Micafungin

Micafungin for injection is indicated for:

• Treatment of Candidemia, Acute Disseminated Candidiasis,
  Candida
  Peritonitis and Abscesses in adult and pediatric patients 4 months of age and older
  [see Clinical Studies (

  14.1 Treatment of Candidemia and Other

  Candida

  Infections in Adult and Pediatric Patients 4 Months of Age and Older

  Two dose levels of micafungin were evaluated in a randomized, double-blind study to determine the efficacy and safety versus caspofungin in patients with invasive candidiasis and candidemia. Patients were randomized to receive once daily intravenous infusions (IV) of micafungin, either 100 mg/day or 150 mg/day or caspofungin (70 mg loading dose followed by 50 mg maintenance dose). Patients in both study arms were permitted to switch to oral fluconazole after at least 10 days of intravenous therapy, provided they were non-neutropenic, had improvement or resolution of clinical signs and symptoms, had a

  Candida

  isolate which was susceptible to fluconazole and had documentation of 2 negative cultures drawn at least 24 hours apart. Patients were stratified by APACHE II score (20 or less or greater than 20) and by geographic region. Patients with

  Candida

  endocarditis were excluded from this analysis. Outcome was assessed by overall treatment success based on clinical (complete resolution or improvement in attributable signs and symptoms and radiographic abnormalities of the

  Candida

  infection and no additional antifungal therapy) and mycological (eradication or presumed eradication) response at the end of IV therapy. Deaths that occurred during IV study drug therapy were treated as failures.

  In this study, 111/578 (19.2%) of the patients had baseline APACHE II scores of greater than 20 and 50/578 (8.7%) were neutropenic at baseline (absolute neutrophil count less than 500 cells/mm³). Outcome, relapse and mortality data are shown for the recommended dose of micafungin (100 mg/day) and caspofungin in Table 9.

  Table 9 Efficacy Analysis: Treatment Success in Patients in Study 03-0-192 with Candidemia and Other Candida Infections

  *70 mg loading dose on day 1 followed by 50 mg/day thereafter (caspofungin).
  †All patients who received at least one dose of study medication and had documented invasive candidiasis or candidemia. Patients with Candida endocarditis were excluded from the analyses.
  ‡A patient may have had greater than 1 organ of dissemination.
  §A patient may have had greater than 1 baseline infection species.
  ¶All patients who had a culture-confirmed relapse or required systemic antifungal therapy in the post-treatment period for a suspected or proven
  Candida infection. Also includes patients who died or were not assessed in follow-up.
  	Micafungin 100 mg/day n (%) % treatment difference (95% CI)	Caspofungin 70/50 mg/day * n (%)
  Treatment Success at End of IV Therapy †	135/191 (70.7) 7.4 (-2, 16.3)	119/188 (63.3)
  Success in Patients with Neutropenia at Baseline	14/22 (63.6)	5/11 (45.5)
  Success by Site of Infection Candidemia Abscess Acute Disseminated ‡ Endophthalmitis Chorioretinitis Skin Kidney Pancreas Peritoneum Lung/Skin Lung/Spleen Liver Intraabdominal abscess Chronic Disseminated Peritonitis	116/163 (71.2) 4/5 (80) 6/13 (46.2) 1/3 0/3 1/1 2/2 1/1 1/1 0/1 0/1 0 0 0/1 4/6 (66.7)	103/161 (64) 5/9 (55.6) 5/9 (55.6) 1/1 0 0 1/1 0 0 0 0 0/2 3/5 0 2/5 (40)
  Success by Organism§ C. albicans C. glabrata C. tropicalis C. parapsilosis C. krusei C. guilliermondii C. lusitaniae	57/81 (70.4) 16/23 (69.6) 17/27 (63) 21/28 (75) 5/8 (62.5) 1/2 2/3 (66.7)	45/73 (61.6) 19/31 (61.3) 22/29 (75.9) 22/39 (56.4) 2/3 (66.7) 0/1 2/2
  Relapse through 6 Weeks¶ Overall Culture-confirmed relapse Required systemic antifungal therapy Died during follow-up Not assessed	49/135 (36.3) 5 11 17 16	44/119 (37) 4 5 16 19
  Overall study mortality Mortality during IV therapy	58/200 (29) 28/200 (14)	51/193 (26.4) 27/193 (14)

  In two cases of ophthalmic involvement assessed as failures in the above table due to missing evaluation at the end of IV treatment with micafungin, therapeutic success was documented during protocol-defined oral fluconazole therapy.

  ) and Use in Specific Populations (

  8.4 Pediatric Use

  Pediatric Patients 4 Months of Age and Older

  The safety and effectiveness of micafungin for the treatment of esophageal candidiasis, candidemia, acute disseminated candidiasis,

  Candida

  peritonitis and abscesses, esophageal candidiasis and for prophylaxis of

  Candida

  infections in patients undergoing HSCT have been established in pediatric patients 4 months of age and older. Use of micafungin for these indications and in this age group is supported by evidence from adequate and well-controlled studies in adult and pediatric patients with additional pharmacokinetic and safety data in pediatric patients 4 months of age and older

  [see Indications and Usage (1), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14)].

  Pediatric Patients Younger than 4 Months of Age

  Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses

  Without

  Meningoencephalitis and/or Ocular Dissemination in Pediatric Patients Younger Than 4 Months of Age

  The safety and effectiveness of micafungin for the treatment of candidemia, acute disseminated candidiasis,

  Candida

  peritonitis and abscesses

  without

  meningoencephalitis and/or ocular dissemination at a dosage of 4 mg/kg once daily have been established in pediatric patients younger than 4 months of age. This use and dosage of micafungin are supported by evidence from adequate and well-controlled studies in adult and pediatric patients 4 months of age and older with additional pharmacokinetic and safety data in pediatric patients younger than 4 months of age

  [see Adverse Reactions (

  6.1) and Clinical Pharmacology (12.3)]

  .

  Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses

  With

  Meningoencephalitis and/or Ocular Dissemination in Pediatric Patients Younger Than 4 Months of Age

  The safety and effectiveness of micafungin has

  not

  been established for the treatment of candidemia

  with

  meningoencephalitis and/or ocular dissemination in pediatric patients younger than 4 months of age.

  In a rabbit model of hematogenous

  Candida

  meningoencephalitis (HCME) with

  Candida

  albicans

  (minimum inhibitory concentration of 0.125 mcg/mL), a decrease in mean fungal burden in central nervous system (CNS) compartments assessed as the average of combined fungal burden in the cerebrum, cerebellum, and spinal cord relative to untreated controls, was observed with increasing micafungin dosages administered once daily for 7 days. Data from the rabbit model suggest that a micafungin dose regimen of 4 mg/kg once daily is inadequate to treat meningoencephalitis and that a dose regimen of approximately 10 to 25 mg/kg once daily may be necessary to lower fungal burden in the CNS in pediatric patients younger than 4 months of age

  [see Microbiology (12.4)]

  . In this rabbit model, micafungin concentrations could not be reliably detected in cerebrospinal fluid (CSF). Due to limitations of the study design, the clinical significance of a decreased CNS fungal burden in the rabbit HCME model is uncertain.

  A randomized controlled trial evaluated a micafungin dose regimen of 10 mg/kg once daily in pediatric patients younger than 4 months of age with suspected or proven

  Candida

  meningoencephalitis. Fungal-free survival at 1 week after end of therapy was observed in 60% of micafungin -treated vs. 70% of amphotericin B-treated patients, and allcause mortality was 15% vs. 10%, respectively. However, because this study was terminated early and enrolled only 30 pediatric patients younger than 4 months of age (20 treated with micafungin and 10 treated with amphotericin B) which was 13% of the planned enrollment for the study, no conclusions can be drawn regarding efficacy of micafungin at this dose regimen.

  In six uncontrolled, open-label studies, and a neonatal intensive care unit (ICU) medical records database, pediatric patients younger than 4 months of age with suspected

  Candida

  meningoencephalitis or disseminated candidemia received micafungin at dose regimens ranging from 5 to 15 mg/kg once daily. Across the entire micafungin development program, only 6 pediatric patients with proven

  Candida

  meningoencephalitis were treated with dosages of 2 mg/kg, 8 mg/kg and 10 mg/kg once daily. Micafungin was detected in the CSF of pediatric patients with suspected

  Candida

  meningoencephalitis. No conclusions regarding the efficacy of a particular dosage of micafungin or the penetration of micafungin into the CSF can be drawn due to limitations of the data, including but not limited to, multiple confounding factors, variable study designs, and limited numbers of patients. No new safety signals were observed with the use of micafungin at dosages of 5 to 15 mg/kg once daily in pediatric patients younger than 4 months of age, and there was no discernible dose-response for adverse events.

  Although the dosage for the treatment of candidemia with meningoencephalitis has not been established, antifungal activity in various CNS compartments in the rabbit HCME model and limited clinical trial data suggest that in patients younger than 4 months of age, dose regimens 10 mg/kg once daily or higher may be necessary for the treatment of candidemia with meningoencephalitis. Safety data from clinical studies for micafungin at dose regimens of 10 to 15 mg/kg once daily in pediatric patients younger than 4 months of age did not reveal new safety signals.

  Treatment of Esophageal Candidiasis and Prophylaxis of Candida Infections in Patients Undergoing Hematopoietic Stem Cell Transplantation in Pediatric Patients Younger Than 4 Months of Age

  The safety and effectiveness of micafungin in pediatric patients younger than 4 months of age have not been established for the:

  • Treatment of esophageal candidiasis
  • Prophylaxis of
    Candida
    infections in patients undergoing hematopoietic stem cell transplantation

  )].
• Treatment of Candidemia, Acute Disseminated Candidiasis,
  Candida
  Peritonitis and Abscesses
  without
  meningoencephalitis and/or ocular dissemination in pediatric patients younger than 4 months of age
  [see Use in Specific Populations (

  8.4 Pediatric Use

  Pediatric Patients 4 Months of Age and Older

  The safety and effectiveness of micafungin for the treatment of esophageal candidiasis, candidemia, acute disseminated candidiasis,

  Candida

  peritonitis and abscesses, esophageal candidiasis and for prophylaxis of

  Candida

  infections in patients undergoing HSCT have been established in pediatric patients 4 months of age and older. Use of micafungin for these indications and in this age group is supported by evidence from adequate and well-controlled studies in adult and pediatric patients with additional pharmacokinetic and safety data in pediatric patients 4 months of age and older

  [see Indications and Usage (1), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14)].

  Pediatric Patients Younger than 4 Months of Age

  Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses

  Without

  Meningoencephalitis and/or Ocular Dissemination in Pediatric Patients Younger Than 4 Months of Age

  The safety and effectiveness of micafungin for the treatment of candidemia, acute disseminated candidiasis,

  Candida

  peritonitis and abscesses

  without

  meningoencephalitis and/or ocular dissemination at a dosage of 4 mg/kg once daily have been established in pediatric patients younger than 4 months of age. This use and dosage of micafungin are supported by evidence from adequate and well-controlled studies in adult and pediatric patients 4 months of age and older with additional pharmacokinetic and safety data in pediatric patients younger than 4 months of age

  [see Adverse Reactions (

  6.1) and Clinical Pharmacology (12.3)]

  .

  Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses

  With

  Meningoencephalitis and/or Ocular Dissemination in Pediatric Patients Younger Than 4 Months of Age

  The safety and effectiveness of micafungin has

  not

  been established for the treatment of candidemia

  with

  meningoencephalitis and/or ocular dissemination in pediatric patients younger than 4 months of age.

  In a rabbit model of hematogenous

  Candida

  meningoencephalitis (HCME) with

  Candida

  albicans

  (minimum inhibitory concentration of 0.125 mcg/mL), a decrease in mean fungal burden in central nervous system (CNS) compartments assessed as the average of combined fungal burden in the cerebrum, cerebellum, and spinal cord relative to untreated controls, was observed with increasing micafungin dosages administered once daily for 7 days. Data from the rabbit model suggest that a micafungin dose regimen of 4 mg/kg once daily is inadequate to treat meningoencephalitis and that a dose regimen of approximately 10 to 25 mg/kg once daily may be necessary to lower fungal burden in the CNS in pediatric patients younger than 4 months of age

  [see Microbiology (12.4)]

  . In this rabbit model, micafungin concentrations could not be reliably detected in cerebrospinal fluid (CSF). Due to limitations of the study design, the clinical significance of a decreased CNS fungal burden in the rabbit HCME model is uncertain.

  A randomized controlled trial evaluated a micafungin dose regimen of 10 mg/kg once daily in pediatric patients younger than 4 months of age with suspected or proven

  Candida

  meningoencephalitis. Fungal-free survival at 1 week after end of therapy was observed in 60% of micafungin -treated vs. 70% of amphotericin B-treated patients, and allcause mortality was 15% vs. 10%, respectively. However, because this study was terminated early and enrolled only 30 pediatric patients younger than 4 months of age (20 treated with micafungin and 10 treated with amphotericin B) which was 13% of the planned enrollment for the study, no conclusions can be drawn regarding efficacy of micafungin at this dose regimen.

  In six uncontrolled, open-label studies, and a neonatal intensive care unit (ICU) medical records database, pediatric patients younger than 4 months of age with suspected

  Candida

  meningoencephalitis or disseminated candidemia received micafungin at dose regimens ranging from 5 to 15 mg/kg once daily. Across the entire micafungin development program, only 6 pediatric patients with proven

  Candida

  meningoencephalitis were treated with dosages of 2 mg/kg, 8 mg/kg and 10 mg/kg once daily. Micafungin was detected in the CSF of pediatric patients with suspected

  Candida

  meningoencephalitis. No conclusions regarding the efficacy of a particular dosage of micafungin or the penetration of micafungin into the CSF can be drawn due to limitations of the data, including but not limited to, multiple confounding factors, variable study designs, and limited numbers of patients. No new safety signals were observed with the use of micafungin at dosages of 5 to 15 mg/kg once daily in pediatric patients younger than 4 months of age, and there was no discernible dose-response for adverse events.

  Although the dosage for the treatment of candidemia with meningoencephalitis has not been established, antifungal activity in various CNS compartments in the rabbit HCME model and limited clinical trial data suggest that in patients younger than 4 months of age, dose regimens 10 mg/kg once daily or higher may be necessary for the treatment of candidemia with meningoencephalitis. Safety data from clinical studies for micafungin at dose regimens of 10 to 15 mg/kg once daily in pediatric patients younger than 4 months of age did not reveal new safety signals.

  Treatment of Esophageal Candidiasis and Prophylaxis of Candida Infections in Patients Undergoing Hematopoietic Stem Cell Transplantation in Pediatric Patients Younger Than 4 Months of Age

  The safety and effectiveness of micafungin in pediatric patients younger than 4 months of age have not been established for the:

  • Treatment of esophageal candidiasis
  • Prophylaxis of
    Candida
    infections in patients undergoing hematopoietic stem cell transplantation

  )]
  .
• Treatment of Esophageal Candidiasis in adult and pediatric patients 4 months of age and older
  [see Clinical Studies (

  14.2 Treatment of Esophageal Candidiasis in Adult and Pediatric Patients 4 Months of Age and Older

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

  Micafungin was evaluated in a randomized, double-blind study which compared micafungin 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 less than 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 to 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 10, endoscopic cure, clinical cure, overall therapeutic cure and mycological eradication were comparable for patients in the micafungin and fluconazole treatment groups.

  Table 10 Endoscopic, Clinical and Mycological Outcomes for Esophageal Candidiasis at End-of-Treatment

  *Endoscopic and clinical outcome were measured in the modified intent-to-treat population, including all randomized patients who received 1 or more doses of study treatment. The 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.
  †Calculated as micafungin – fluconazole.
  Treatment Outcome *	Micafungin 150 mg/day n = 260	Fluconazole 200 mg/day n = 258	% Difference † (95% CI)
  Endoscopic Cure	228 (87.7%)	227 (88%)	-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% (-11.6, +5.6)

  Most patients (96%) in this study had

  C. albicans

  isolated at baseline. The efficacy of micafungin 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 weeks 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 greater than 0). There was no statistically significant difference in relapse rates at either 2 weeks or through 4 weeks post-treatment for patients in the micafungin and fluconazole treatment groups, as shown in Table 11.

  Table 11 Relapse of Esophageal Candidiasis at Week 2 and through Week 4 Post-Treatment in Patients with Overall Therapeutic Cure at the End of Treatment

  *Calculated as micafungin – fluconazole; N = number of patients with overall therapeutic cure (both clinical and endoscopic cure at end-of-treatment);
  †Relapse included patients who died or were lost to follow-up and those who received systemic anti-fungal therapy in the post-treatment period.
  Relapse	Micafungin 150 mg/day n = 223	Fluconazole 200 mg/day n = 220	% Difference * (95% CI)
  Relapse†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, 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%) micafungin- 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 micafungin 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 micafungin group and 39.4% in the fluconazole group (treatment difference 12.7%, 95% confidence interval [2.8, 22.7]).

  )].
• Prophylaxis of
  Candida
  Infections in adult and pediatric patients 4 months of age and older undergoing hematopoietic stem cell transplantation
  [see Clinical Studies (

  14.3 Prophylaxis of

  Candida

  Infections in Hematopoietic Stem Cell Transplant Recipients

  In a randomized, double-blind study, micafungin (50 mg IV once daily) was compared to fluconazole (400 mg IV once daily) in 882 [adult (791) and pediatric (91)] patients undergoing an autologous or syngeneic (46%) or allogeneic (54%) stem cell transplant. All pediatric patients, except 2 per group, received allogeneic transplants. 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/mm³or greater or up to a maximum of 42 days after transplant. The average duration of drug administration was 18 days (range 1 day to 51 days). Duration of therapy was slightly longer in the pediatric patients who received micafungin (median duration 22 days) compared to the adult patients who received micafungin (median duration 18 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 less than 500 cells/mm³); persistent or recurrent fever (while ANC less than 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 38.5ºC or higher after having at least one prior temperature higher than 38ºC; or having two days of temperatures higher than 38ºC after having at least one prior temperature higher than 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 adult and pediatric micafungin recipients and in 73.7% of adult and pediatric patients who received fluconazole (7% difference [95% CI = 1.5, 12.5]), as shown in Table 12, 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 micafungin and 2 in the fluconazole group.

  The efficacy of micafungin against infections caused by fungi other than

  Candida

  has not been established.

  Table 12 Results from Clinical Study of Prophylaxis of Candida Infections in Hematopoietic Stem Cell Transplant Recipients

  *Difference (micafungin – fluconazole): + 7% [95% CI=1.5, 12.5].
  †Through end-of-study (4 weeks post-therapy).
  ‡Through end-of-therapy.
  Outcome of Prophylaxis	Micafungin 50 mg/day (n = 425)	Fluconazole 400 mg/day (n = 457)
  Success*	343 (80.7%)	337 (73.7%)
  Failure:	82 (19.3%)	120 (26.3%)
  All Deaths† 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‡	53 (12.5%)	83 (18.2%)
  Lost to follow-up	5 (1.2%)	3 (0.7%)

  )].

• The safety and effectiveness of Micafungin have
  not
  been established for the treatment of candidemia
  with
  meningoencephalitis and/or ocular dissemination in pediatric patients younger than 4 months of age as a higher dose may be needed
  [see Use in Specific Populations (

  8.4 Pediatric Use

  Pediatric Patients 4 Months of Age and Older

  The safety and effectiveness of micafungin for the treatment of esophageal candidiasis, candidemia, acute disseminated candidiasis,

  Candida

  peritonitis and abscesses, esophageal candidiasis and for prophylaxis of

  Candida

  infections in patients undergoing HSCT have been established in pediatric patients 4 months of age and older. Use of micafungin for these indications and in this age group is supported by evidence from adequate and well-controlled studies in adult and pediatric patients with additional pharmacokinetic and safety data in pediatric patients 4 months of age and older

  [see Indications and Usage (1), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14)].

  Pediatric Patients Younger than 4 Months of Age

  Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses

  Without

  Meningoencephalitis and/or Ocular Dissemination in Pediatric Patients Younger Than 4 Months of Age

  The safety and effectiveness of micafungin for the treatment of candidemia, acute disseminated candidiasis,

  Candida

  peritonitis and abscesses

  without

  meningoencephalitis and/or ocular dissemination at a dosage of 4 mg/kg once daily have been established in pediatric patients younger than 4 months of age. This use and dosage of micafungin are supported by evidence from adequate and well-controlled studies in adult and pediatric patients 4 months of age and older with additional pharmacokinetic and safety data in pediatric patients younger than 4 months of age

  [see Adverse Reactions (

  6.1) and Clinical Pharmacology (12.3)]

  .

  Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses

  With

  Meningoencephalitis and/or Ocular Dissemination in Pediatric Patients Younger Than 4 Months of Age

  The safety and effectiveness of micafungin has

  not

  been established for the treatment of candidemia

  with

  meningoencephalitis and/or ocular dissemination in pediatric patients younger than 4 months of age.

  In a rabbit model of hematogenous

  Candida

  meningoencephalitis (HCME) with

  Candida

  albicans

  (minimum inhibitory concentration of 0.125 mcg/mL), a decrease in mean fungal burden in central nervous system (CNS) compartments assessed as the average of combined fungal burden in the cerebrum, cerebellum, and spinal cord relative to untreated controls, was observed with increasing micafungin dosages administered once daily for 7 days. Data from the rabbit model suggest that a micafungin dose regimen of 4 mg/kg once daily is inadequate to treat meningoencephalitis and that a dose regimen of approximately 10 to 25 mg/kg once daily may be necessary to lower fungal burden in the CNS in pediatric patients younger than 4 months of age

  [see Microbiology (12.4)]

  . In this rabbit model, micafungin concentrations could not be reliably detected in cerebrospinal fluid (CSF). Due to limitations of the study design, the clinical significance of a decreased CNS fungal burden in the rabbit HCME model is uncertain.

  A randomized controlled trial evaluated a micafungin dose regimen of 10 mg/kg once daily in pediatric patients younger than 4 months of age with suspected or proven

  Candida

  meningoencephalitis. Fungal-free survival at 1 week after end of therapy was observed in 60% of micafungin -treated vs. 70% of amphotericin B-treated patients, and allcause mortality was 15% vs. 10%, respectively. However, because this study was terminated early and enrolled only 30 pediatric patients younger than 4 months of age (20 treated with micafungin and 10 treated with amphotericin B) which was 13% of the planned enrollment for the study, no conclusions can be drawn regarding efficacy of micafungin at this dose regimen.

  In six uncontrolled, open-label studies, and a neonatal intensive care unit (ICU) medical records database, pediatric patients younger than 4 months of age with suspected

  Candida

  meningoencephalitis or disseminated candidemia received micafungin at dose regimens ranging from 5 to 15 mg/kg once daily. Across the entire micafungin development program, only 6 pediatric patients with proven

  Candida

  meningoencephalitis were treated with dosages of 2 mg/kg, 8 mg/kg and 10 mg/kg once daily. Micafungin was detected in the CSF of pediatric patients with suspected

  Candida

  meningoencephalitis. No conclusions regarding the efficacy of a particular dosage of micafungin or the penetration of micafungin into the CSF can be drawn due to limitations of the data, including but not limited to, multiple confounding factors, variable study designs, and limited numbers of patients. No new safety signals were observed with the use of micafungin at dosages of 5 to 15 mg/kg once daily in pediatric patients younger than 4 months of age, and there was no discernible dose-response for adverse events.

  Although the dosage for the treatment of candidemia with meningoencephalitis has not been established, antifungal activity in various CNS compartments in the rabbit HCME model and limited clinical trial data suggest that in patients younger than 4 months of age, dose regimens 10 mg/kg once daily or higher may be necessary for the treatment of candidemia with meningoencephalitis. Safety data from clinical studies for micafungin at dose regimens of 10 to 15 mg/kg once daily in pediatric patients younger than 4 months of age did not reveal new safety signals.

  Treatment of Esophageal Candidiasis and Prophylaxis of Candida Infections in Patients Undergoing Hematopoietic Stem Cell Transplantation in Pediatric Patients Younger Than 4 Months of Age

  The safety and effectiveness of micafungin in pediatric patients younger than 4 months of age have not been established for the:

  • Treatment of esophageal candidiasis
  • Prophylaxis of
    Candida
    infections in patients undergoing hematopoietic stem cell transplantation

  )].
• Micafungin has not been adequately studied in patients with endocarditis, osteomyelitis and meningoencephalitis due to
  Candida.
• The efficacy of micafungin against infections caused by fungi other than
  Candida
  has not been established.

• Infuse over 1 hour. (
  2.5 Infusion Volume and Duration

  Administer micafungin by intravenous infusion only. Infuse over one hour. More rapid infusions may result in more frequent histamine-mediated reactions

  [see Warnings and Precautions ].

  Flush an existing intravenous line with 0.9% Sodium Chloride Injection, USP, prior to infusion of Micafungin.

  Pediatric Patients

  Micafungin should be infused over one hour. To decrease the risk of infusion reactions, concentrations above 1.5 mg/mL should be administered via central catheter

  [see Warnings and Precautions ].
  )
• See Full Prescribing Information for intravenous (IV) preparation and administration instructions. (
  2 DOSAGE AND ADMINISTRATION

  Recommended Dosage Administered by Indication, Weight and Age

  Adult	Pediatric Patients 4 Months and Older 30 kg or less	Pediatric Patients 4 Months and Older greater than 30 kg		Pediatric Patients Younger than 4 Months of Age
  Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses
  100 mg daily	2 mg/kg/day (maximum 100 mg daily)		See below
  Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses without Meningoencephalitis and/or Ocular Dissemination
  See above	See above		4 mg/kg/day
  Treatment of Esophageal Candidiasis
  150 mg daily	3 mg/kg/day	2.5 mg/kg/day (maximum 150 mg daily)	Not approved
  Prophylaxis of Candida Infections in HSCT Recipients
  50 mg daily	1 mg/kg/day (maximum 50 mg daily)		Not approved

  • Infuse over 1 hour.
  • See Full Prescribing Information for intravenous (IV) preparation and administration instructions.

  2.1 Dosage for Adults

  The recommended dosage for adult patients based on indications are shown in Table 1.

  Table 1 Micafungin Dosage in Adult Patients

  *In patients treated successfully for candidemia and other Candida infections, the mean duration of treatment was 15 days (range 10 days to 47 days).
  ‡In patients treated successfully for esophageal candidiasis, the mean duration of treatment was 15 days (range 10 days to 30 days).
  §In hematopoietic stem cell transplant (HSCT) recipients who experienced success of prophylactic therapy, the mean duration of prophylaxis was 19 days (range 6 days to 51 days).
  Indication	Recommended Reconstituted Dose Once Daily
  Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses*	100 mg
  Treatment of Esophageal Candidiasis‡	150 mg
  Prophylaxis of Candida Infections in HSCT Recipients§	50 mg

  2.2 Dosage for Pediatric Patients 4 Months and Older

  The recommended dosage for pediatric patients 4 months of age and older based on indication and weight are shown in Table 2.

  Table 2 Micafungin Dosage in Pediatric Patients (4 Months of Age and Older)

  Indication	Dosage for Pediatric Patients 4 Months of Age and Older
  	30 kg or less	Greater than 30 kg
  Treatment of Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses	2 mg/kg once daily (maximum daily dose 100 mg)
  Treatment of Esophageal Candidiasis	3 mg/kg once daily	2.5 mg/kg once daily (maximum daily dose 150 mg)
  Prophylaxis of Candida Infections in HSCT Recipients	1 mg/kg once daily (maximum daily dose 50 mg)

  2.3 Dosage for Pediatric Patients Younger than 4 Months of Age

  Treatment of Candidemia, Acute Disseminated Candidiasis,

  Candida

  Peritonitis and Abscesses

  without

  meningoencephalitis and/or ocular dissemination

  The recommended dosage is 4 mg/kg once daily.

  The safety and effectiveness of MYCAMINE have

  not

  been established for the treatment of candidemia

  with

  meningoencephalitis and/or ocular dissemination in pediatric patients younger than 4 months of age as a higher dose may be needed

  [see Use in Specific Populations , Clinical Pharmacology and Microbiology ].

  2.4 Directions for Reconstitution, Dilution and Preparation

  Do not mix or co-infuse micafungin with other medications. Micafungin has been shown to precipitate when mixed directly with a number of other commonly used medications. Please read this entire section carefully before beginning reconstitution.

  Reconstitution

  Reconstitute micafungin vials by aseptically adding 5 mL of one of the following compatible solutions:

  • 0.9% Sodium Chloride Injection, USP (without a bacteriostatic agent)
  • 5% Dextrose Injection, USP

  To minimize excessive foaming, gently dissolve the micafungin powder by swirling the vial.

  Do not vigorously shake the vial

  . Visually inspect the vial for particulate matter.

  Micafungin for injection 50 mg vial:

  after reconstitution each mL contains 10 mg of micafungin.

  Micafungin for injection 100 mg vial:

  after reconstitution each mL contains 20 mg of micafungin.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if there is any evidence of precipitation or foreign matter. Aseptic technique must be strictly observed in all handling since no preservative or bacteriostatic agent is present in micafungin for injection or in the materials specified for reconstitution and dilution.

  The reconstituted product should be protected from light and may be stored in the original vial for up to 24 hours at room temperature, 25°C (77°F).

  Dilution and Preparation

  The diluted solution should be protected from light. It is not necessary to cover the infusion drip chamber or the tubing.

  Adult Patients:

  • Add the appropriate volume of reconstituted micafungin into 100 mL of 0.9% Sodium Chloride Injection, USP or 100 mL of 5% Dextrose Injection, USP.
  • Appropriately label the bag.

  Pediatric Patients

  1.      Calculate the total micafungin dose in milligrams (mg) by multiplying the recommended pediatric dose (mg/kg) for a given indication

  [see Table 2]

  and the weight of the patient in kilograms (kg).

  2.      To calculate the volume (mL) of drug needed, divide the calculated dose (mg) from step 1 by the final concentration of the selected reconstituted vial(s) (either 10 mg/mL for the 50 mg vial

  or

  20 mg/mL for the 100 mg vial), see example below:

  Using 50 mg vials:

  Divide the calculated mg dose (from step 1) by 10 mg/mL to determine the volume (mL) needed.

  OR

  Using 100 mg vials:

  Divide the calculated mg dose (from step 1) by 20 mg/mL to determine the volume (mL) needed.

  3.      Withdraw the calculated volume (mL) of drug needed from the selected concentration and size of reconstituted micafungin vial(s) used in Step 2 (ensure the selected concentration and vial size used to calculate the dose is also used to prepare the infusion).

  4.      Add the withdrawn volume of drug (step 3) to a 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP intravenous infusion bag or syringe. Ensure that the final concentration of the solution is between 0.5 mg/mL to 4 mg/mL.

  To decrease the risk of infusion reactions, concentrations above 1.5 mg/mL should be administered via central catheter

  [see Warnings and Precautions ].

  5.     Appropriately label the infusion bag or syringe. For concentrations above 1.5 mg/mL, if required, label to specifically warn to administer the solution via central catheter.

  The diluted infusion bag should be protected from light and may be stored for up to 24 hours at room temperature, 25°C (77°F).

  Micafungin for injection is preservative-free. Discard partially used vials.

  2.5 Infusion Volume and Duration

  Administer micafungin by intravenous infusion only. Infuse over one hour. More rapid infusions may result in more frequent histamine-mediated reactions

  [see Warnings and Precautions ].

  Flush an existing intravenous line with 0.9% Sodium Chloride Injection, USP, prior to infusion of Micafungin.

  Pediatric Patients

  Micafungin should be infused over one hour. To decrease the risk of infusion reactions, concentrations above 1.5 mg/mL should be administered via central catheter

  [see Warnings and Precautions ].
  )

Micafungin for injection, USP is a sterile, white color lyophilized powder or cake in an amber glass vial for reconstitution for intravenous infusion and are available as:

• 50 mg single-dose vial
• 100 mg single-dose vial

Pregnancy – Based on animal data, micafungin may cause fetal harm. Advise pregnant women of the risk to the fetus. (

• Hypersensitivity Reactions: Anaphylaxis and anaphylactoid reactions (including shock) have been observed. Discontinue micafungin and administer appropriate treatment. (
  5.1 Hypersensitivity Reactions

  Isolated cases of serious hypersensitivity (anaphylaxis and anaphylactoid) reactions (including shock) have been reported in patients receiving micafungin. If these reactions occur, micafungin infusion should be discontinued and appropriate treatment administered.
  )
• Hematological Effects: Isolated cases of acute intravascular hemolysis, hemolytic anemia and hemoglobinuria have been reported. Monitor rate of hemolysis. Discontinue if severe. (
  5.2 Hematological Effects

  Acute intravascular hemolysis and hemoglobinuria was seen in a healthy volunteer during infusion of micafungin (200 mg) and oral prednisolone (20 mg). Cases of significant hemolysis and hemolytic anemia have also been reported in patients treated with micafungin. Patients who develop clinical or laboratory evidence of hemolysis or hemolytic anemia during micafungin therapy should be monitored closely for evidence of worsening of these conditions and evaluated for the risk/benefit of continuing micafungin therapy.
  )
• Hepatic Effects: Abnormalities in liver tests; isolated cases of hepatic impairment, hepatitis and hepatic failure have been observed. Monitor hepatic function. Discontinue if severe dysfunction occurs. (
  5.3 Hepatic Effects

  Laboratory abnormalities in liver function tests have been seen in healthy volunteers and patients treated with micafungin. In some patients with serious underlying conditions who were receiving micafungin along with multiple concomitant medications, clinical hepatic abnormalities have occurred and isolated cases of significant hepatic impairment, hepatitis and hepatic failure have been reported. Patients who develop abnormal liver function tests during micafungin therapy should be monitored for evidence of worsening hepatic function and evaluated for the risk/benefit of continuing micafungin therapy.
  )
• Renal Effects: Elevations in BUN and creatinine; isolated cases of renal impairment or acute renal failure have been reported. Monitor renal function. (
  5.4 Renal Effects

  Elevations in BUN and creatinine, and isolated cases of significant renal impairment or acute renal failure have been reported in patients who received micafungin. In fluconazole-controlled trials, the incidence of drug-related renal adverse reactions was 0.4% for micafungin-treated patients and 0.5% for fluconazole-treated patients. Patients who develop abnormal renal function tests during micafungin therapy should be monitored for evidence of worsening renal function.
  )
• Infusion and Injection Site Reactions can occur including rash, pruritus, facial swelling and vasodilatation. Monitor infusion closely, slow infusion rate if necessary. (
  2.5 Infusion Volume and Duration

  Administer micafungin by intravenous infusion only. Infuse over one hour. More rapid infusions may result in more frequent histamine-mediated reactions

  [see Warnings and Precautions ].

  Flush an existing intravenous line with 0.9% Sodium Chloride Injection, USP, prior to infusion of Micafungin.

  Pediatric Patients

  Micafungin should be infused over one hour. To decrease the risk of infusion reactions, concentrations above 1.5 mg/mL should be administered via central catheter

  [see Warnings and Precautions ].
  ,
  5.5 Infusion and Injection Site Reactions

  Possible histamine-mediated symptoms have been reported with micafungin, including rash, pruritus, facial swelling and vasodilatation. Slow the infusion rate if infusion reaction occurs

  [see Dosage and Administration ].

  Injection site reactions, including phlebitis and thrombophlebitis have been reported, at micafungin doses of 50 mg/day to 150 mg/day. These reactions tended to occur more often in patients receiving micafungin via peripheral intravenous administration

  [see

  Dosage and Administration and

  Adverse Reactions ].
  )