Anidulafungin
- Dosage:
- A single 200 mg loading dose of anidulafungin on Day 1, followed by 100 mg daily dose thereafter.
- Duration of treatment should be based on the patient's clinical response.
- Antifungal therapy should continue for at least 14 days after the last positive culture.
- Dosage:
- A single 100 mg loading dose of anidulafungin on Day 1, followed by 50 mg daily dose thereafter.
- Patients should be treated for a minimum of 14 days and for at least 7 days following resolution of symptoms.
- Candida infection of the cardiovascular system
- Candida osteoarticular infections
- Chronic disseminated candidiasis
- Primary empiric antifungal therapy for suspected candidiasis in non-neutropenic patients
- Oropharyngeal candidiasis in patients with HIV
- Oropharyngeal candidiasis
Laboratory abnormalities in liver function tests have been seen in healthy volunteers and patients treated with anidulafungin. In some patients with serious underlying medical conditions who were receiving multiple concomitant medications along with anidulafungin, clinically significant hepatic abnormalities have occurred. Isolated cases of significant hepatic dysfunction, hepatitis, or hepatic failure have been reported in patients; a causal relationship to anidulafungin has not been established. Patients who develop abnormal liver function tests during anidulafungin therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing anidulafungin therapy.
Anaphylactic reactions, including shock were reported with the use of anidulafungin. If these reactions occur, anidulafungin should be discontinued and appropriate treatment administered.
Infusion-related adverse reactions, possibly histamine-mediated, have been reported with anidulafungin, including rash, urticaria, flushing, pruritus, bronchospasm, dyspnea, and hypotension. To reduce occurrence of these reactions, do not exceed a rate of anidulafungin infusion of 1.1 mg/minute.
The safety of anidulafungin for Injection was assessed in 929 individuals, including 257 healthy subjects and 672 patients in clinical trials of candidemia, other forms of Candida infections, and esophageal candidiasis. A total of 633 patients received anidulafungin at daily doses of either 50 mg or 100 mg. A total of 481 patients received anidulafungin for 14 days.
Three studies (one comparative vs. fluconazole, two non-comparative) assessed the efficacy and safety of anidulafungin (100 mg) in patients with candidemia and other Candida infections.
The data described below reflect exposure to anidulafungin and fluconazole in 127 and 118 patients, respectively, with candidemia and other forms of invasive candidiasis, in the randomized, comparative trial of the efficacy and safety of anidulafungin to that of fluconazole. In anidulafungin-treated patients, the age range was 1689 years, the gender distribution was 51% male and 49% female, and the race distribution was 72% White, 18% Black/African American, 9% other races. Patients were randomized to receive once daily IV anidulafungin (200 mg loading dose followed by 100 mg maintenance dose) or IV fluconazole (800 mg loading dose followed by 400 mg maintenance dose). Treatment was administered for at least 14 and not more than 42 days.
The number of patients with adverse reactions leading to discontinuation of study medication was 11.5% in the anidulafungin arm and 21.6% in the fluconazole arm. The most common adverse reactions leading to study drug discontinuation were multi-organ failure and systemic Candida infection in the anidulafungin arm.
Table 2 presents adverse reactions that were reported in 5% of subjects receiving anidulafungin or fluconazole therapy in this trial.
The data described below reflect exposure to anidulafungin and fluconazole in 300 and 301 patients, respectively, with esophageal candidiasis in a randomized trial comparing the efficacy and safety of anidulafungin to that of oral fluconazole. In anidulafungin-treated patients, the age range was 1868 years, the gender distribution was 42% male and 58% female and the race distribution was 15% White, 49% Black/African American, 15% Asian, 0.3 % Hispanic, 21% other races. Patients were randomized to receive IV anidulafungin (100 mg on day 1, followed by 50 mg per day) or oral fluconazole (200 mg on day 1, followed by 100 mg per day) for 7 days beyond resolution of symptoms (range, 1421 days).
Twenty eight (9%) patients in the anidulafungin arm and 36 (12%) patients in the fluconazole arm had adverse reactions leading to discontinuation of study medication. The most common adverse reactions leading to study drug discontinuation were maculopapular rash for the anidulafungin arm. The most common adverse reactions leading to discontinuation were rash and increased AST for the fluconazole arm.
Table 3 presents adverse reactions that were reported in 5% of subjects receiving anidulafungin therapy.
The following selected adverse reactions occurred in <2% of patients:
- Blood and Lymphatic: coagulopathy, thrombocytopenia
- Cardiac: atrial fibrillation, bundle branch block (right), sinus arrhythmia, ventricular extrasystoles
- Eye: eye pain, vision blurred, visual disturbance
- General and Administration Site: infusion related reaction, peripheral edema, rigors
- Hepatobiliary: abnormal liver function tests, cholestasis, hepatic necrosis
- Infections: clostridial infection
- Investigations: amylase increased, bilirubin increased, CPK increased, electrocardiogram QT prolonged, gamma-glutamyl transferase increased, lipase increased, potassium decreased, prothrombin time prolonged, urea increased
- Nervous System: convulsion, dizziness
- Respiratory, Thoracic and Mediastinal: cough
- Skin and Subcutaneous Tissue: angioneurotic edema, erythema, pruritus, sweating increased, urticaria
- Vascular: flushing, hot flushes, thrombophlebitis superficial
- Immune: Anaphylactic shock, anaphylactic reaction, bronchospasm
Administration of multiple doses of anidulafungin and cyclosporine to healthy subjects resulted in no significant alteration in the steady state pharmacokinetics of either drug. No dosage adjustment of cyclosporine or anidulafungin is needed when the two drugs are co-administered.
Administration of multiple doses of anidulafungin and voriconazole to healthy subjects resulted in no significant alteration in the steady state pharmacokinetics of either drug. No dosage adjustment of voriconazole or anidulafungin is needed when the two drugs are co-administered.
Administration of multiple doses of anidulafungin and a single dose of tacrolimus to healthy subjects resulted in no significant alteration in the steady state pharmacokinetics of either drug. No dosage adjustment of tacrolimus or anidulafungin is needed when the two drugs are co-administered.
Administration of multiple doses of anidulafungin and rifampin to patients resulted in no significant alteration in the steady state pharmacokinetics of anidulafungin. No dosage adjustment of anidulafungin is needed when it is co-administered with rifampin.
Administration of multiple doses of anidulafungin and liposomal amphotericin B to patients resulted in no significant alteration in the steady state pharmacokinetics of anidulafungin. No dosage adjustment of anidulafungin is needed when it is co-administered with liposomal amphotericin B.
Of the total number of subjects (N = 197) in the pivotal clinical studies of anidulafungin, 35% were 65 years and over, while 18% were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Anidulafungin is not dialyzable.
The maximum non-lethal dose of anidulafungin in rats was 50 mg/kg, a dose which is equivalent to 10 times the recommended daily dose for esophageal candidiasis (50 mg/day) or equivalent to 5 times the recommended daily dose for candidemia and other Candida infections (100 mg/day), based on relative body surface area comparisons.
The clearance of anidulafungin is about 1 L/h and anidulafungin has a terminal elimination half-life of 4050 hours.
The pharmacokinetics of anidulafungin following IV administration are characterized by a short distribution half-life (0.51 hour) and a volume of distribution of 3050 L that is similar to total body fluid volume. Anidulafungin is extensively bound (>99%) to human plasma proteins.
Hepatic metabolism of anidulafungin has not been observed. Anidulafungin is not a clinically relevant substrate, inducer, or inhibitor of cytochrome P450 (CYP450) isoenzymes. It is unlikely that anidulafungin will have clinically relevant effects on the metabolism of drugs metabolized by CYP450 isoenzymes.
Anidulafungin undergoes slow chemical degradation at physiologic temperature and pH to a ring-opened peptide that lacks antifungal activity. The in vitro degradation half-life of anidulafungin under physiologic conditions is about 24 hours. In vivo, the ring-opened product is subsequently converted to peptidic degradants and eliminated.
In a single-dose clinical study, radiolabeled (14C) anidulafungin was administered to healthy subjects. Approximately 30% of the administered radioactive dose was eliminated in the feces over 9 days, of which less than 10% was intact drug. Less than 1% of the administered radioactive dose was excreted in the urine. Anidulafungin concentrations fell below the lower limits of quantitation 6 days post-dose. Negligible amounts of drug-derived radioactivity were recovered in blood, urine, and feces 8 weeks post-dose.
Anidulafungin has been shown to be active against Candida albicans, C. glabrata, C. parapsilosis, and C. tropicalis both in vitro and in clinical infections. Because of the potential for reduced susceptibility to anidulafungin, it is recommended that susceptibility be determined by a standardized method.
Anidulafungin minimal inhibitory concentrations (MICs) were determined for isolates of Candida spp. obtained during clinical studies using a standardized method. However, no correlation between in vitro activity as determined by this method and clinical outcome was established.
Echinocandin resistance is due to point mutations within the genes (FKS1 and FKS2) encoding for subunits in the glucan synthase enzyme complex. There have been reports of Candida isolates with reduced susceptibility to anidulafungin, suggesting a potential for development of drug resistance. The clinical significance of this observation is not fully understood.
Long-term animal carcinogenicity studies of anidulafungin have not been conducted.
Anidulafungin was not genotoxic in the following in vitro studies: bacterial reverse mutation assays, a chromosome aberration assay with Chinese hamster ovary cells, and a forward gene mutation assay with mouse lymphoma cells. Anidulafungin was not genotoxic in mice using the in vivo micronucleus assay.
In 3 month studies, liver toxicity, including single cell hepatocellular necrosis, hepatocellular hypertrophy and increased liver weights were observed in monkeys and rats at doses equivalent to 56 times human exposure. For both species, hepatocellular hypertrophy was still noted one month after the end of dosing.
The safety and efficacy of anidulafungin were evaluated in a Phase 3, randomized, double-blind study of patients with candidemia and/or other forms of invasive candidiasis. Patients were randomized to receive once daily IV anidulafungin (200 mg loading dose followed by 100 mg maintenance dose) or IV fluconazole (800 mg loading dose followed by 400 mg maintenance dose). Patients were stratified by APACHE II score (20 and >20) and the presence or absence of neutropenia. Patients with Candida endocarditis, osteomyelitis or meningitis, or those with infection due to C. krusei, were excluded from the study. Treatment was administered for at least 14 and not more than 42 days. Patients in both study arms were permitted to switch to oral fluconazole after at least 10 days of intravenous therapy, provided that they were able to tolerate oral medication, were afebrile for at least 24 hours, and the last blood cultures were negative for Candida species.
Patients who received at least one dose of study medication and who had a positive culture for Candida species from a normally sterile site before entry into the study (modified intent-to-treat  population) were included in the analysis of global response at the end of IV therapy. A successful global response required clinical cure or improvement (significant, but incomplete resolution of signs and symptoms of the Candida infection and no additional antifungal treatment), and documented or presumed microbiological eradication. Patients with an indeterminate outcome were analyzed as failures in this population.
Two hundred and fifty-six patients in the intent-to-treat (ITT) population were randomized and received at least one dose of study medication. In anidulafungin-treated patients, the age range was 1689 years, the gender distribution was 50% male and 50% female, and the race distribution was 71% White, 20% Black/African American, 7% Hispanic, 2% other races. The median duration of IV therapy was 14 and 11 days in the anidulafungin and fluconazole arms, respectively. For those who received oral fluconazole, the median duration of oral therapy was 7 days for the anidulafungin arm and 5 days for the fluconazole arm.
Patient disposition is presented in Table 7.
Two hundred and forty-five patients (127 anidulafungin, 118 fluconazole) met the criteria for inclusion in the MITT population. Of these, 219 patients (116 anidulafungin, 103 fluconazole) had candidemia only. Risk factors for candidemia among patients in both treatment arms in this study were: presence of a central venous catheter (78%), receipt of broad-spectrum antibiotics (69%), recent surgery (42%), recent hyperalimentation (25%), and underlying malignancy (22%). The most frequent species isolated at baseline was C. albicans (62%), followed by C. glabrata (20%), C. parapsilosis (12%) and C. tropicalis (11%). The majority (97%) of patients were non-neutropenic (ANC >500) and 81% had APACHE II scores less than or equal to 20.
Global success rates in patients with candidemia and other Candida infections are summarized in Table 8.
Table 9 presents global response by patients with candidemia or multiple sites of Candida infection and mortality data for the MITT population.
Anidulafungin was evaluated in a double-blind, double-dummy, randomized Phase 3 study. Three hundred patients received anidulafungin (100 mg loading dose IV on Day 1 followed by 50 mg/day IV) and 301 received oral fluconazole (200 mg loading dose on Day 1 followed by 100 mg/day). Treatment duration was 7 days beyond resolution of symptoms for a minimum of 14 and a maximum of 21 days.
Of the 442 patients with culture confirmed esophageal candidiasis, most patients (91%) had C. albicans isolated at the baseline.
Treatment groups were similar in demographic and other baseline characteristics. In anidulafungin-treated patients, the age range was 1669 years, the gender distribution was 42% male and 58% female, and the race distribution was 15% White, 49% Black/African American, 15% Asian, 0.3 % Hispanic, 21% other races.
In this study, of 280 patients tested, 237 (84.6%) tested HIV positive. In both groups the median time to resolution of symptoms was 5 days and the median duration of therapy was 14 days.
Efficacy was assessed by endoscopic outcome at end of therapy (EOT). Patients were considered clinically evaluable if they received at least 10 days of therapy, had an EOT assessment with a clinical outcome other than 'indeterminate', had an endoscopy at EOT, and did not have any protocol violations prior to the EOT visit that would affect an assessment of efficacy.
An endoscopic success, defined as cure (endoscopic grade of 0 on a 4-point severity scale) or improvement (decrease of one or more grades from baseline), was seen in 225/231 (97.4%) anidulafungin-treated patients and 233/236 (98.7%) fluconazole-treated patients (Table 10). The majority of these patients were endoscopic cures (grade=0). Two weeks after completing therapy, the anidulafungin group had significantly more endoscopically-documented relapses than the fluconazole group, 120/225 (53.3%) vs. 45/233 (19.3%), respectively (Table 10).
Clinical success (cure or improvement in clinical symptoms including odynophagia/dysphagia and retrosternal pain) occurred in 229/231 (99.1%) of the anidulafungin-treated patients and 235/236 (99.6%) of the fluconazole-treated patients at the end of therapy. For patients with C. albicans, microbiological success occurred in 142/162 (87.7%) of the anidulafungin-treated group and 157/166 (94.6%) of the fluconazole-treated group at the end of therapy. For patients with Candida species other than C. albicans, success occurred in 10/12 (83.3%) of the anidulafungin-treated group and 14/16 (87.5%) of the fluconazole-treated group.
- NDC 0049-0114-28
- Single-Use Vial of anidulafungin 100 mg
- NDC 0049-0116-28
- Anidulafungin reconstituted solution: Stored at up to 25C (77F) for up to 24 hours.
Inform patients about the risk of developing abnormal liver function tests and/or hepatic dysfunction. Advise the patient that liver function tests may be monitored during treatment.
Inform the patient that anaphylactic reactions, including shock were reported with anidulafungin. Inform the patient if these reactions occur, anidulafungin may be discontinued and appropriate treatment administered.
Inform the patient that anidulafungin is also known to cause infusion-related adverse reactions, possibly histamine-mediated. Inform the patient to report symptoms including rash, urticaria, flushing, pruritus, dyspnea, and hypotension to their healthcare provider.
Inform patients that anidulafungin has not been studied in pregnant women or nursing mothers so the effects of anidulafungin on pregnant women or nursing infants are not known. Instruct patients to tell their healthcare provider if they are pregnant, become pregnant, or are thinking about becoming pregnant. Instruct patients to tell their healthcare provider if they plan to breast-feed their infant.
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