Eraxis (Pfizer Canada, PM 00016357) Product Monograph

SUMMARY PRODUCT INFORMATION

* For a complete listing, see Dosage Forms, Composition and Packaging section.

INDICATIONS AND CLINICAL USE

ERAXIS (anidulafungin) is indicated for:

• treatment of invasive candidiasis/candidemia in adult non-neutropenic patients.

ERAXIS has not been studied in endocarditis, osteomyelitis, or meningitis due to Candida. Infections caused by C. krusei have not been studied. Neutropenic patients have not been studied in sufficient numbers to determine the efficacy of the drug in this group (see CLINICAL TRIALS).

CONTRAINDICATIONS

ERAXIS is contraindicated to patients with known hypersensitivity to anidulafungin, any component of ERAXIS, or other echinocandins. For a complete listing see the Dosage Forms, Composition and Packaging section of the Product Monograph.

WARNINGS AND PRECAUTIONS

General

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Infusion Related

Infusion-related adverse events have been reported with anidulafungin, including rash, urticaria, flushing, pruritus, dyspnea, bronchospasm and hypotension. Infusion-related events are infrequent when the rate of anidulafungin infusion does not exceed 1.1 mg/minute (see ADVERSE REACTIONS, Adverse Drug Reaction Overview).

Carcinogenesis and Mutagenesis

No long - term studies in animals have been performed to evaluate the carcinogenic potential of anidulafungin. For information on animal data, see the DETAILED PHARMACOLOGY and TOXICOLOGY sections of the Product Monograph.

Hepatic

Laboratory abnormalities in liver function tests have been seen in healthy subjects 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

Anaphylactic reactions, including shock, were reported with the use of anidulafungin. If these reactions occur, anidulafungin should be discontinued and appropriate treatment administered.

Special Populations

Pregnant Women: Animal studies have shown no selective reproductive toxicity (see TOXICOLOGY). There are no adequate and well-controlled studies in pregnant women. Therefore, ERAXIS (anidulafungin) should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

Nursing Women: Animal studies have shown excretion of anidulafungin in breast milk (see TOXICOLOGY). It is not known whether anidulafungin is excreted in human breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with anidulafungin should be made taking into account the benefit of breast-feeding to the child and the benefit of anidulafungin to the woman.

Pediatrics: The experience in children is limited. Use in patients under 18 years of age is not recommended until further data become available, unless the potential benefit justifies the risk (see DOSAGE and ADMINISTRATION, CLINICAL PHARMACOLOGY, Pharmacokinetics).

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Nine hundred and twenty-nine (929) patients received intravenous anidulafungin in clinical trials (672 in Phase 2/3 studies and 257 in Phase 1 studies). Of the 669 Phase 2/3 patients for whom safety data are available, 505 received anidulafungin for ≥ 14 days.

Three studies (one comparative vs fluconazole, two non-comparative) assessed the efficacy of anidulafungin (100 mg) in patients with candidemia and other deep tissue Candida infections. In these three studies [invasive candidiasis/candidaemia (ICC) database], a total of 204 patients received anidulafungin, 119 for ≥ 14 days. Adverse events were typically mild to moderate and seldom led to discontinuation.

Infusion-related adverse events have been reported with anidulafungin, including rash, urticaria, flushing, pruritus, dyspnea, bronchospasm and hypotension. These events can be minimized by infusing anidulafungin at a rate that does not exceed 1.1 mg/minute.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The following table presents drug-related adverse events (MedDRA terms) from the ICC database, that were reported in ≥2.0% of subjects receiving ERAXIS or fluconazole therapy for candidemia/other Candida infections in the comparative study.

^a Treatment-related AEs are defined as those that are possibly or probably related to study treatment, as determined by the investigator.

^b Maintenance dose

Less Common Clinical Trial Adverse Drug Reactions

The drug-related adverse events (MedDRA terms) listed below were reported from the ICC database, with frequencies of ≤1.0% in patients receiving ERAXIS therapy for candidemia/other Candida infections in the comparative study (N=131), and from clinical trial post-marketing reports with frequency not known (cannot be estimated from the available data).

Cardiac Disorders: Atrial fibrillation, bundle branch block right, sinus arrhythmia, ventricular extrasystoles

Eye Disorders: Vision blurred, eye pain, visual disturbance

Gastrointestinal Disorders: Nausea, abdominal pain upper, fecal incontinence, loose stools

Hepatobiliary Disorders: Cholestasis

Infections and Infestations: Candidiasis, clostridial infection, oral candidiasis

Investigations: AST ↑, blood amylase ↑, blood creatinine ↑, lipase ↑

Metabolism and Nutrition Disorders: Hyperkalemia, hypercalcemia, hypernatremia

Nervous System Disorders: Headache, convulsion

Skin and Subcutaneous Tissue Disorders: Rash, pruritis generalized, rash papular, urticaria

Social Circumstances: Early adult transition

Vascular Disorders: Deep vein thrombosis, hot flush, hypertension

Respiratory, Thoracic and Mediastinal Disorders: Bronchospasm

Abnormal Hematologic Findings

The following potentially clinically-significant changes from baseline in hematology values were reported in ≥2.0% of subjects receiving ERAXIS or fluconazole therapy for candidemia/other Candida infections in the comparative study.

EIV=End of IV Therapy; 6w FU=6 week follow-up visit

^a Maintenance dose

Note: Post baseline potentially clinically-significant change values that are within normal range are not included.

Abnormal Chemistry Findings

The following potentially clinically-significant changes from baseline in chemistry values were reported in ≥2.0% of subjects receiving ERAXIS or fluconazole therapy for candidemia/other Candida infections in the comparative study.

EIV=End of IV Therapy; 6w FU=6 week follow-up visit

^a Maintenance dose [Missing footnote from NDS]

Note: Post baseline potentially clinically-significant change values that are within normal range are not included.

Post-Market Adverse Drug Reactions

The following adverse events have been reported during the post-approval period of ERAXIS. Because these reactions are reported voluntarily from populations of uncertain size, it is not always possible to reliably estimate their frequency. A causal relationship to ERAXIS could not be excluded for these adverse events. Adverse events were reported in the following SOC (system organ classes):

Metabolism and Nutrition Disorders (dehydration), Hepatobiliary Disorders (bile duct obstruction), General disorders and administration site conditions (injection site reaction). Nervous system disorders (cerebrovascular accident, convulsion), Blood and lymphatic system disorders (leucopenia), Investigations (Blood creatinine increased, blood urea increased, tacrolimus drug level decreased, hepatic enzyme increased, liver function test abnormal, white blood cell count decreased). Immune system disorders (Anaphylactic shock, anaphylactic reaction).

DRUG INTERACTIONS

Overview

Preclinical in vitro and in vivo studies and clinical studies have demonstrated that anidulafungin is not a clinically-relevant substrate, inducer or inhibitor of cytochrome P450 isoenzymes. Interaction studies have only been performed in adults. Anidulafungin has negligible renal clearance (<1%). Minimal interactions are expected with concomitant medications (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

In vitro studies showed that anidulafungin is not metabolized by human cytochrome P450 or by isolated human hepatocytes, and anidulafungin does not significantly inhibit the activities of human CYP isoforms (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4) at clinically-relevant concentrations. Of note, these in vitro studies do not fully exclude possible in vivo interactions.

No clinically-relevant drug-drug interactions were observed with the following drugs likely to be co-administered with anidulafungin.

Drug-Drug Interactions

Drug interaction studies were performed with anidulafungin and other medicinal products likely to be co-administered (Table 4 and Table 5). Co-administration with cyclosporine increased the steady-state AUC of anidulafungin by 22%, and adverse events observed in the study were consistent with adverse events observed from other studies with the administration of anidulafungin alone. A separate in vitro study showed that anidulafungin has no effect on the metabolism of cyclosporine. No dosage adjustment of either drug is recommended when anidulafungin is co-administered with cyclosporine, voriconazole or tacrolimus.

Table 4. Effect of Other Drugs on the Pharmacokinetic Parameters of Anidulafungin

† 90% confidence interval not reported * Statistically significant (p<0.05)

Table 5. Effect of Anidulafungin on the Pharmacokinetic Parameters of Other Drugs

Other Medications

The pharmacokinetics of anidulafungin were examined in 27 patients that were co-administered with liposomal amphotericin B as well as in 27 patients that were co-administered with rifampin (potent CYP450 inducer). The population pharmacokinetic analysis suggested that when compared to data from patients that did not receive amphotericin B or rifampin, the pharmacokinetics of anidulafungin were not significantly altered by co-administration with amphotericin B or rifampin. No dose adjustment for anidulafungin is recommended when co-administered with amphotericin B or rifampin.

Population pharmacokinetic analysis has shown that the pharmacokinetic parameters of anidulafungin were not affected by the presence of concomitant medications which are known metabolic substrates, inhibitors or inducers of cytochrome P450 isoenzymes.

Population pharmacokinetic analysis also indicated that overall healthy subjects, HIV positive subjects, and HIV-positive patients with fungal infections appeared to have comparable exposure parameters.

Drug-Food Interactions

Not applicable since ERAXIS (anidulafungin) is a parenterally administered product.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Dosing Considerations

ERAXIS should be reconstituted with Water for Injection to a concentration of 3.33 mg/mL and subsequently diluted to a concentration of 0.77 mg/mL before use according to the instructions given in section Reconstitution.

Recommended Dose and Dosage Adjustment

Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.

A single 200 mg loading dose should be administered on Day 1, followed by 100 mg daily thereafter. Duration of treatment should be based on the patient’s clinical response. In general, antifungal therapy should continue for at least 14 days after the last positive culture.

Renal and Hepatic Impairment

No dosing adjustments are required for patients with mild, moderate or severe hepatic impairment. No dosing adjustments are required for patients with any degree of renal insufficiency, including those on dialysis. Anidulafungin can be given without regard to the timing of hemodialysis (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions).

Other Special Populations

No dose adjustments are required for adult patients based on patient gender, ethnicity, HIV positivity, or geriatric status. (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions).

Children and Adolescents

The experience in children is limited. Use in patients under 18 years of age is not recommended until further data become available, unless the potential benefit justifies the risk (see WARNINGS and PRECAUTIONS, ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

Administration

It is recommended that ERAXIS is administered at a maximum rate of infusion that does not exceed 1.1 mg/minute.

Reconstitution:

Anidulafungin must be reconstituted with sterile Water for Injection and subsequently diluted with ONLY 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline). The compatibility of reconstituted anidulafungin with intravenous substances, additives, or medications other than 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline) has not been established.

Aseptically reconstitute each vial with 30 mL sterile Water for Injection to provide a concentration of 3.33 mg/mL. The reconstitution time can be up to 5 minutes.

If not used immediately, the reconstituted solution should be stored at 15 - 30 °C for up to 24 hours.

Dilution and Infusion

Aseptically transfer the contents of the reconstituted vial(s) into an IV bag (or bottle) containing either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline) obtaining an anidulafungin concentration of 0.77 mg/ml. The table below provides the volumes required for each dose.

Dilution Requirements for Anidulafungin Administration

^A Either Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline).

^B Infusion solution concentration is 0.77 mg/mL

The rate of infusion should not exceed 1.1 mg/minute (equivalent to 1.4 mL/minute).

The infusion solution may be stored at 15 - 30 °C for 48 hours or stored frozen for at least 72 hours. The infusion solution must be administered within 24 hours. For single use only.

Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. If particulate matter or discolouration are identified, discard the solution.

For further information on storage and stability for the infusion and reconstituted solution, see section STORAGE AND STABILITY.

OVERDOSAGE

For the management of a suspected drug overdose, contact your regional Poison Control Centre.

As with any overdose, general supportive measures should be utilized as necessary.

During clinical trials a single 400 mg dose of anidulafungin was inadvertently administered as a loading dose. No clinical adverse events were reported. In a study of 10 healthy subjects administered a loading dose of 260 mg followed by 130 mg daily, anidulafungin was well tolerated with no dose limiting toxicity; 3 of the 10 subjects experienced transient, asymptomatic transaminase elevations (≤3 x ULN).

Anidulafungin is not dialyzable.

The maximum non-lethal single dose of anidulafungin in rats was 50 mg/kg, a dose which is equivalent to 5 times the recommended daily dose in humans for Candidemia and other Candida infections [100 mg/day] , based on the relative body surface area comparison.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

ERAXIS (anidulafungin) is a semi-synthetic echinocandin, a lipopeptide synthesized from a fermentation product of Aspergillus nidulans.

Pharmacodynamics

Anidulafungin selectively inhibits 1,3-β-D glucan synthase, an enzyme present in fungal, but not mammalian cells. This results in inhibition of the formation of 1,3-β-D-glucan, an essential component of the fungal cell wall. Anidulafungin has shown fungicidal activity against Candida species and activity against regions of active cell growth of the hyphae of Aspergillus fumigatus.

Anidulafungin has in vitro activity against various pathogenic fungi of the Aspergillus and Candida species (see MICROBIOLOGY).

Pharmacokinetics

The pharmacokinetics of anidulafungin following IV administration have been characterized in healthy subjects, special populations and patients. Systemic exposures of anidulafungin are dose-proportional and have low intersubject variability (coefficient of variation <25%) as shown in Table

1. 6. The steady state was achieved on the first day after a loading dose (twice the daily maintenance dose).

^a Parameters were obtained from separate studies ^b LD/MD: loading dose/maintenance dose once daily ^c Data were collected on Day 7

^d Safety and efficacy of these doses has not been established ^e See OVERDOSAGE

C_max,ss = the steady state peak concentration

C_min,ss = the steady state trough concentration AUC_ss = the steady state area under concentration vs. time curve CL = clearance

t_1/2 = the terminal elimination half-life

CV = coefficient of variation*

The clearance and terminal elimination half-life of anidulafungin are about 1 L/h and 40-50 hours, respectively. Both of these pharmacokinetic parameters have been found to be independent of dosage. The pharmacokinetics of anidulafungin in patients with fungal infections are similar to those observed in healthy subjects (see Special Populations and Conditions, Patients with fungal infections).

Distribution: The pharmacokinetics of anidulafungin are characterized by a rapid distribution half-life (0.5-1 hour) and a volume of distribution of 30-50 L that is similar to total body fluid volume. Anidulafungin is extensively bound (>99%) to human plasma proteins.

Biotransformation: Hepatic metabolism of anidulafungin has not been observed. Anidulafungin is not a clinically-relevant substrate, inducer, or inhibitor of cytochrome P450 isoenzymes. It is unlikely that anidulafungin will have clinically-relevant effects on the metabolism of drugs metabolized by cytochrome P450 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 approximately 24 hours. In vivo, the ring-opened product is subsequently converted to peptidic degradants and eliminated mainly through biliary excretion.

Excretion: In a single-dose clinical study, radiolabeled (¹⁴C) anidulafungin (~ 88 mg) 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.

Linearity: Anidulafungin displays linear pharmacokinetics across a wide range of once daily doses (15-130 mg).

Special Populations and Conditions

Patients with fungal infections: Population pharmacokinetic analyses from four Phase 2/3 clinical studies including 107 males and 118 female patients with fungal infections showed that the pharmacokinetic parameters of anidulafungin are not affected by age, race, or the presence of concomitant medications which are known metabolic substrates, inhibitors or inducers of cytochrome P450 isoenzymes. The pharmacokinetics of anidulafungin in patients with fungal infections are similar to those observed in healthy subjects. The pharmacokinetic parameters of anidulafungin estimated using population pharmacokinetic modeling following IV administration of a maintenance dose of 50 mg/day or 100 mg/day (following a loading dose) are presented in Table

7.

^a All the parameters were estimated by population modeling using a two-compartment model with first order elimination; AUC_ss, C_max,ss and C_min,ss (steady state trough plasma concentration) were estimated using individual PK parameters and infusion rate of 1 mg/min to administer recommended doses of 50 or 100 mg/day.

^b t_{1/2, β} is the predominant elimination half-life that characterizes the majority of the concentration-time profile. ^c LD/MD: loading dose/maintenance dose

CV = coefficient of variation*

Pediatrics: The pharmacokinetics of anidulafungin after daily doses were investigated in 24 immunocompromised pediatric (2 to 11 years old) and adolescent (12 to 17 years old) patients with neutropenia. The steady state was achieved on the first day after a loading dose (twice the maintenance dose), and the steady state C_max and AUC_ss increase in a dose-proportional manner. The systemic exposures following the daily maintenance doses of 0.75 and 1.5 mg/kg/day in patients aged 2 to 17 years old were comparable to those observed in adults following 50 and 100 mg/day, respectively.

Geriatrics: The population pharmacokinetic analysis showed that median clearance differed slightly between the elderly group (patients ≥ 65, median CL = 1.07 L/h) and the non-elderly group (patients < 65, median CL = 1.22 L/h), however the range of clearance was similar.

Gender: Plasma concentrations of anidulafungin in healthy men and women were similar. In multiple-dose patient studies, drug clearance was slightly faster (approximately 22%) in men.

Ethnicity: Anidulafungin pharmacokinetics were similar among Caucasians, Blacks, Asians, and Hispanics.

HIV Positivity: Dosage adjustments are not required based on HIV status, irrespective of concomitant anti-retroviral therapy.

Hepatic Insufficiency: Anidulafungin is not hepatically metabolized. Anidulafungin pharmacokinetics were examined in subjects with Child-Pugh Class A, B or C hepatic insufficiency. Anidulafungin concentrations were not increased in subjects with any degree of hepatic insufficiency. Although slight decrease in AUC was observed in patients with Child-Pugh C hepatic insufficiency, the decrease was within the range of population estimates noted for healthy subjects.

Renal Insufficiency: Anidulafungin has negligible renal clearance (< 1%). In a clinical study of subjects with mild, moderate, severe or end stage (dialysis-dependent) renal insufficiency, anidulafungin pharmacokinetics were similar to those observed in subjects with normal renal function. Anidulafungin is not dialyzable and may be administered without regard to the timing of hemodialysis.

STORAGE AND STABILITY

Unreconstituted Vials:

Unreconstituted vials should be stored at 2-8ºC. Excursions for 96 hours up to 25°C are permitted, and the powder can be returned to refrigerated storage.

Reconstituted Solution:

Reconstitute with water for injection. The reconstituted solution may be stored at 15 - 30°C for up to 24 hours. Chemical and physical in-use stability of the reconstituted solution has been demonstrated for 24 hours at 25°C.

Infusion Solution:

The infusion solution should be stored at 15 - 30°C, for up to 48 hours or stored frozen for at least 72 hours. Chemical and physical in-use stability of the infusion solution has been demonstrated for 48 hours at 25ºC.

SPECIAL HANDLING INSTRUCTIONS

Not applicable.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Form and Packaging:

ERAXIS (anidulafungin) is marketed as a carton containing 1 vial of 100 mg anidulafungin.

Anidulafungin powder:

100 mg lyophile in a 30 mL Type 1 glass vial with an elastomeric stopper and aluminium seal with flip-off cap.

Composition:

Anidulafungin powder: Each vial contains 100 mg anidulafungin and the following inactive ingredients: Fructose, mannitol, polysorbate 80, tartaric acid and sodium hydroxide and/or hydrochloric acid for pH adjustment.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Common name: Anidulafungin

Chemical name: 1-[(4R,5R)-4,5-dihydroxy-N²-[[4"-(pentyloxy)[1,1':4',1"-terphenyl]-

4-yl]carbonyl]-L-ornithine]echinocandin B.

Molecular formula: C₅₈H₇₃N₇O₁₇

Molecular weight: 1140.2

Structural formula:

HO OH

NH

HN O

OH CH₃ H

N O

H H

OH

H HHN

OH O

NH

H

HO

HO

H

HO H

O

N

O HO

H₃C

H

H

H

HHO

H₃C H

O O

NH

Description: Anidulafungin is a white to off-white solid. It is slightly soluble in ethanol, water/acetonitrile (1:1) and is insoluble in water, citrate buffer, acetonitrile and ethanol/water (1:1).

pK_a: 9.5

CLINICAL TRIALS

Study Demographics and Trial Design

Candidemia and Other Forms of Invasive Candidiasis

The safety and efficacy of anidulafungin were evaluated in a pivotal Phase 3, randomized, double-blind, multicentre, multinational study of patients with candidemia and/or other forms of invasive candidiasis, associated with clinical signs of infection. Patients were randomized to receive once daily i.v. anidulafungin (200 mg loading dose followed by 100 mg maintenance dose) or i.v. 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 most recent 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 [MITT] population) were included in the primary analysis of global response at the end of i.v. therapy. A successful global response required clinical improvement and microbiological eradication. Patients were followed for 6 weeks beyond the end of all therapy.

Two hundred and fifty-six (256) patients (aged 16 to 91 years) were randomized to treatment and received at least one dose of study medication. The median duration of i.v. therapy was 14 and 11 days in the ERAXIS (anidulafungin) and fluconazole arms, respectively. For those who received oral fluconazole, the median duration of oral therapy was 7 days for the ERAXIS arm and 5 days for the fluconazole arm.

Patient disposition is presented in Table 8.

^a: 37 (28.2%) and 45 (36.0%) patients in the ERAXIS and fluconazole groups, respectively, discontinued the study prior to 6-week follow-up.

^b: 97 (74.0%) and 77 (61.6%) of the patients completed study medication in the ERAXIS and fluconazole groups, respectively.

Two hundred and forty-five (245) patients (127 anidulafungin, 118 fluconazole) met the criteria for inclusion in the MITT population. Of these, 219 patients (116 anidulafungin (91.3%), 103 fluconazole (87.3%)) had candidemia only; 5.5% patients in the anidulafungin arm and 9.3% patients in the fluconazole arm had infections at other normally sterile sites; finally 3.1% patients in the anidulafungin arm and 3.4% patients in the fluconazole arm had both (candidemia and infections at other normally sterile sites). The most frequent species isolated at baseline were C. albicans (63.8% anidulafungin, 59.3% fluconazole), followed by C. glabrata (15.7%, 25.4%), C. parapsilosis (10.2%, 13.6%) and C. tropicalis (11.8%, 9.3%).The majority (97%) of patients were non-neutropenic (ANC > 500) and 81% had APACHE II scores less than or equal to 20.

Table 9 presents outcome and mortality data for the MITT population.

^a Calculated as ERAXIS minus fluconazole

Global success rates in patients with candidemia and other Candida infections are summarized in Table 10.

^a Calculated as ERAXIS minus fluconazole

^b 33 patients in each study arm (26% -ERAXIS and 28.8 % fluconazole-treated) switched to oral fluconazole after the end of i.v.therapy.

^c 98.3% confidence intervals, adjusted post hoc for multiple comparisons of secondary time points

DETAILED PHARMACOLOGY

Pharmacodynamics

ECG Evaluation

No placebo-controlled, randomized, phase I study with a positive control arm for QT prolongation was performed in order to evaluate the effect of anidulafungin on the QT interval.

In the clinical trials of patients with candidemia and other Candida infections, ECGs were evaluated at screening and at post-dose (within 3 hours of drug infusion) on day 3 or on day 6. There were no notable differences between anidulafungin-treated patients and fluconazole-treated patients in the mean change from baseline in QTc interval or in the distribution of patients among QTc interval changes from baseline.

Pharmacokinetics

The relevant human pharmacokinetic data can be found in Sections ACTION AND CLINICAL PHARMACOLOGY and DRUG INTERACTIONS.

The oral bioavailability of anidulafungin is very low (2-7%).

No specific tissue distribution study of anidulafungin has been done in humans. The tissue distribution of anidulafungin, however, was evaluated extensively in preclinical species. It has been noted in rat studies that anidulafungin crosses the placenta and can be found in fetal blood, and anidulafungin is secreted in milk. Crossing of the blood-brain barrier was limited in healthy

uninfected rats. However, in rabbits with disseminated candidiasis, anidulafungin has been shown to cross the blood-brain barrier and reduce fungal burden in the brain. At the intravenous dose of 5 mg/kg, maximum concentrations of anidulafungin in rat liver (15.9 mg/kg), spleen (24.2 mg/kg), kidney (16.1 mg/kg), and lung (31.1 mg/kg) were greater than the observed plasma concentration of 5.3 mg/L. Skin (4.0 mg/kg) and muscle (3.8 mg/kg) contained similar levels of anidulafungin as plasma. Anidulafungin is widely distributed in all species with the steady-state volume of distribution approximately equivalent to the total body water.

The disposition of anidulafungin was similar across all species. A clear allometric relationship was observed for anidulafungin clearance across mice, rats, rabbits, dogs, monkeys and humans. Clearance was dependent on the weight of the species such that clearance per kilogram (CL/kg) was similar across species.

Special Populations and Conditions

The relevant human pharmacokinetic data can be found in Sections ACTION AND CLINICAL PHARMACOLOGY and WARNINGS AND PRECAUTIONS.

Animal Pharmacology

Studies were conducted to evaluate the effects of ERAXIS on the cardiovascular, respiratory, renal, and central nervous systems in animals following a single IV dose.

Cardiovascular: The potential for anidulafungin to cause hemodynamic or electrocardiographic (ECG) effects in rats and monkeys was evaluated. Administration of ERAXIS to rats resulted in decreased blood pressure during the first hour following dosing (maximum decrease at 10 min after dosing), accompanied by a compensatory increase in heart rate during the first 20 min following dosing (maximum increase at 20 minutes). These effects occurred only in the highest tested dose, providing a clinical margin of exposure approximately 5-fold higher than the human C_max, _ss for the 200/100 mg dosing regimen. The hemodynamic changes observed in rats, and their timecourse, are consistent with histamine-mediated infusion-related reactions that occur in single and repeat-dose studies in rats, but not monkeys, given high doses of ERAXIS.

To further characterize cardiovascular safety, a study in telemetered monkeys was performed. No drug-related effects observed on blood pressure, heart rate, or electrocardiogram interval analyses were observed at the highest dose tested (35 mg/kg), providing a clinical margin of exposure approximately 9-fold the human C_max, _ss for the 200/100 mg dosing regimen.

Central Nervous System: Behavioral pharmacology studies in mice evaluated the potential of ERAXIS to impact several aspects of the CNS including general observations, autonomic function, spontaneous activity, pro- or anticonvulsant activity in response to either electroshock or a drug, enzyme competition/CNS depression, neuromuscular function, sensorimotor reactivity, and analgesic potential. ERAXIS had no effect on any parameter evaluated except analgesic potential. At the highest dose tested, ERAXIS significantly reduced responses suggesting it may have analgesic-like activity at clinically-relevant doses (based on body surface area calculations).

Renal: Following single IV doses of ERAXIS in rats, the following endpoints were evaluated as a measure of renal pharmacology: urine volume, pH, and chloride, as well as urinary and serum concentrations of sodium, potassium, and creatinine, and osmolality (urine and serum). Creatinine clearance and fractional excretion of sodium were also calculated. Following treatment, rats in the highest dose group experienced marked decreases in sodium and chloride excretion, as well as a significant reduction in urine volume. Effects were not observed at lower doses. The effect on chloride, the counter ion, is considered secondary to the effect on sodium. The effects on sodium excretion and urine volume are considered to result from hemodynamic changes that occur in the rat at the same doses. These effects were observed at a dose that provides a clinical margin of exposure approximately 5-fold higher than the human C_max, _ss for the 200/100 mg dosing regimen.

Respiratory: Rats were used as a model to evaluate the potential for ERAXIS to cause respiratory effects using a chamber and pressure transducer system. No effects were observed at any dose tested, providing a clinical margin of exposure at the no observed effect level (NOEL) of approximately 5-fold the human C_max, ss for the 200/100 mg dosing regimen.

MICROBIOLOGY

Activity in vitro

Anidulafungin is active in vitro against Candida spp. including C. albicans, C. glabrata, C.krusei, C. parapsilosis, C. tropicalis, C. dubliniensis, C. lusitaniae and C. guilliermondii and Aspergillus species including A. fumigatus, A. flavus, A. niger and A. terreus. Its activity is not affected by resistance to other classes of antifungal agents, in particular fluconazole.

MICs were determined according to the Clinical and Laboratory Standard Institute (CLSI) approved standard reference method M27 for susceptibility testing of yeasts. The relationship between clinical response and in vitro activity remains to be elucidated.

There have been reports of Candida isolates with reduced susceptibility to echinocandins including anidulafungin, but the clinical significance of this observation is unknown.

Activity in vivo

Parenterally administered anidulafungin was effective against Candida spp. in immunocompetent and immunocompromised mouse and rabbit models. Anidulafungin treatment prolonged survival and also reduced the organ burden of Candida spp.

Experimental infections included disseminated C. albicans infection in neutropenic rabbits, esophageal/oropharyngeal infection of neutropenic rabbits with fluconazole-resistant C. albicans and disseminated infection of neutropenic mice with fluconazole-resistant C. glabrata. Anidulafungin has also demonstrated activity against Aspergillus fumigatus in mouse and rabbit infection models.

TOXICOLOGY

Acute Toxicity

The acute median lethal dose (LD₅₀) was 71 mg/kg in rats and >100 mg/kg in mice. The maximum non-lethal dose in rats was 50 mg/kg and the minimal lethal dose in this species was 100 mg/kg. A maximum non-lethal dose in mice was not identified as no deaths were observed at the highest dose tested (100 mg/kg).

Repeat Dose Toxicity

Anidulafungin has been evaluated via intravenous infusion in rats and monkeys in repeat dose toxicity studies of 1- and 3-months duration. Additionally, immunotoxicity was assessed after 1 month of dosing (T-dependent antibody response, T-cell receptor-driven proliferation, immunophenotyping).

In 3 month studies, liver toxicity, including single cell hepatocellular necrosis, hepatocellular hypertrophy and increased liver weights accompanied by increases in hepatic enzymes and cholesterol were observed in monkeys and rats at doses equivalent to 4-6 times human exposure. For both species, hepatocellular hypertrophy was still noted one month after the end of dosing.

Rats given high doses of anidulafungin experienced transient infusion-related (histamine-mediated) reactions within the first 10-20 minutes of the infusion or 1 hour after dosing. These were characterized by hemodynamic changes (decreases in blood pressure and increases in heart rate in the safety pharmacology studies) and clinical signs that included ataxia, sternal recumbence, restlessness, red skin and ears, and swollen muzzles. These reactions generally subsided after 1-5 days of dosing. Similar reactions were not reported in monkeys. The occurrence at the first dose and the lack of persistance following repeated dosing argue against an immunogenic/systemic hypersensitivity effect.

Reproductive Toxicology

Anidulafungin produced no adverse effects on fertility in male or female rats at intravenous doses of 20 mg/kg/day (equivalent to 2 times the proposed therapeutic maintenance dose of 100 mg/day on the basis of relative body surface area).

Embryo-fetal development studies were conducted with doses up to 20 mg/kg/day in rats and rabbits (equivalent to 2 and 4 times, respectively, the proposed therapeutic maintenance dose of 100 mg/day on the basis of relative body surface area). Anidulafungin did not produce any drug-related developmental toxicity in rats. Developmental effects observed in rabbits (slightly reduced fetal weights) occurred in the high dose group only, a dose that also produced maternal toxicity.

Anidulafungin crossed the placental barrier in rats and was detected in fetal plasma. Anidulafungin was found in the milk of lactating rats. It is not known whether anidulafungin is excreted in human milk.

Carcinogenicity

No long - term studies in animals have been performed to evaluate the carcinogenic potential of anidulafungin.

Mutagenicity

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.

REFERENCES

1. 1. Arevalo MP, Carrillo-Munoz AJ, Salgado J, et al. Antifungal activity of the echinocandin anidulafungin (VER002, LY-303366) against yeast pathogens: a comparative study with M27-A microdilution method. J Antimicrob Chemother. 2003;51(1):163-6.
2. 2. Benjamin DK, Jr., Driscoll T, Seibel NL, et al. Safety and pharmacokinetics of intravenous anidulafungin in children with neutropenia at high risk for invasive fungal infections. Antimicrob Agents Chemother. 2006;50(2):632-8.
3. 3. Dowell JA, Knebel W, Ludden T, et al. Population pharmacokinetic analysis of anidulafungin, an echinocandin antifungal. J Clin Pharmacol. 2004;44(6):590-8.
4. 4. Dowell JA, Schranz J, Baruch A, et al. Safety and pharmacokinetics of coadministered voriconazole and anidulafungin. J Clin Pharmacol. 2005;45(12):1373-82.
5. 5. Groll AH, Mickiene D, Petraitiene R, et al. Pharmacokinetic and pharmacodynamic modeling of anidulafungin (LY303366): reappraisal of its efficacy in neutropenic animal models of opportunistic mycoses using optimal plasma sampling. Antimicrob Agents Chemother 2001;45:2845-55.
6. 6. Karlowsky JA, Harding GA, Zelenitsky SA, et al. In vitro kill curves of a new semisynthetic echinocandin, LY-303366, against fluconazole-sensitive and -resistant Candida species. Antimicrob Agents Chemother. 1997;41(1):2576-8.
7. 7. Karlowsky JA, Hoban DJ, Zhanel GG, et al. In vitro interactions of anidulafungin with azole antifungals, amphotericin B and 5-fluorocytosine against Candida species. Int J Antimicrob Agents. 2006;27(2):174-7.
8. 8. Krause DS, Reinhardt J, Vazquez JA, et al. Phase 2, randomized, dose-ranging study evaluating the safety and efficacy of anidulafungin in invasive candidiasis and candidemia. Antimicrob Agents Chemother. 2004;48(6):2021-4.
9. 9. Krause DS, Simjee AE, van Rensburg C, et al. A randomized, double-blind trial of anidulafungin versus fluconazole for the treatment of esophageal candidiasis. Clin Infect Dis. 9-5-2004;39(6):770-5.
10. 10. Marco F, Danes C, Almela M, et al. Trends in frequency and in vitro susceptibilities to antifungal agents, including voriconazole and anidulafungin, of Candida bloodstream isolates. Results from a six-year study (996-200). Diagn Microbiol Infect Dis. 2003;46(4):259-64.
11. 11. Messer SA, Kirby JT, Sader HS, et al. Initial results from a longitudinal international surveillance programme for anidulafungin (2003). J Antimicrob Chemother. 2004;54(6):1051-6.
12. 12. Moore CB, Oakley KL, Denning DW. In vitro activity of a new echinocandin, LY303366, and comparison with fluconazole, flucytosine and amphotericin B against Candida species. Clin Microbiol Infect. 200;7(1):11-6.
13. 13. Murdoch D, Plosker GL. Anidulafungin. Drugs. 2004;64(19):2249-58.
14. 14.

    Oakley KL, Moore CB, Denning DW. In vitro activity of the echinocandin antifungal agent

    LY303,366 in comparison with itraconazole and amphotericin B against Aspergillus spp. Antimicrob Agents Chemother. 998;42(10):2726-30.

15. 15. Petraitis V, Petraitiene R, Groll AH, et al. Antifungal efficacy, safety, and single-dose pharmacokinetics of LY303366, a novel echinocandin B, in experimental pulmonary aspergillosis in persistently neutropenic rabbits. Antimicrob Agents Chemother. 998;42(11):2898-905.
16. 16.

    Pfaller MA. Anidulafungin: an echinocandin antifungal. Expert Opin Investig Drugs.

    2004;13(9):1183-97.

17. 17.

    Pfaller MA, Boyken L, Hollis RJ, et al. In vitro activities of anidulafungin against more than

    2,500 clinical isolates of Candida spp., including 315 isolates resistant to fluconazole. J Clin Microbiol. 2005;43(11):5425-7.

18. 18.

    Pfaller MA, Diekema DJ, Boyken L, et al. Effectiveness of anidulafungin in eradicating

    Candida species in invasive candidiasis. Antimicrob Agents Chemother. 2005;49(11):4795-7.

19. 19. Pfizer Inc [Data on File]. Clinical study report: anidulafungin, VER002-7. An open label and non-comparative study of the safety and efficacy of intravenous anidulafungin plus AmBisome® [(amphotericin B) liposome for injection] as a treatment for invasive aspergillosis. [Report]. 2005.
20. 20. Phillip A, Odabasi Z, Rodriguez J, et al. In vitro synergy testing of anidulafungin with itraconazole, voriconazole, and amphotericin B against Aspergillus spp. and Fusarium spp. Antimicrob Agents Chemother. 2005;49(8):3572-4.
21. 21.

    Raasch RH. Anidulafungin: review of a new echinocandin antifungal agent. Expert Rev Anti

    Infect Ther. 2004;2(4):499-508.

22. 22.

    Roling EE, Klepser ME, Wasson A, et al. Antifungal activities of fluconazole, caspofungin

    (MK0991), and anidulafungin (LY 303366) alone and in combination against Candida spp. and Cryptococcus neoformans via time-kill methods. Diagn Microbiol Infect Dis. 2002;43(1):13-7.

23. 23. Vazquez J. Anidulafungin: a novel echinocandin. Therapy. 2006;3(1):39-54.
24. 24. Zhanel GG, Karlowsky JA, Zelenitsky SA, et al. Susceptibilities of Candida species isolated from the lower gastrointestinal tracts of high-risk patients to the new semisynthetic echinocandin LY303366 and other antifungal agents. Antimicrob Agents Chemother. 1998;42(9):2446-8.