Mycamine (Micafungin Sodium) - Description and Clinical Pharmacology

INTRAVENOUS INFUSION (not for IV bolus injection)

Description

MYCAMINE is a sterile, lyophilized product for intravenous (IV) infusion that contains micafungin sodium. Micafungin sodium is a semisynthetic lipopeptide (echinocandin) synthesized by a chemical modification of a fermentation product of Coleophoma empetri F-11899. Micafungin inhibits the synthesis of 1, 3-β-D-glucan, an integral component of the fungal cell wall.

Each single-use vial contains 50 mg micafungin sodium, 200 mg lactose, with citric acid and/or sodium hydroxide (used for pH adjustment). MYCAMINE must be diluted with 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP (see DOSAGE AND ADMINISTRATION). Following reconstitution with 0.9% Sodium Chloride Injection, USP, the resulting pH of the solution is between 5.0-7.0.

Micafungin sodium is chemically designated as:

Pneumocandin A0,1-[(4 R,5 R)-4,5-dihydroxy- N ²-[4-[5-[4-(pentyloxy)phenyl]-3-isoxazolyl]benzoyl]-L-ornithine]-4-[(4 S)-4-hydroxy-4-[4-hydroxy-3-(sulfooxy)phenyl]-L-threonine]-, monosodium salt.

The chemical structure of micafungin sodium is:

CLINICAL PHARMACOLOGY

Pharmacokinetics

The pharmacokinetics of micafungin were determined in healthy subjects, hematopoietic stem cell transplant recipients, and patients with esophageal candidiasis up to a maximum daily dose of 8 mg/kg body weight.

The relationship of area under the concentration-time curve (AUC) to micafungin dose was linear over the daily dose range of 50 mg to 150 mg and 3 mg/kg to 8 mg/kg body weight.

Steady-state pharmacokinetic parameters in relevant patient populations after repeated daily administration are presented in the table below.

Table 1: Pharmacokinetic Parameters of Micafungin in Adult Patients

Population	N	Dose (mg)	Pharmacokinetic Parameters (Mean ± Standard Deviation)
			Cmax (mcg/mL)	AUC0-24 (mcg·h/mL)	t½ (h)	Cl (mL/min/kg)
HIVHIV=human immunodeficiency virus- Positive Patients with ECEC = esophageal candidiasis (Day 14 or 21)	20 20 14	50 100 150	5.1±1.0 10.1±2.6 16.4±6.5	54±13 115±25 167±40	15.6±2.8 16.9±4.4 15.2±2.2	0.300±0.063 0.301±0.086 0.297±0.081
		per kg
HSCTHSCT = hematopoietic stem cell transplant Recipients (Day 7)	8 10 8 8	3 4 6 8	21.1±2.84 29.2±6.2 38.4±6.9 60.8±26.9	234±34 339±72 479±157 663±212	14.0±1.4 14.2±3.2 14.9±2.6 17.2±2.3	0.214±0.031 0.204±0.036 0.224±0.064 0.223±0.081

Distribution

The mean ± standard deviation volume of distribution of micafungin at terminal phase was 0.39 ± 0.11 L/kg body weight when determined in adult patients with esophageal candidiasis at the dose range of 50 mg to 150 mg.

Micafungin is highly (>99%) protein bound in vitro, independent of plasma concentrations over the range of 10 to 100 mcg/mL. The primary binding protein is albumin; however, micafungin, at therapeutically relevant concentrations, does not competitively displace bilirubin binding to albumin. Micafungin also binds to a lesser extent to α₁-acid-glycoprotein.

Metabolism

Micafungin is metabolized to M-1 (catechol form) by arylsulfatase, with further metabolism to M-2 (methoxy form) by catechol-O­methyltransferase. M-5 is formed by hydroxylation at the side chain (ω-1 position) of micafungin catalyzed by cytochrome P450 (CYP) isozymes. Even though micafungin is a substrate for and a weak inhibitor of CYP3A in vitro, hydroxylation by CYP3A is not a major pathway for micafungin metabolism in vivo. Micafungin is neither a P-glycoprotein substrate nor inhibitor in vitro.

In four healthy volunteer studies, the ratio of metabolite to parent exposure (AUC) at a dose of 150 mg/day was 6% for M-1, 1% for M-2, and 6% for M-5. In patients with esophageal candidiasis, the ratio of metabolite to parent exposure (AUC) at a dose of 150 mg/day was 11% for M-1, 2% for M-2, and 12% for M-5.

Excretion

The excretion of radioactivity following a single intravenous dose of ¹⁴C-micafungin sodium for injection (25 mg) was evaluated in healthy volunteers. At 28 days after administration, mean urinary and fecal recovery of total radioactivity accounted for 82.5% (76.4 to 87.9%) of the administered dose. Fecal excretion is the major route of elimination (total radioactivity at 28 days was 71.0% of the administered dose).

Special Populations

MYCAMINE disposition has been studied in a variety of populations as described below.

Race and Gender

No dose adjustment of MYCAMINE is required based on gender or race. After 14 daily doses of 150 mg to healthy subjects, micafungin AUC in women was greater by approximately 23% compared with men, due to smaller body weight. No notable differences among white, black, and Hispanic subjects were seen. The micafungin AUC was greater by 26% in Japanese subjects compared to blacks, due to smaller body weight.

Renal Insufficiency

MYCAMINE does not require dose adjustment in patients with renal impairment.

A single 1-hour infusion of 100 mg MYCAMINE was administered to 9 subjects with severe renal dysfunction (creatinine clearance <30 mL/min) and to 9 age-, gender-, and weight-matched subjects with normal renal function (creatinine clearance >80 mL/min). The maximum concentration (C_max) and AUC were not significantly altered by severe renal impairment.

Since micafungin is highly protein bound, it is not dialyzable. Supplementary dosing should not be required following hemodialysis.

Hepatic Insufficiency

A single 1-hour infusion of 100 mg MYCAMINE was administered to 8 subjects with moderate hepatic dysfunction (Child-Pugh score 7-9) and 8 age-, gender-, and weight-matched subjects with normal hepatic function. The C_max and AUC values of micafungin were lower by approximately 22% in subjects with moderate hepatic insufficiency. This difference in micafungin exposure does not require dose adjustment of MYCAMINE in patients with moderate hepatic impairment. The pharmacokinetics of MYCAMINE have not been studied in patients with severe hepatic insufficiency.

Geriatric

The exposure and disposition of a 50 mg MYCAMINE dose administered as a single 1-hour infusion to 10 healthy subjects aged 66-78 years were not significantly different from those in 10 healthy subjects aged 20-24 years. No dose adjustment is necessary for the elderly.

MICROBIOLOGY

Mechanism of Action

Micafungin, the active ingredient in MYCAMINE, inhibits the synthesis of 1,3-β-D-glucan, an essential component of fungal cell walls, which is not present in mammalian cells.

Activity In Vitro

Micafungin exhibited in-vitro activity against C. albicans, C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis. Standardized susceptibility testing methods for 1,3- β -D-glucan synthesis inhibitors have not been established, and the results of susceptibility studies do not correlate with clinical outcome.

Activity In Vivo

Micafungin sodium has shown activity in both mucosal and disseminated murine models of candidiasis. Micafungin sodium, administered to immunosuppressed mice in models of disseminated candidiasis prolonged survival and/or decreased the mycological burden.

Drug Resistance

The potential for development of drug resistance is not known.

CLINICAL STUDIES

Treatment of Esophageal Candidiasis

In two controlled trials involving 763 patients with esophageal candidiasis, 445 adults with endoscopically-proven candidiasis received MYCAMINE, and 318 received fluconazole for a median duration of 14 days (range 1-33 days).

MYCAMINE was evaluated in a phase 3, randomized, double-blind study which compared MYCAMINE 150 mg/day (n=260) to intravenous fluconazole 200 mg/day (n=258) in adults with endoscopically-proven esophageal candidiasis. Most patients in this study had HIV infection, with CD4 cell counts <100 cells/mm³. Outcome was assessed by endoscopy and by clinical response at the end of treatment. Endoscopic cure was defined as endoscopic grade 0, based on a scale of 0-3. Clinical cure was defined as complete resolution in clinical symptoms of esophageal candidiasis (dysphagia, odynophagia, and retrosternal pain). Overall therapeutic cure was defined as both clinical and endoscopic cure. Mycological eradication was determined by culture, and by histological or cytological evaluation of esophageal biopsy or brushings obtained endoscopically at the end of treatment. As shown in Table 5, endoscopic cure, clinical cure, overall therapeutic cure, and mycological eradication were comparable for patients in the MYCAMINE and fluconazole treatment groups.

Table 5: Endoscopic, Clinical, and Mycological Outcomes for Esophageal Candidiasis at End-of-Treatment

Treatment Outcome Endoscopic and clinical outcome were measured in modified intent-to-treat population, including all randomized patients who received ≥ 1 dose of study treatment. Mycological outcome was determined in the per protocol (evaluable) population, including patients with confirmed esophageal candidiasis who received at least 10 doses of study drug, and had no major protocol violations.	MYCAMINE 150 mg/day	Fluconazole 200 mg/day	% Differencecalculated as MYCAMINE – fluconazole (95% CI)
	N=260	N=258
Endoscopic Cure	228 (87.7%)	227 (88.0%)	-0.3% (-5.9, +5.3)
Clinical Cure	239 (91.9%)	237 (91.9%)	0.06% (-4.6, +4.8)
Overall Therapeutic Cure	223 (85.8%)	220 (85.3%)	0.5% (-5.6, +6.6)
Mycological Eradication	141/189 (74.6%)	149/192 (77.6%)	-3.0% (-11.6, +5.6)

Most patients (96%) in this study had Candida albicans isolated at baseline. The efficacy of MYCAMINE was evaluated in less than 10 patients with Candida species other than C. albicans, most of which were isolated concurrently with C. albicans.

Relapse was assessed at 2 and 4 weeks post-treatment in patients with overall therapeutic cure at end of treatment. Relapse was defined as a recurrence of clinical symptoms or endoscopic lesions (endoscopic grade > 0). There was no statistically significant difference in relapse rates at either 2 weeks or through 4 weeks post-treatment for patients in the MYCAMINE and fluconazole treatment groups, as shown in Table 6.

Table 6: Relapse of Esophageal Candidiasis at Week 2 and through Week 4 Post-Treatment in Patients with Overall Therapeutic Cure at the End of Treatment

Relapse	MYCAMINE 150 mg/day NN=number of patients with overall therapeutic cure (both clinical and endoscopic cure at end-of-treatment); =223	Fluconazole 200 mg/day N=220	% Difference calculated as MYCAMINE – fluconazole; (95% CI)
RelapseRelapse included patients who died or were lost to follow-up, and those who received systemic anti-fungal therapy in the post-treatment period  at Week 2	40 (17.9%)	30 (13.6%)	4.3% (-2.5, 11.1)
Relapse Through Week 4 (cumulative)	73 (32.7%)	62 (28.2%)	4.6% (-4.0, 13.1)

In this study, 459 of 518 (88.6%) patients had oropharyngeal candidiasis in addition to esophageal candidiasis at baseline. At the end of treatment 192/230 (83.5%) MYCAMINE treated patients and 188/229 (82.1%) of fluconazole treated patients experienced resolution of signs and symptoms of oropharyngeal candidiasis. Of these, 32.3% in the MYCAMINE group, and 18.1% in the fluconazole group (treatment difference = 14.2%; 95% confidence interval [5.6, 22.8]) had symptomatic relapse at 2 weeks post-treatment. Relapse included patients who died or were lost to follow-up, and those who received systemic antifungal therapy during the post-treatment period. Cumulative relapse at 4 weeks post-treatment was 52.1% in the MYCAMINE group and 39.4% in the fluconazole group (treatment difference 12.7%, 95% confidence interval [2.8, 22.7]).

Prophylaxis of Candida Infections in Hematopoietic Stem Cell Transplant Recipients

In a randomized, double-blind study, MYCAMINE (50 mg IV once daily) was compared to fluconazole (400 mg IV once daily) in 882 patients undergoing an autologous or syngeneic (46%) or allogeneic (54%) stem cell transplant.

The status of the patients’ underlying malignancy at the time of randomization was: 365 (41%) patients with active disease, 326 (37%) patients in remission, and 195 (22%) patients in relapse. The more common baseline underlying diseases in the 476 allogeneic transplant recipients were: chronic myelogenous leukemia (22%), acute myelogenous leukemia (21%), acute lymphocytic leukemia (13%), and non-Hodgkin’s lymphoma (13%). In the 404 autologous and syngeneic transplant recipients the more common baseline underlying diseases were: multiple myeloma (37.1%), non-Hodgkin's lymphoma (36.4%), and Hodgkin's disease (15.6%). During the study, 198 of 882 (22.4%) transplant recipients had proven graft-versus-host disease; and 475 of 882 (53.9%) recipients received immunosuppressive medications for treatment or prophylaxis of graft-versus-host disease.

Study drug was continued until the patient had neutrophil recovery to an absolute neutrophil count (ANC) of ≥500 cells/mm³ or up to a maximum of 42 days after transplant. The average duration of drug administration was 18 days (range 1 to 51 days).

Successful prophylaxis was defined as the absence of a proven, probable, or suspected systemic fungal infection through the end of therapy (usually 18 days), and the absence of a proven or probable systemic fungal infection through the end of the 4-week post-therapy period. A suspected systemic fungal infection was diagnosed in patients with neutropenia (ANC < 500 cells/mm³); persistent or recurrent fever (while ANC <500 cells/mm³) of no known etiology; and failure to respond to at least 96 hours of broad spectrum antibacterial therapy. A persistent fever was defined as four consecutive days of fever greater than 38ºC. A recurrent fever was defined as having at least one day with temperatures ≥ 38.5 ºC after having at least one prior temperature > 38 ºC; or having two days of temperatures > 38 ºC after having at least one prior temperature > 38ºC. Transplant recipients who died or were lost to follow-up during the study were considered failures of prophylactic therapy.

Successful prophylaxis was documented in 80.7% of recipients who received MYCAMINE, and in 73.7% of recipients who received fluconazole (7.0% difference [95% CI = 1.5, 12.5]), as shown in Table 7, along with other study endpoints. The use of systemic antifungal therapy post-treatment was 42% in both groups.

The number of proven breakthrough Candida infections was 4 in the MYCAMINE and 2 in the fluconazole group.

The efficacy of MYCAMINE against infections caused by fungi other than Candida has not been established.

Table 7: Results from Clinical Study of Prophylaxis of Candida Infections in Hematopoietic Stem Cell Transplant Recipients

Outcome of Prophylaxis	MYCAMINE 50 mg/day (n=425)	Fluconazole 400 mg/day (n=457)
Success  Difference (MYCAMINE – Fluconazole): +7.0% [95% CI=1.5, 12.5]	343 (80.7%)	337 (73.7%)
Failure:	82 (19.3%)	120 (26.3%)
All Deaths Through end-of-study (4 weeks post- therapy) Proven/probable fungal infection prior to death	18 (4.2%) 1 (0.2%)	26 (5.7%) 3 (0.7%)
Proven/probable fungal infection (not resulting in death)	6 (1.4%)	8 (1.8%)
Suspected fungal infection Through end-of-therapy	53 (12.5%)	83 (18.2%)
Lost to follow-up	5 (1.2%)	3 (0.7%)

Rx only

Made in Japan

Marketed by:

Astellas Pharma US, Inc.

Deerfield, IL 60015-2548

MYCAMINE is a trademark of Astellas Pharma, Inc., Tokyo, Japan.