hypokalemia, 14.3% were from ophthalmologic disorders, 5.7% were from nausea, 2.8% were from edema, 1.4% were from rash and 1.4% was from keratitis [32C].
Drug interactions A case report attributed sulfonylurea toxicity to concomitant gliclazide and voriconazole use. The patient was a 56-year-old man with a past medical history of type 2 diabetes mellitus and bone marrow transplantation 8 months prior for myelofibrosis. The reported
medications include metformin 2500 mg by mouth in divided doses, gliclazide modified release 90 mg by mouth daily, insulin lispro 6 units subcutaneously with meals and insulin glargine 18 units subcutaneously at night, prednisone 5 mg by mouth daily and was recently started on antifungal therapy prior to admission. The patient was started on voriconazole for suspicion of fungal pneumonia. Six days later the patient developed hallucinations and was transitioned to fluconazole. Of note, on voriconazole therapy, the patient had not required any short acting insulin due to low glucose readings 54–72 mg/dL. The day after transition to fluconazole, the patient presented to the emergency department for confusion and lethargy. He was found to have a blood glucose of 25 mg/dL. He was treated for hypoglycemia and gliclazide was permanently discontinued given the concern of an azole mediated drug interaction [33A].
MICONAZOLE Drug interactions A retrospective analysis of registry data from the United Kingdom was performed to identify significant drug interactions with warfarin. There were 175 patients who had received a combination of miconazole oral gel and warfarin. Prior to miconazole prescription documentation, the mean INR (95% CI) was 2.48 (2.44–2.52). After documentation of miconazole oral gel prescription, the mean INR (95% CI) was 5.83 (5.31–6.36). The mean time between recorded INRs was 19 days [34C]. Acenocoumarol, like warfarin, is an anticoagulant that functions as a vitamin K antagonist. A retrospective analysis was performed to identify the significance of the drug interaction between acenocoumarol and warfarin. A total of 29 patients were included in the study. Patients had received at least 7 days of acenocoumarol, followed by 7 days of a combination of acenocoumarol targeted to an INR of 2.5 with 62 mg of miconazole oral gel. The day before administration of miconazole, the mean INR was 2.2. However, on day 7 of miconazole with warfarin, the mean INR was 4.5 [35c]. An open-label, randomized, cross-over study was conducted to evaluate the drug interaction between three vaginal miconazole nitrate formulations on a vaginal ring containing segesterone acetate and ethinyl estradiol. The study was conducted over three menstrual cycles in healthy women with regular menses. Twenty-nine participants completed the study. While concomitant administration of miconazole cream did not affect hormone levels, the maximum ethinyl estradiol geometric ratio for AUC was elevated at 1.67 (1.51–1.86) with a single-dose of miconazole suppositories. However, no serious treatment adverse events were reported [36c].
REFERENCES
AMPHOTERICIN Observational study A randomized trial assessed different the safety and efficacy of different induction treatment regimens for cryptococcal meningitis in HIV infected adults. Patients were randomized to receive to receive an oral regimen of fluconazole plus flucytosine for 2 weeks, 1 week of amphotericin B, or 2 weeks of amphotericin B. Each patient assigned to receive amphotericin B was also randomly assigned to receive fluconazole or flucytosine as a partner drug. A total of 721 patients were included. Amphotericin B was dosed at 1 mg/kg/day, flucytosine was dosed at 100 mg/kg/day and fluconazole was dosed at 1200 mg/day. Grade 4 anemia occurred in 8.8% of patients who were randomized to 2 weeks of amphotericin B, 4.9% of patients who were randomized to receive 1 week of amphotericin B and in 0.9% of patients who did not receive amphotericin B. A grade 3 or 4 increase in the serum creatinine level developed in 4.9% of patients who did not receive amphotericin B, 6.2% of patients in the 1-week amphotericin B groups, and 8.8% of patients in the 2-week amphotericin B groups [37MC].
PYRIMADINE ANALOGUES Flucytosine See Section ‘Observational study’.
ECHINOCANDINS Anidulafungin An open-label, single-arm, prospective study was performed to assess the safety of anidulafungin for invasive candidiasis including candidemia in patients between the ages of 2 and 18 years old. Forty-nine patients were eligible for inclusion and at least one treatment emergent adverse effect was reported in all patients. Diarrhea, vomiting and pyrexia were most frequent and occurred in 22.4%, 24.5% and 18.4% of patients respectively. There were 4 patients who discontinued treatment due to an adverse event that was deemed to be related to anidulafungin. These adverse events include increased transaminases, increased alanine/aspartate aminotransferases, vomiting and pruritis [38c].
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