Micafungin in Sodium Chloride Injection is indicated for:

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Limitations of Use

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If a dose of Micafungin in Sodium Chloride Injection is required that does not equal 50 mg, 100 mg, or 150 mg, this product is not recommended for use and an alternative formulation of micafungin should be considered.

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

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 1. Micafungin in Sodium Chloride Injection Dosage in Adult Patients</span> </caption> <col width="50%"/> <col width="50%"/> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>In patients treated successfully for candidemia and other <span class="Italics">Candida </span>infections, the mean duration of treatment was 15 days (range 10 to 47 days).</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>In patients treated successfully for esophageal candidiasis, the mean duration of treatment was 15 days (range 10 to 30 days).</dd> <dt> <a href="#footnote-reference-3" name="footnote-3">‡</a> </dt> <dd>In hematopoietic stem cell transplant (HSCT) recipients who experienced success of prophylactic therapy, the mean duration of prophylaxis was 19 days (range 6 to 51 days).</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Indication</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Recommended Dose Once Daily</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">Treatment of Candidemia, Acute Disseminated Candidiasis, <span class="Italics">Candida </span>Peritonitis and Abscesses<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">100 mg</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">Treatment of Esophageal Candidiasis<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">150 mg</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Prophylaxis of <span class="Italics">Candida </span>Infections in HSCT Recipients<a class="Sup" href="#footnote-3" name="footnote-reference-3">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">50 mg</span> </p> </td> </tr> </tbody> </table></div>

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

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 2. Micafungin in Sodium Chloride Injection Dosage in Pediatric Patients (4 Months of Age and Older)<a class="Sup" href="#footnote-4" name="footnote-reference-4">*</a></span> </caption> <col width="63%"/> <col width="15%"/> <col width="22%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-4" name="footnote-4">*</a> </dt> <dd>If a dose of Micafungin in Sodium Chloride Injection is required that does not equal 50 mg, 100 mg, or 150 mg, this product is not recommended for use and an alternative formulation of micafungin should be considered <span class="Italics">[</span><span class="Italics"><a href="#ID_a44e263e-6398-4b1f-b57c-05455aa7ed62">see Use in Specific Populations (8.4)</a></span><span class="Italics">]</span>.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Indication</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"> <p class="First"> <span class="Bold">Dosage for Pediatric Patients<br/>4 Months of Age and Older</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">30 kg or less</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Greater than 30 kg</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Treatment of Candidemia, Acute Disseminated Candidiasis, <span class="Italics">Candida </span>Peritonitis and Abscesses</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"> <p class="First">2 mg/kg once daily<br/>(maximum daily dose 100 mg)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Treatment of Esophageal Candidiasis</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3 mg/kg once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2.5 mg/kg once daily<br/>(maximum daily dose 150 mg)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Prophylaxis of <span class="Italics">Candida </span>Infections in HSCT Recipients</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"> <p class="First">1 mg/kg once daily<br/>(maximum daily dose 50 mg)</p> </td> </tr> </tbody> </table></div>

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. If a dose of Micafungin in Sodium Chloride Injection is required that does not equal 50 mg, 100 mg, or 150 mg, this product is not recommended for use and an alternative formulation of micafungin should be considered.

The safety and effectiveness of Micafungin in Sodium Chloride Injection 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), Clinical Pharmacology (12.3) and Microbiology (12.4)].

Do not mix or co-infuse Micafungin in Sodium Chloride Injection 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 to prepare for administration.

Preparation for Administration

Storage Conditions or Stability

Adult Patients

Administer Micafungin in Sodium Chloride Injection by intravenous infusion only. Infuse over one hour. More rapid infusions may result in more frequent histamine-mediated reactions [see Warnings and Precautions (5.5)].

Flush an existing intravenous line with Sodium Chloride Injection prior to infusion of Micafungin in Sodium Chloride Injection.

Pediatric Patients

Infuse Micafungin in Sodium Chloride Injection over one hour [see Dosage and Administration (2.3, 2.4)].

Injection: Micafungin in Sodium Chloride Injection is available as a clear and colorless, sterile, refrigerated, premixed, iso-osmotic, nonpyrogenic solution in ready to use single-dose Galaxy containers as follows:

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Micafungin in Sodium Chloride Injection is contraindicated in persons with known hypersensitivity to micafungin, any component of Micafungin in Sodium Chloride Injection, or other echinocandins.

{ "type": "p", "children": [], "text": "Micafungin in Sodium Chloride Injection is contraindicated in persons with known hypersensitivity to micafungin, any component of Micafungin in Sodium Chloride Injection, or other echinocandins." }

Isolated cases of serious hypersensitivity (anaphylaxis and anaphylactoid) reactions (including shock) have been reported in patients receiving micafungin for injection. If these reactions occur, Micafungin in Sodium Chloride Injection infusion should be discontinued and appropriate treatment administered.

Acute intravascular hemolysis and hemoglobinuria was seen in a healthy volunteer during infusion of micafungin for injection (200 mg) and oral prednisolone (20 mg). Cases of significant hemolysis and hemolytic anemia have also been reported in patients treated with micafungin for injection. Patients who develop clinical or laboratory evidence of hemolysis or hemolytic anemia during Micafungin in Sodium Chloride Injection therapy should be monitored closely for evidence of worsening of these conditions and evaluated for the risk/benefit of continuing Micafungin in Sodium Chloride Injection therapy.

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 in Sodium Chloride Injection therapy should be monitored for evidence of worsening hepatic function and evaluated for the risk/benefit of continuing Micafungin in Sodium Chloride Injection therapy.

Elevations in BUN and creatinine, and isolated cases of significant renal impairment or acute renal failure have been reported in patients who received micafungin for injection. In fluconazole-controlled trials, the incidence of drug-related renal adverse reactions was 0.4% for micafungin for injection-treated patients and 0.5% for fluconazole-treated patients. Patients who develop abnormal renal function tests during Micafungin in Sodium Chloride Injection therapy should be monitored for evidence of worsening renal function.

Possible histamine-mediated symptoms have been reported with micafungin for injection, including rash, pruritus, facial swelling, and vasodilatation. Slow the infusion rate if infusion reaction occurs [see Dosage and Administration (2.6)].

Injection site reactions, including phlebitis and thrombophlebitis have been reported, at micafungin for injection doses of 50 to 150 mg/day. These reactions tended to occur more often in patients receiving micafungin for injection via peripheral intravenous administration [see Adverse Reactions (6.1)].

Each 50 mg/50 mL Galaxy container of Micafungin in Sodium Chloride Injection contains 200 mg of sodium, each 100 mg/100 mL Galaxy container of Micafungin in Sodium Chloride Injection contains 400 mg of sodium, and each 150 mg/150 mL Galaxy container of Micafungin in Sodium Chloride Injection contains 600 mg of sodium. Avoid use of Micafungin in Sodium Chloride Injection in patients with congestive heart failure, elderly patients, and patients requiring restricted sodium intake.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of micafungin for injection cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.

The overall safety of micafungin for injection was assessed in 520 healthy volunteers and 3417 adult and pediatric patients who received single or multiple doses of micafungin for injection across 50 clinical trials, including the invasive candidiasis, esophageal candidiasis and prophylaxis trials. The doses of micafungin for injection administered included doses above and below the recommended doses [see Dosage and Administration (2.1, 2.2, 2.3)] and ranged from 0.75 mg/kg to 15 mg/kg in pediatric patients and 12.5 mg to 150 mg/day or greater in adults.

Clinical Trials Experience in Adults

In clinical trials with micafungin for injection, 2497/2748 (91%) adult patients experienced at least one adverse reaction.

Candidemia and Other Candida Infections

In a randomized, double-blind trial for the treatment of candidemia and other Candida infections, adverse reactions occurred in 183/200 (92%) and 171/193 (89%) patients in the micafungin for injection 100 mg/day, and caspofungin (70 mg loading dose followed by 50 mg/day dose) treatment groups, respectively. Selected adverse reactions occurring in 5% or more of the patients and more frequently in the micafungin for injection treatment group, are shown in Table 3.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 3. Selected<a class="Sup" href="#footnote-5" name="footnote-reference-5">*</a> Adverse Reactions in Adult Patients with Candidemia and Other Candida Infections</span> </caption> <col width="47%"/> <col width="24%"/> <col width="14%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-5" name="footnote-5">*</a> </dt> <dd>During IV Treatment + 3 days.</dd> <dt> <a href="#footnote-reference-6" name="footnote-6">†</a> </dt> <dd>Within a system organ class, patients may experience more than 1 adverse reactions</dd> <dt> <a href="#footnote-reference-7" name="footnote-7">‡</a> </dt> <dd>70 mg loading dose on day 1 followed by 50 mg/day thereafter (caspofungin).</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Adverse Reactions by System Organ Class</span><a class="Sup" href="#footnote-6" name="footnote-reference-6">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Micafungin for Injection<br/>100 mg<br/>n (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Caspofungin</span><a class="Sup" href="#footnote-7" name="footnote-reference-7">‡</a><span class="Bold"> <br/>n (%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Number of Patients</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">200</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">193</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal Disorders</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">81 (41)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">76 (39)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">15 (8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">14 (7)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Vomiting</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">18 (9)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">16 (8)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Metabolism and Nutrition Disorders</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">77 (39)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">73 (38)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hypoglycemia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">12 (6)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">9 (5)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hyperkalemia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">10 (5)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">5 (3)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">General Disorders/Administration Site Conditions</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">59 (30)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">51 (26)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Investigations</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">36 (18)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">37 (19)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Blood Alkaline Phosphatase Increased</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">11 (6)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">8 (4)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Cardiac Disorders</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">35 (18)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">36 (19)</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Atrial Fibrillation</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">5 (3)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td> </tr> </tbody> </table></div>

Patient base: all randomized patients who received at least 1 dose of trial drug.

In a second, supportive, randomized, double-blind trial for the treatment of candidemia and other Candida infections, adverse reactions occurred in 245/264 (93%) and 250/265 (94%) adult and pediatric patients in the micafungin for injection (100 mg/day) and amphotericin B liposome (3 mg/kg/day) treatment groups, respectively. In this trial, the following adverse reactions were reported in patients at least 16 years of age in the micafungin for injection and amphotericin B liposome treatment groups, respectively: nausea (10% vs. 8%), diarrhea (11% vs. 11%), vomiting (13% vs. 9%), abnormal liver tests (4% vs. 3%), increased aspartate aminotransferase (3% vs. 2%), and increased blood alkaline phosphatase (3% vs. 2%).

Esophageal Candidiasis

In a randomized, double-blind study for treatment of esophageal candidiasis, a total of 202/260 (78%) patients who received micafungin for injection 150 mg/day and 186/258 (72%) patients who received intravenous fluconazole 200 mg/day experienced an adverse reaction. Adverse reactions resulting in discontinuation were reported in 17 (7%) micafungin for injection-treated patients; and in 12 (5%) fluconazole-treated patients. Selected treatment-emergent adverse reactions occurring in 5% or more of the patients and more frequently in the micafungin for injection group, are shown in Table 4.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 4. Selected<a class="Sup" href="#footnote-8" name="footnote-reference-8">*</a> Adverse Reactions in Adult Patients with Esophageal Candidiasis</span> </caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-8" name="footnote-8">*</a> </dt> <dd>During treatment + 3 days.</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">†</a> </dt> <dd>Within a system organ class, patients may experience more than 1 adverse reaction.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Adverse Reactions by System Organ Class</span><a class="Sup" href="#footnote-9" name="footnote-reference-9">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Micafungin for Injection<br/>150 mg/day<br/>n (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Fluconazole<br/>200 mg/day<br/>n (%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Number of Patients</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">260</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">258</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal Disorders</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">84 (32)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">93 (36)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">27 (10)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">29 (11)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Nausea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">20 (8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">23 (9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Vomiting</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">17 (7)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">17 (7)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">General Disorders/Administration Site Conditions</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">52 (20)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">45 (17)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Pyrexia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">34 (13)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">21 (8)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Nervous System Disorders</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">42 (16)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">40 (16)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Headache</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">22 (9)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">20 (8)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Vascular Disorders</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">54 (21)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">21 (8)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Phlebitis</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">49 (19)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">13 (5)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Skin and Subcutaneous Tissue Disorders</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">36 (14)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">26 (10)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Rash</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">14 (5)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">6 (2)</p> </td> </tr> </tbody> </table></div>

Patient base: all randomized patients who received at least 1 dose of trial drug.

Prophylaxis of Candida Infections in Hematopoietic Stem Cell Transplant Recipients

A double-blind trial was conducted in a total of 882 patients scheduled to undergo an autologous or allogeneic hematopoietic stem cell transplant. The median duration of treatment was 18 days (range 1 to 51 days) in both treatment arms.

All adult patients who received micafungin for injection (382) or fluconazole (409) experienced at least one adverse reaction during the study. Treatment-emergent adverse reactions resulting in micafungin for injection discontinuation were reported in 15 (4%) adult patients; while those resulting in fluconazole discontinuation were reported in 32 (8%). Selected adverse reactions reported in 15% or more of adult patients and more frequently in the micafungin for injection treatment arm, are shown in Table 5.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 5. Selected Adverse Reactions in Adult Patients During Prophylaxis of Candida Infection in Hematopoietic Stem Cell Transplant Recipients</span> </caption> <col width="41%"/> <col width="26%"/> <col width="14%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">System Organ Class</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Micafungin for Injection<br/>50 mg/day<br/>n (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Fluconazole<br/>400 mg/day<br/>n (%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Number of Patients</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">382</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">409</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal Disorders</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">377 (99)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">404 (99)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">294 (77)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">327 (80)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Nausea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">270 (71)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">290 (71)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Vomiting</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">252 (66)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">274 (67)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Abdominal Pain</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">100 (26)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">93 (23)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Blood and Lymphatic System Disorders</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">368 (96)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">385 (94)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Neutropenia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">288 (75)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">297 (73)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Thrombocytopenia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">286 (75)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">280 (69)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Skin and Subcutaneous Tissue Disorders</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">257 (67)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">275 (67)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Rash</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">95 (25)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">91 (22)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Nervous System Disorders</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">250 (65)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">254 (62)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Headache</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">169 (44)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">154 (38)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Psychiatric Disorders</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">233 (61)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">235 (58)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Insomnia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">142 (37)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">140 (34)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Anxiety</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">84 (22)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">87 (21)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Cardiac Disorders</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">133 (35)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">138 (34)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Tachycardia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">99 (26)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">91 (22)</p> </td> </tr> <tr class="Last"> <td class="Toprule" colspan="3" valign="top"> <p class="First">Patient base: all randomized adult patients who received at least 1 dose of trial drug.</p> </td> </tr> </tbody> </table></div>

Other selected adverse reactions reported at less than 5% in adult clinical trials are listed below:

Clinical Trials Experience in Pediatric Patients

The safety of micafungin for injection was assessed in 593 pediatric patients, 425 of whom were 4 months through 16 years of age and 168 of whom were 3 days to less than 4 months of age who received at least one dose of micafungin for injection across 15 clinical trials.

Of the 425 pediatric patients, 4 months through 16 years of age enrolled in 11 clinical trials, 235 (55%) were male, 290 (68%) were white, with the following age distribution: 62 (15%) 4 months to <2 years, 108 (25%) 2 to 5 years, 140 (33%) 6 to 11 years, and 115 (27%) 12 to 16 years of age. The mean treatment duration was 26.1 days. A total of 246 patients received at least one dose of micafungin for injection ranging from 2 to 10 mg/kg. Overall, 388/425 (91%) patients experienced at least one adverse reaction. Adverse reactions occurring in ≥15% or more of micafungin-treated pediatric patients 4 months of age and older are: vomiting (32%), diarrhea (24%), pyrexia (24%), hypokalemia (22%), nausea (21%), mucosal inflammation (19%), thrombocytopenia (19%), abdominal pain (18%), headache (15%), and hypertension (15%).

Two randomized, double-blind active-controlled trials included pediatric patients. In the invasive candidiasis/candidemia trial, the efficacy and safety of micafungin for injection (2 mg/kg/day for patients weighing 40 kg or less and 100 mg/day for patients weighing greater than 40 kg) was compared to amphotericin B liposome (3 mg/kg/day) in 112 pediatric patients. Treatment-emergent adverse reactions occurred in 51/56 (91%) of patients in the micafungin for injection group and 52/56 (93%) of patients in the amphotericin B liposome group. Treatment-emergent adverse reactions resulting in drug discontinuation were reported in 2 (4%) micafungin for injection-treated pediatric patients and in 9 (16%) amphotericin B liposome-treated pediatric patients.

The prophylaxis study in patients undergoing HSCT investigated the efficacy of micafungin for injection (1 mg/kg/day for patients weighing 50 kg or less and 50 mg/day for patients weighing greater than 50 kg) as compared to fluconazole (8 mg/kg/day for patients weighing 50 kg or less and 400 mg/day for patients weighing greater than 50 kg). All 91 pediatric patients experienced at least one treatment-emergent adverse reaction. Three (7%) pediatric patients discontinued micafungin for injection due to adverse reaction, while one (2%) patient discontinued fluconazole.

Selected adverse reactions, occurring in 15% or more of the patients and more frequently in a micafungin for injection group, for the two comparative trials are shown in Table 6.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 6. Selected Adverse Reactions in Pediatric Patients with Candidemia and Other Candida Infections (C/IC), and in Hematopoietic Stem-Cell Recipients During Prophylaxis of Candida Infections</span> </caption> <col width="36%"/> <col width="19%"/> <col width="14%"/> <col width="19%"/> <col width="11%"/> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-10" name="footnote-10">*</a> </dt> <dd>Within a system organ class, patients may experience more than 1 adverse reaction.</dd> <dt> <a href="#footnote-reference-11" name="footnote-11">†</a> </dt> <dd>Study population included 20 pediatric patients younger than 4 months of age (10 in each arm).</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <span class="Bold">Adverse Reactions</span><a class="Sup" href="#footnote-10" name="footnote-reference-10">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"> <p class="First"> <span class="Bold">C/IC</span><a class="Sup" href="#footnote-11" name="footnote-reference-11">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"> <p class="First"> <span class="Bold">Prophylaxis</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Micafungin for Injection<br/>n = 56<br/>n (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Amphotericin B<br/>liposome<br/>n = 56<br/>n (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Micafungin for Injection<br/>n = 43<br/>n (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Fluconazole<br/>n = 48<br/>n (%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Gastrointestinal disorders</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">22 (40)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">18 (32)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">43 (100)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">45 (94)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Vomiting</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">10 (18)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">8 (14)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">28 (65)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">32 (67)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4 (7)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">5 (9)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">22 (51)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">31 (65)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Nausea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4 (7)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4 (7)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">30 (70)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">25 (52)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Abdominal pain</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2 (4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2 (4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">15 (35)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">12 (25)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Abdominal distension</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1 (2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1 (2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">8 (19)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">6 (13)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">General disorders and administration site conditions</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">14 (25)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">14 (25)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">41 (95)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">46 (96)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Pyrexia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">5 (9)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">9 (16)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">26 (61)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">31 (65)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Infusion-related reaction</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3 (5)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">7 (16)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4 (8)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Skin and subcutaneous tissue disorders</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">11 (20)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">8 (14)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">33 (77)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">38 (79)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Pruritus</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1 (2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">14 (33)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">15 (31)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Rash</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1 (2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1 (2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">13 (30)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">13 (27)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Urticaria</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1 (2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">8 (19)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4 (8)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Respiratory, thoracic and mediastinal disorders</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">9 (16)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">13 (23)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">30 (70)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">33 (69)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Epistaxis</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4 (9)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">8 (17)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Blood and lymphatic system disorders</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">17 (30)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">13 (23)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">40 (93)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">44 (92)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Thrombocytopenia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">5 (9)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3 (5)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">31 (72)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">37 (77)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Neutropenia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3 (5)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4 (7)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">33 (77)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">34 (71)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Anemia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">10 (18)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">6 (11)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">22 (51)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">24 (50)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Febrile neutropenia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">7 (16)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">7 (15)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Investigations</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">12 (21)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">8 (14)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">24 (56)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">25 (52)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Alanine aminotransferase <br/>increased</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">7 (16)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1 (2)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Urine output decreased</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">10 (23)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">8 (17)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Cardiac disorders</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">7 (13)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3 (5)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">10 (23)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">17 (35)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Tachycardia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2 (4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1 (2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">7 (16)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">12 (25)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Renal and urinary disorders</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4 (7)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4 (7)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">16 (37)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">15 (31)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hematuria</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">10 (23)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">7 (15)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Psychiatric disorders</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3 (5)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1 (2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">20 (47)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">9 (19)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Anxiety</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">10 (23)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3 (6)</p> </td> </tr> </tbody> </table></div>

Other clinically significant adverse reactions reported at less than 15% in pediatric clinical trials are listed below:

Clinical Trials Experience in Pediatric Patients Younger than 4 Months of Age

The safety of micafungin for injection was assessed in 168 pediatric patients younger than 4 months of age who received varying doses of micafungin for injection in 9 clinical trials. The mean treatment duration was 16.6 days. A total of 59 patients received micafungin for injection at doses ≤4 mg/kg/day and 109 patients received micafungin for injection doses >4 mg/kg/day [5 to 15 mg/kg/day (approximately 1.3 to 3.8 times the recommended dosage in pediatric patients less than 4 months old)].

The adverse reaction profile of micafungin for injection in pediatric patients younger than 4 months of age was generally comparable to that of pediatric patients 4 months of age and older and adults. The most frequent adverse reactions (≥15%) in pediatric patients younger than 4 months old receiving a micafungin for injection dose of approximately 4 mg/kg/day included hypokalemia (25%), thrombocytopenia (25%), acidosis (20%), sepsis (20%), anemia (15%), oxygen saturation decreased (15%), and vomiting (15%). No new safety signals were seen in patients who received 5 to 15 mg/kg/day [see Use in Specific Populations (8.4)].

Additional clinically significant adverse reactions reported in less than 15% of pediatric patients younger than 4 months of age who received approximately 4 mg/kg/day are listed below:

The following adverse reactions have been identified during post-approval use of micafungin for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

CYP3A4, CYP2C9 and CYP2C19 Inhibitors

Co-administration of Micafungin in Sodium Chloride Injection with cyclosporine, itraconazole, voriconazole and fluconazole did not alter the pharmacokinetics of micafungin.

CYP2C19 and CYP3A4 Inducer

Co-administration of Micafungin in Sodium Chloride Injection with rifampin and ritonavir did not alter the pharmacokinetics of micafungin.

Co-administration of Micafungin in Sodium Chloride Injection with Other Drugs

Co-administration of Micafungin in Sodium Chloride Injection with mycophenolate mofetil (MMF), amphotericin B, tacrolimus, prednisolone, sirolimus and nifedipine did not alter the pharmacokinetics of micafungin.

CYP3A4 Substrates

There was no effect of single or multiple doses of micafungin for injection on cyclosporine, tacrolimus, prednisolone, voriconazole and fluconazole pharmacokinetics.

Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state micafungin for injection compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state micafungin for injection compared with nifedipine alone. Itraconazole AUC and Cmax were increased by 22% and 11%, respectively. Patients receiving sirolimus, nifedipine, and itraconazole in combination with micafungin for injection should be monitored for sirolimus, nifedipine, and itraconazole toxicity and the sirolimus, nifedipine, and itraconazole dosage should be reduced if necessary.

UDP-Glycosyltransferase Substrate

Co-administration of mycophenolate mofetil (MMF) with micafungin for injection did not alter the pharmacokinetics of MMF.

Risk Summary

Based on findings from animal studies, Micafungin for Injection may cause fetal harm when administered to a pregnant woman (see Data). There is insufficient human data on the use of micafungin for injection in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, intravenous administration of micafungin sodium to pregnant rabbits during organogenesis at doses four times the maximum recommended human dose resulted in visceral abnormalities and increased abortion (see Data). Advise pregnant women of the risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

In an embryo-fetal toxicity study in pregnant rabbits, intravenous administration of micafungin sodium during organogenesis (days 6 to 18 of gestation) resulted in fetal visceral abnormalities and abortion at 32 mg/kg, a dose equivalent to four times the recommended human dose based on body surface area comparisons. Visceral abnormalities included abnormal lobation of the lung, levocardia, retrocaval ureter, anomalous right subclavian artery, and dilatation of the ureter.

Risk Summary

There are no data on the presence of micafungin in human milk, the effects on the breast-fed infant or the effects on milk production. Micafungin was present in the milk of lactating rats following intravenous administration. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Micafungin in Sodium Chloride Injection, and any potential adverse effects on the breast-fed child from Micafungin in Sodium Chloride Injection, or from the underlying maternal condition.

Micafungin in Sodium Chloride Injection is indicated in pediatric patients for whom appropriate dosing with this formulation can be achieved. Because of the limitations of the available strengths and administration requirements (i.e., administration of fractional doses is not recommended) of Micafungin in Sodium Chloride Injection, and to avoid unintentional overdose, this product is not recommended for use if a dose of Micafungin in Sodium Chloride Injection that does not equal 50 mg, 100 mg, or 150 mg is required, and an alternative formulation of micafungin should be considered [see Dosage and Administration (2.3, 2.4)].

Pediatric Patients 4 Months of Age and Older

The safety and effectiveness of micafungin for injection 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 injection 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 for injection 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 for injection have 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 for injection 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 for injection-treated vs. 70% of amphotericin B-treated patients, and all-cause 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 for injection 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 for injection 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 for injection at dose regimens ranging from 5 to 15 mg/kg once daily. Across the entire micafungin for injection 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 for injection 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 for injection 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 for injection 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 for injection in pediatric patients younger than 4 months of age have not been established for the:

A total of 418 subjects in clinical studies of micafungin for injection were 65 years of age and older, and 124 subjects were 75 years of age and older. No overall differences in safety and effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The exposure and disposition of a 50 mg micafungin for injection dose administered as a single 1-hour infusion to 10 healthy subjects aged 66 to 78 years were not significantly different from those in 10 healthy subjects aged 20 to 24 years. No dose adjustment is necessary for the elderly.

Each 50 mg/50 mL Galaxy container of Micafungin in Sodium Chloride Injection contains 200 mg of sodium, each 100 mg/100 mL Galaxy container of Micafungin in Sodium Chloride Injection contains 400 mg of sodium, and each 150 mg/150 mL Galaxy container of Micafungin in Sodium Chloride Injection contains 600 mg of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure and other conditions requiring restricted sodium intake [see Warnings and Precautions (5.6)].

Micafungin in Sodium Chloride Injection does not require dose adjustment in patients with renal impairment. Supplementary dosing should not be required following hemodialysis [see Clinical Pharmacology (12.3)].

Dose adjustment of Micafungin in Sodium Chloride Injection is not required in patients with mild, moderate, or severe hepatic impairment [see Clinical Pharmacology (12.3)].

No dose adjustment of Micafungin in Sodium Chloride Injection 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 19% in Japanese subjects compared to blacks, due to smaller body weight.

There has been no evidence of either psychological or physical dependence or withdrawal or rebound effects with micafungin for injection.

{ "type": "p", "children": [], "text": "There has been no evidence of either psychological or physical dependence or withdrawal or rebound effects with micafungin for injection." }

Micafungin is highly protein bound and, therefore, is not dialyzable. No cases of micafungin for injection overdosage have been reported. Repeated daily doses up to 8 mg/kg (maximum total dose of 896 mg) in adult patients, up to 6 mg/kg in pediatric patients 4 months of age and older, and up to 15 mg/kg in pediatric patients younger than 4 months of age have been administered in clinical trials with no reported dose-limiting toxicity [see Adverse Reactions (6.1) and Use in Specific Populations (8.4)].

{ "type": "p", "children": [], "text": "Micafungin is highly protein bound and, therefore, is not dialyzable. No cases of micafungin for injection overdosage have been reported. Repeated daily doses up to 8 mg/kg (maximum total dose of 896 mg) in adult patients, up to 6 mg/kg in pediatric patients 4 months of age and older, and up to 15 mg/kg in pediatric patients younger than 4 months of age have been administered in clinical trials with no reported dose-limiting toxicity [see Adverse Reactions (6.1) and Use in Specific Populations (8.4)].\n" }

Micafungin in Sodium Chloride Injection is a premixed, iso-osmotic, sterile, nonpyrogenic solution for intravenous (IV) infusion that contains micafungin sodium. Micafungin sodium is a semisynthetic lipopeptide (echinocandin).

{ "type": "p", "children": [], "text": "Micafungin in Sodium Chloride Injection is a premixed, iso-osmotic, sterile, nonpyrogenic solution for intravenous (IV) infusion that contains micafungin sodium. Micafungin sodium is a semisynthetic lipopeptide (echinocandin)." }

Micafungin in Sodium Chloride Injection is supplied as a refrigerated 50 mL, 100 mL, or 150 mL single-dose GALAXY container in the following presentations:

{ "type": "p", "children": [], "text": "Micafungin in Sodium Chloride Injection is supplied as a refrigerated 50 mL, 100 mL, or 150 mL single-dose GALAXY container in the following presentations:" }

50 mg/50 mL (1 mg/mL): containing 50 mg of micafungin (equivalent to 50.87 mg of micafungin sodium); 36 mg citric acid, anhydrous; 450 mg sodium chloride; 92 mg sodium citrate dihydrate;

{ "type": "p", "children": [], "text": "50 mg/50 mL (1 mg/mL): containing 50 mg of micafungin (equivalent to 50.87 mg of micafungin sodium); 36 mg citric acid, anhydrous; 450 mg sodium chloride; 92 mg sodium citrate dihydrate;" }

100 mg/100 mL (1 mg/mL): containing 100 mg of micafungin (equivalent to 101.73 mg of micafungin sodium); 72 mg citric acid, anhydrous; 900 mg sodium chloride; 184 mg sodium citrate dihydrate;

{ "type": "p", "children": [], "text": "100 mg/100 mL (1 mg/mL): containing 100 mg of micafungin (equivalent to 101.73 mg of micafungin sodium); 72 mg citric acid, anhydrous; 900 mg sodium chloride; 184 mg sodium citrate dihydrate;" }

150 mg/150 mL (1 mg/mL): containing 150 mg of micafungin (equivalent to 152.60 mg of micafungin sodium); 108 mg citric acid, anhydrous; 1350 mg sodium chloride; 276 mg sodium citrate dihydrate.

{ "type": "p", "children": [], "text": "150 mg/150 mL (1 mg/mL): containing 150 mg of micafungin (equivalent to 152.60 mg of micafungin sodium); 108 mg citric acid, anhydrous; 1350 mg sodium chloride; 276 mg sodium citrate dihydrate." }

{ "type": "", "children": [], "text": "" }

The premixed solution is clear and colorless, with a pH range of 4.5 to 5.1.

{ "type": "p", "children": [], "text": "The premixed solution is clear and colorless, with a pH range of 4.5 to 5.1." }

Micafungin sodium is chemically designated as:

{ "type": "p", "children": [], "text": "Micafungin sodium is chemically designated as:" }

Pneumocandin A0,1-[(4R,5R)-4,5-dihydroxy-N2-[4-[5-[4-(pentyloxy) phenyl]-3-isoxazolyl]benzoyl]-L-ornithine]-4-[(4S)-4-hydroxy-4-[4-hydroxy-3-(sulfooxy)phenyl]-L-threonine]-, monosodium salt.

{ "type": "p", "children": [], "text": "Pneumocandin A0,1-[(4R,5R)-4,5-dihydroxy-N2-[4-[5-[4-(pentyloxy) phenyl]-3-isoxazolyl]benzoyl]-L-ornithine]-4-[(4S)-4-hydroxy-4-[4-hydroxy-3-(sulfooxy)phenyl]-L-threonine]-, monosodium salt." }

The chemical structure of micafungin sodium is:

{ "type": "p", "children": [], "text": "The chemical structure of micafungin sodium is:" }

The empirical/molecular formula is C56H70N9NaO23S and the formula weight is 1292.26.

{ "type": "p", "children": [], "text": "The empirical/molecular formula is C56H70N9NaO23S and the formula weight is 1292.26." }

Micafungin sodium is a light-sensitive, hygroscopic white powder that is freely soluble in water, isotonic sodium chloride solution, N,N-dimethylformamide and dimethylsulfoxide, slightly soluble in methyl alcohol, and practically insoluble in acetonitrile, ethyl alcohol (95%), acetone, diethyl ether and n-hexane.

{ "type": "p", "children": [], "text": "Micafungin sodium is a light-sensitive, hygroscopic white powder that is freely soluble in water, isotonic sodium chloride solution, N,N-dimethylformamide and dimethylsulfoxide, slightly soluble in methyl alcohol, and practically insoluble in acetonitrile, ethyl alcohol (95%), acetone, diethyl ether and n-hexane." }

Micafungin is a member of the echinocandin class of antifungal agents [see Microbiology (12.4)].

The pharmacodynamics of micafungin related to hematogenous Candida meningoencephalitis are described in other sections of the prescribing information [see Use in Specific Populations (8.4) and Microbiology (12.4)].

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. Typically, 85% of the steady-state concentration is achieved after three daily micafungin for injection doses.

Steady-state pharmacokinetic parameters in relevant patient populations after repeated daily administration are presented in Table 7.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 7. Pharmacokinetic Parameters of Micafungin in Adult Patients</span> </caption> <col width="18%"/> <col width="4%"/> <col width="11%"/> <col width="12%"/> <col width="13%"/> <col width="11%"/> <col width="14%"/> <tfoot> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-12" name="footnote-12">*</a> </dt> <dd>AUC<span class="Sub">0-infinity</span> is presented for Day 1; AUC<span class="Sub">0-24</span> is presented for steady-state.</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">†</a> </dt> <dd>candidemia or other <span class="Italics">Candida </span>infections.</dd> <dt> <a href="#footnote-reference-14" name="footnote-14">‡</a> </dt> <dd>human immunodeficiency virus.</dd> <dt> <a href="#footnote-reference-15" name="footnote-15">§</a> </dt> <dd>esophageal candidiasis.</dd> <dt> <a href="#footnote-reference-16" name="footnote-16">¶</a> </dt> <dd>hematopoietic stem cell transplant.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <span class="Bold">Population</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <span class="Bold">n</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <span class="Bold">Dose (mg)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="4" valign="middle"> <p class="First"> <span class="Bold">Pharmacokinetic Parameters<br/>(Mean ± Standard Deviation)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">C<span class="Sub">max</span><span class="Sub"></span> <br/>(mcg/mL)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">AUC<span class="Sub">0-24</span></span><a class="Sup" href="#footnote-12" name="footnote-reference-12">*</a><span class="Bold"><span class="Sub"></span> <br/>(mcg h/mL)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">t<span class="Sub">1/2</span> <br/>(h)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Cl<br/>(mL/min/kg)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">Patients with IC<a class="Sup" href="#footnote-13" name="footnote-reference-13">†</a> <br/>[Day 1]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">100</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5.7 ± 2.2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">83 ± 51</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">14.5 ± 7.0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.359 ± 0.179</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">[Steady-State]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">20</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">100</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">10.1 ± 4.4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">97 ± 29</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">13.4 ± 2.0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0.298 ± 0.115</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">HIV<a class="Sup" href="#footnote-14" name="footnote-reference-14">‡</a> – Positive<br/>Patients with EC<a class="Sup" href="#footnote-15" name="footnote-reference-15">§</a> <br/>[Day 1]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">20<br/>20<br/>14</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">50<br/>100<br/>150</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4.1 ± 1.4<br/>8.0 ± 2.4<br/>11.6 ± 3.1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">36 ± 9<br/>108 ± 31<br/>151 ± 45</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">14.9 ± 4.3<br/>13.8 ± 3.0<br/>14.1 ± 2.6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0.321 ± 0.098<br/>0.327 ± 0.093<br/>0.340 ± 0.092</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">[Day 14 or 21]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">20<br/>20<br/>14</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">50<br/>100<br/>150</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">5.1 ± 1.0<br/>10.1 ± 2.6<br/>16.4 ± 6.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">54 ± 13<br/>115 ± 25<br/>167 ± 40</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">15.6 ± 2.8<br/>16.9 ± 4.4<br/>15.2 ± 2.2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0.300 ± 0.063<br/>0.301 ± 0.086<br/>0.297 ± 0.081</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">HSCT<a class="Sup" href="#footnote-16" name="footnote-reference-16">¶</a> Recipients<br/>[Day 7]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <br/>8<br/>10<br/>8<br/>8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Italics">per kg<br/> </span>3<br/>4<br/>6<br/>8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <br/>21.1 ± 2.84<br/>29.2 ± 6.2<br/>38.4 ± 6.9<br/>60.8 ± 26.9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <br/>234 ± 34<br/>339 ± 72<br/>479 ± 157<br/>663 ± 212</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <br/>14.0 ± 1.4<br/>14.2 ± 3.2<br/>14.9 ± 2.6<br/>17.2 ± 2.3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <br/>0.214 ± 0.031<br/>0.204 ± 0.036<br/>0.224 ± 0.064<br/>0.223 ± 0.081</p> </td> </tr> </tbody> </table></div>

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 (greater than 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.

Micafungin is neither a substrate nor an inhibitor of P-glycoprotein.

Elimination

Metabolism

Micafungin is metabolized to M-1 (catechol form) by arylsulfatase, with further metabolism to M-2 (methoxy form) by catechol-O-methyltransferase. 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% of the administered dose).

Specific Populations

Pediatric Patients

Pediatric Patients 4 Months of Age and Older

Micafungin pharmacokinetics in 229 pediatric patients 4 months through 16 years of age were characterized using population pharmacokinetics. Micafungin exposure was dose proportional across the dose and age range studied.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 8. Summary (Mean +/- Standard Deviation) of Micafungin Pharmacokinetics in Pediatric Patients 4 Months of Age and Older (Steady-State)</span> </caption> <col width="19%"/> <col width="5%"/> <col width="8%"/> <col width="13%"/> <col width="13%"/> <col width="12%"/> <col width="15%"/> <tfoot> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-17" name="footnote-17">*</a> </dt> <dd>Or the equivalent if receiving the adult dose (50, 100, or 150 mg).</dd> <dt> <a href="#footnote-reference-18" name="footnote-18">†</a> </dt> <dd>Derived from simulations from the population PK model.</dd> <dt> <a href="#footnote-reference-19" name="footnote-19">‡</a> </dt> <dd>Derived from the population PK model.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Body weight group</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Dose</span><a class="Sup" href="#footnote-17" name="footnote-reference-17">*</a><span class="Bold"> <br/>mg/kg</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">C<span class="Sub">max.ss</span></span><a class="Sup" href="#footnote-18" name="footnote-reference-18">†</a><span class="Bold"><span class="Sub"></span> <br/>(mcg/mL)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">AUC<span class="Sub">.ss</span></span><a class="Sup" href="#footnote-18">†</a><span class="Bold"><span class="Sub"></span> <br/>(mcg h/mL)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">t<span class="Sub">1/2</span></span><a class="Sup" href="#footnote-19" name="footnote-reference-19">‡</a><span class="Bold"><span class="Sub"></span> <br/>(h)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">CL</span><a class="Sup" href="#footnote-19">‡</a><span class="Bold"> <br/>mL/min/kg)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="3" valign="middle"> <p class="First">30 kg or less</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="3" valign="middle"> <p class="First">149</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1.0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">7.1 +/- 4.7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">55 +/- 16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="3" valign="middle"> <p class="First">12.5 +/- 4.6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="3" valign="middle"> <p class="First">0.328 +/- 0.091</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2.0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">14.2 +/- 9.3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">109 +/- 31</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3.0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">21.3 +/- 14.0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">164 +/- 47</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="3" valign="middle"> <p class="First">Greater than 30 kg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="3" valign="middle"> <p class="First">80</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1.0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">8.7 +/- 5.6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">67 +/- 17</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="3" valign="middle"> <p class="First">13.6 +/- 8.8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="3" valign="middle"> <p class="First">0.241 +/- 0.061</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2.0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">17.5 +/- 11.2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">134 +/- 33</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">23.0 +/- 14.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">176 +/- 42</p> </td> </tr> </tbody> </table></div>

Pediatric Patients Younger than 4 Months of Age

Micafungin pharmacokinetic data in 103 pediatric patients less than 4 months of age were assessed using population pharmacokinetics. Predicted micafungin AUC estimates were dose proportional across the dose regimens and age ranges studied. The body weight-normalized micafungin clearance in pediatric patients less than 4 months of age is higher than the body weight-normalized micafungin clearance in older pediatric patients greater than 4 months of age and adults. Administration of 4 mg/kg once daily micafungin to pediatric patients less than 4 months of age produces a mean (SD) steady-state AUC of 131 (50) mcg·h/mL, which is comparable to the steady-state AUC in pediatric patients 4 months of age and older administered micafungin 2 mg/kg/day and adults administered 100 mg once daily.

Patients with Renal Impairment

Micafungin in Sodium Chloride Injection does not require dose adjustment in patients with renal impairment. A single 1-hour infusion of 100 mg micafungin for injection was administered to 9 adult subjects with severe renal impairment (creatinine clearance less than 30 mL/min) and to 9 age-, gender-, and weight-matched subjects with normal renal function (creatinine clearance greater than 80 mL/min). The maximum concentration (Cmax) 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.

Patients with Hepatic Impairment

Mechanism of Action

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

Activity in Animal Models of Candidiasis

Activity of micafungin has been demonstrated in both mucosal and disseminated murine and rabbit models of candidiasis. Micafungin administered to immunocompetent or immunosuppressed mice or rabbits with disseminated candidiasis prolonged survival (mice) and/or decreased the fungal burden in different organs including brain in a dose-dependent manner (mice and rabbits). Overall, antifungal activity of micafungin was demonstrated in the brain and eye tissues of nonneutropenic rabbits with HCME infected with a micafungin-sensitive strain of C. albicans; however, the activity varied in different central nervous system and ocular compartments. In the cerebrum, culture negativity was achieved at a micafungin dose regimen of 32 mg/kg once daily for 7 days; whereas, in spinal cord, vitreous humor, and choroid, culture negativity was achieved at micafungin dose regimens of 24 to 32 mg/kg once daily. Compared to untreated animals, micafungin dose regimens between 8 and 24 mg/kg once daily reduced fungal burden in the cerebrum and cerebellum. When cerebrum, cerebellum and spinal cord data were combined, a decrease in fungal burden relative to untreated controls was evident at micafungin dose regimens between 16 and 32 mg/kg once daily [see Use in Specific Populations (8.4)].

Resistance

There have been reports of clinical failures in patients receiving micafungin for injection therapy due to the development of drug resistance. Some of these reports have identified specific mutations in the FKS protein component of the glucan synthase enzyme that are associated with higher MICs and breakthrough infection.

Antimicrobial Activity

Micafungin has been shown to be active against most isolates of the following Candida species, both in vitro and in clinical infections [see Indications and Usage (1)]:

Candida albicans

Candida glabrata

Candida guilliermondii

Candida krusei

Candida parapsilosis

Candida tropicalis

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

Hepatic carcinomas and adenomas were observed in a 6-month intravenous toxicology study with an 18-month recovery period of micafungin sodium in rats designed to assess the reversibility of hepatocellular lesions.

Rats administered micafungin sodium for 3 months at 32 mg/kg/day (corresponding to 8 times the highest recommended human dose [150 mg/day], based on AUC comparisons), exhibited colored patches/zones, multinucleated hepatocytes and altered hepatocellular foci after 1 or 3-month recovery periods, and adenomas were observed after a 21-month recovery period. Rats administered micafungin sodium at the same dose for 6 months exhibited adenomas after a 12-month recovery period; after an 18-month recovery period, an increased incidence of adenomas was observed and, additionally, carcinomas were detected. A lower dose of micafungin sodium (equivalent to 5 times the human AUC) in the 6-month rat study resulted in a lower incidence of adenomas and carcinomas following 18 months recovery. The duration of micafungin dosing in these rat studies (3 or 6 months) exceeds the usual duration of Micafungin in Sodium Chloride Injection dosing in patients, which is typically less than 1 month for treatment of esophageal candidiasis, but dosing may exceed 1 month for Candida prophylaxis.

Although the increase in carcinomas in the 6-month rat study did not reach statistical significance, the persistence of altered hepatocellular foci subsequent to micafungin for injection dosing, and the presence of adenomas and carcinomas in the recovery periods suggest a causal relationship between micafungin sodium, altered hepatocellular foci, and hepatic neoplasms. Whole-life carcinogenicity studies of micafungin for injection in animals have not been conducted, and it is not known whether the hepatic neoplasms observed in treated rats also occur in other species, or if there is a dose threshold for this effect.

Micafungin sodium was not mutagenic or clastogenic when evaluated in a standard battery of in vitro and in vivo tests (i.e., bacterial reversion - S. typhimurium, E. coli; chromosomal aberration; intravenous mouse micronucleus).

Male rats treated intravenously with micafungin sodium for 9 weeks showed vacuolation of the epididymal ductal epithelial cells at or above 10 mg/kg (about 0.6 times the recommended clinical dose for esophageal candidiasis, based on body surface area comparisons). Higher doses (about twice the recommended clinical dose, based on body surface area comparisons) resulted in higher epididymis weights and reduced numbers of sperm cells. In a 39-week intravenous study in dogs, seminiferous tubular atrophy and decreased sperm in the epididymis were observed at 10 and 32 mg/kg, doses equal to about 2 and 7 times the recommended clinical dose, based on body surface area comparisons. There was no impairment of fertility in animal studies with micafungin sodium.

High doses of micafungin sodium (5 to 8 times the highest recommended human dose, based on AUC comparisons) have been associated with irreversible changes to the liver when administered for 3 or 6 months, and these changes may be indicative of pre-malignant processes [see Nonclinical Toxicology (13.1)].

Two dose levels of micafungin for injection 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 for injection, 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 for injection (100 mg/day) and caspofungin in Table 9.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 9. Efficacy Analysis: Treatment Success in Patients in Study 03-0-192 with Candidemia and Other Candida Infections</span> </caption> <col width="45%"/> <col width="32%"/> <col width="15%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-20" name="footnote-20">*</a> </dt> <dd>70 mg loading dose on day 1 followed by 50 mg/day thereafter (caspofungin).</dd> <dt> <a href="#footnote-reference-21" name="footnote-21">†</a> </dt> <dd>A patient may have had greater than 1 organ of dissemination.</dd> <dt> <a href="#footnote-reference-22" name="footnote-22">‡</a> </dt> <dd>A patient may have had greater than 1 baseline infection species.</dd> <dt> <a href="#footnote-reference-23" name="footnote-23">§</a> </dt> <dd>All patients who had a culture-confirmed relapse or required systemic antifungal therapy in the post-treatment period for a suspected or proven <span class="Italics">Candida</span> infection. Also includes patients who died or were not assessed in follow-up.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Micafungin for Injection<br/>100 mg/day<br/>n (%)<br/>% treatment difference (95% CI)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Caspofungin</span><a class="Sup" href="#footnote-20" name="footnote-reference-20">*</a><span class="Bold"> <br/>70/50 mg/day<br/>n (%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Treatment Success at End of IV Therapy</span><a class="Sup" href="#footnote-20">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">135/191 (70.7)<br/>7.4<br/>(-2.0, 16.3)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">119/188 (63.3)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Success in Patients with Neutropenia at Baseline</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">14/22 (63.6)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">5/11 (45.5)</p> </td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Success by Site of Infection</span> </p> </td><td class="Lrule Rrule Toprule" valign="middle"></td><td class="Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Candidemia</span> </p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">116/163 (71.2)</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">103/161 (64)</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Abscess</span> </p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">4/5 (80)</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">5/9 (55.6)</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Acute Disseminated</span><a class="Sup" href="#footnote-21" name="footnote-reference-21">†</a> </p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">6/13 (46.2)</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">5/9 (55.6)</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span>Endophthalmitis</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">1/3</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">1/1</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span>Chorioretinitis</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">0/3</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span>Skin</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">1/1</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span>Kidney</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">2/2</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">1/1</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span>Pancreas</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">1/1</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span>Peritoneum</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">1/1</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span>Lung/Skin</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">0/1</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span>Lung/Spleen</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">0/1</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span>Liver</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">0</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">0/2</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span>Intraabdominal abscess</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">0</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">3/5</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Chronic Disseminated</span> </p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">0/1</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Peritonitis</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">4/6 (66.7)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">2/5 (40)</p> </td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Success by Organism</span><a class="Sup" href="#footnote-22" name="footnote-reference-22">‡</a> </p> </td><td class="Lrule Rrule Toprule" valign="middle"></td><td class="Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span><span class="Italics">C</span><span class="Italics">. albicans</span> </p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">57/81 (70.4)</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">45/73 (61.6)</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span><span class="Italics">C. glabrata</span> </p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">16/23 (69.6)</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">19/31 (61.3)</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span><span class="Italics">C. tropicalis</span> </p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">17/27 (63)</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">22/29 (75.9)</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span><span class="Italics">C. parapsilosis</span> </p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">21/28 (75)</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">22/39 (56.4)</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span><span class="Italics">C. krusei</span> </p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">5/8 (62.5)</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">2/3 (66.7)</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span><span class="Italics">C. guilliermondii</span> </p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">1/2</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">0/1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span><span class="Italics">C. lusitaniae</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">2/3 (66.7)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">2/2</p> </td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Relapse through 6 Weeks</span><a class="Sup" href="#footnote-23" name="footnote-reference-23">§</a> </p> </td><td class="Lrule Rrule Toprule" valign="middle"></td><td class="Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First">Overall</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">49/135 (36.3)</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">44/119 (37)</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span>Culture-confirmed relapse</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">5</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">4</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span>Required systemic antifungal therapy</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">11</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">5</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span>Died during follow-up</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">17</p> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">16</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span>Not assessed</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">19</p> </td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Overall study mortality</span> </p> </td><td align="center" class="Lrule Rrule Toprule" valign="middle"> <p class="First">58/200 (29)</p> </td><td align="center" class="Lrule Rrule Toprule" valign="middle"> <p class="First">51/193 (26.4)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"></span>Mortality during IV therapy</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">28/200 (14)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">27/193 (14)</p> </td> </tr> </tbody> </table></div>

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 for injection, therapeutic success was documented during protocol-defined oral fluconazole therapy.

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

Micafungin for injection was evaluated in a randomized, double-blind study which compared micafungin for injection 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 for injection and fluconazole treatment groups.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 10. Endoscopic, Clinical, and Mycological Outcomes for Esophageal Candidiasis at End-of-Treatment</span> </caption> <col width="24%"/> <col width="24%"/> <col width="16%"/> <col width="18%"/> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-24" name="footnote-24">*</a> </dt> <dd>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.</dd> <dt> <a href="#footnote-reference-25" name="footnote-25">†</a> </dt> <dd>Calculated as micafungin for injection – fluconazole.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Treatment Outcome</span><a class="Sup" href="#footnote-24" name="footnote-reference-24">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Micafungin for Injection<br/>150 mg/day<br/>n = 260</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Fluconazole<br/>200 mg/day<br/>n = 258</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">% Difference</span><a class="Sup" href="#footnote-25" name="footnote-reference-25">†</a><span class="Bold"> <br/>(95% CI)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Endoscopic Cure</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">228 (87.7%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">227 (88.0%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">-0.3% (-5.9, +5.3)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Clinical Cure</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">239 (91.9%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">237 (91.9%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0.06% (-4.6, +4.8)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Overall Therapeutic Cure</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">223 (85.8%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">220 (85.3%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0.5% (-5.6, +6.6)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Mycological Eradication</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">141/189 (74.6%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">149/192 (77.6%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">-3.0% (-11.6, +5.6)</p> </td> </tr> </tbody> </table></div>

Most patients (96%) in this study had C. albicans isolated at baseline. The efficacy of micafungin for injection 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 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 for injection and fluconazole treatment groups, as shown in Table 11.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>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</span> </caption> <col width="35%"/> <col width="24%"/> <col width="13%"/> <col width="17%"/> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-26" name="footnote-26">*</a> </dt> <dd>Calculated as micafungin for injection – fluconazole; N = number of patients with overall therapeutic cure (both clinical and endoscopic cure at end-of-treatment);</dd> <dt> <a href="#footnote-reference-27" name="footnote-27">†</a> </dt> <dd>Relapse included patients who died or were lost to follow-up, and those who received systemic anti-fungal therapy in the post-treatment period.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Relapse</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Micafungin for Injection<br/>150 mg/day<br/>n = 223</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Fluconazole<br/>200 mg/day<br/>n = 220</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">% Difference</span><a class="Sup" href="#footnote-26" name="footnote-reference-26">*</a><span class="Bold"> <br/>(95% CI)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Relapse<a class="Sup" href="#footnote-27" name="footnote-reference-27">†</a> at Week 2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">40 (17.9%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">30 (13.6%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4.3% (-2.5, 11.1)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Relapse<a class="Sup" href="#footnote-27">†</a> through Week 4 (cumulative)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">73 (32.7%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">62 (28.2%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4.6% (-4.0, 13.1)</p> </td> </tr> </tbody> </table></div>

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 for injection-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 for injection 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 for injection group and 39.4% in the fluconazole group (treatment difference 12.7%, 95% confidence interval [2.8, 22.7]).

In a randomized, double-blind study, micafungin for injection (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/mm3 or greater or up to a maximum of 42 days after transplant. The average duration of drug administration was 18 days (range 1 to 51 days). Duration of therapy was slightly longer in the pediatric patients who received micafungin for injection (median duration 22 days) compared to the adult patients who received micafungin for injection (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 for injection recipients, and in 73.7% of adult and pediatric patients who received fluconazole (7.0% 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 for injection and 2 in the fluconazole group.

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

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 12. Results from Clinical Study of Prophylaxis of Candida Infections in Hematopoietic Stem Cell Transplant Recipients</span> </caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-28" name="footnote-28">*</a> </dt> <dd>Difference (micafungin for injection – fluconazole): +7.0% [95% CI=1.5, 12.5].</dd> <dt> <a href="#footnote-reference-29" name="footnote-29">†</a> </dt> <dd>Through end-of-study (4 weeks post-therapy).</dd> <dt> <a href="#footnote-reference-30" name="footnote-30">‡</a> </dt> <dd>Through end-of-therapy.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Outcome of Prophylaxis</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Micafungin for Injection<br/>50 mg/day<br/>(n = 425)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Fluconazole<br/>400 mg/day<br/>(n = 457)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Success<a class="Sup" href="#footnote-28" name="footnote-reference-28">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">343 (80.7%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">337 (73.7%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Failure:</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">82 (19.3%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">120 (26.3%)</p> </td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="top"> <p class="First">All Deaths<a class="Sup" href="#footnote-29" name="footnote-reference-29">†</a> </p> </td><td align="center" class="Lrule Rrule Toprule" valign="middle"> <p class="First">18 (4.2%)</p> </td><td align="center" class="Lrule Rrule Toprule" valign="middle"> <p class="First">26 (5.7%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Proven/probable fungal infection prior to death</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">1 (0.2%)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">3 (0.7%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Proven/probable fungal infection (not resulting in death)<a class="Sup" href="#footnote-29">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">6 (1.4%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">8 (1.8%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Suspected fungal infection<a class="Sup" href="#footnote-30" name="footnote-reference-30">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">53 (12.5%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">83 (18.2%)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Lost to follow-up</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">5 (1.2%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3 (0.7%)</p> </td> </tr> </tbody> </table></div>

How Supplied

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Micafungin in Sodium Chloride Injection is supplied as a clear and colorless refrigerated, premixed, iso-osmotic, sterile, nonpyrogenic solution for intravenous infusion, and is available in the following packaging configurations:

{ "type": "p", "children": [], "text": "Micafungin in Sodium Chloride Injection is supplied as a clear and colorless refrigerated, premixed, iso-osmotic, sterile, nonpyrogenic solution for intravenous infusion, and is available in the following packaging configurations:" }

<div class="scrollingtable"><table width="100%"> <col width="8%"/> <col width="17%"/> <col width="18%"/> <col width="7%"/> <col width="50%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="bottom">Code</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="bottom">NDC Multiple Cartons</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">NDC Individual Carton</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="bottom">Size</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="bottom">Number of Containers/Carton</th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">2G3434</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NDC 0338-9051-12</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NDC 0338-9051-01</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">50 mL</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12 individually packaged 50 mg/50 mL (1 mg/mL) single-dose Galaxy containers</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">2G3435</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NDC 0338-9053-12</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NDC 0338-9053-01</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">100 mL</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12 individually packaged 100 mg/100 mL (1 mg/mL) single-dose Galaxy containers</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2G3433</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NDC 0338-9055-10</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NDC 0338-9055-01</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">150 mL</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10 individually packaged 150 mg/150 mL (1 mg/mL) single-dose Galaxy containers</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"8%\"/>\n<col width=\"17%\"/>\n<col width=\"18%\"/>\n<col width=\"7%\"/>\n<col width=\"50%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"bottom\">Code</th><th align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"bottom\">NDC Multiple Cartons</th><th align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">NDC Individual Carton</th><th align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"bottom\">Size</th><th align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"bottom\">Number of Containers/Carton</th>\n</tr>\n</thead>\n<tbody>\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">2G3434</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">NDC 0338-9051-12</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">NDC 0338-9051-01</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">50 mL</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">12 individually packaged 50 mg/50 mL (1 mg/mL) single-dose Galaxy containers</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">2G3435</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">NDC 0338-9053-12</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">NDC 0338-9053-01</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">100 mL</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">12 individually packaged 100 mg/100 mL (1 mg/mL) single-dose Galaxy containers</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">2G3433</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">NDC 0338-9055-10</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">NDC 0338-9055-01</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">150 mL</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">10 individually packaged 150 mg/150 mL (1 mg/mL) single-dose Galaxy containers</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Storage and Handling

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Store Micafungin in Sodium Chloride Injection in the refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not use after the expiration date printed on the carton and container label.

{ "type": "p", "children": [], "text": "Store Micafungin in Sodium Chloride Injection in the refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not use after the expiration date printed on the carton and container label." }

If needed, Micafungin in Sodium Chloride Injection may be stored at room temperature 20°C to 25°C (68°F to 77°F) for up to 30 days in the original carton to protect from light. Once stored at room temperature, do not place back in the refrigerator. Discard Micafungin in Sodium Chloride Injection after 30 days if stored at room temperature.

{ "type": "p", "children": [], "text": "If needed, Micafungin in Sodium Chloride Injection may be stored at room temperature 20°C to 25°C (68°F to 77°F) for up to 30 days in the original carton to protect from light. Once stored at room temperature, do not place back in the refrigerator. Discard Micafungin in Sodium Chloride Injection after 30 days if stored at room temperature." }

Do not freeze and do not use Micafungin in Sodium Chloride Injection if it has been frozen.

{ "type": "p", "children": [], "text": "Do not freeze and do not use Micafungin in Sodium Chloride Injection if it has been frozen." }

Hypersensitivity

{ "type": "p", "children": [], "text": "\nHypersensitivity\n" }

Inform patients about the serious adverse effects of Micafungin in Sodium Chloride Injection including hypersensitivity reactions, e.g., anaphylaxis and anaphylactoid reactions including shock.

{ "type": "p", "children": [], "text": "Inform patients about the serious adverse effects of Micafungin in Sodium Chloride Injection including hypersensitivity reactions, e.g., anaphylaxis and anaphylactoid reactions including shock." }

Hepatic

{ "type": "p", "children": [], "text": "\nHepatic\n" }

Inform patients about the serious adverse effects of Micafungin in Sodium Chloride Injection including hepatic effects, e.g., abnormal liver tests, hepatic impairment, hepatitis or worsening hepatic failure.

{ "type": "p", "children": [], "text": "Inform patients about the serious adverse effects of Micafungin in Sodium Chloride Injection including hepatic effects, e.g., abnormal liver tests, hepatic impairment, hepatitis or worsening hepatic failure." }

Hematologic

{ "type": "p", "children": [], "text": "\nHematologic\n" }

Inform patients about the serious adverse effects of Micafungin in Sodium Chloride Injection including hematological effects, e.g., acute intravascular hemolysis, hemolytic anemia and hemoglobinuria.

{ "type": "p", "children": [], "text": "Inform patients about the serious adverse effects of Micafungin in Sodium Chloride Injection including hematological effects, e.g., acute intravascular hemolysis, hemolytic anemia and hemoglobinuria." }

Renal

{ "type": "p", "children": [], "text": "\nRenal\n" }

Inform patients about the serious adverse effects of Micafungin in Sodium Chloride Injection including renal effects, e.g., elevations in BUN and creatinine, renal impairment or acute renal failure.

{ "type": "p", "children": [], "text": "Inform patients about the serious adverse effects of Micafungin in Sodium Chloride Injection including renal effects, e.g., elevations in BUN and creatinine, renal impairment or acute renal failure." }

Embryo-Fetal Toxicity

{ "type": "p", "children": [], "text": "\nEmbryo-Fetal Toxicity\n" }

Advise pregnant women and females of reproductive potential of the potential risk of Micafungin in Sodium Chloride Injection to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.

{ "type": "p", "children": [], "text": "Advise pregnant women and females of reproductive potential of the potential risk of Micafungin in Sodium Chloride Injection to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy." }

Concomitant Medications

{ "type": "p", "children": [], "text": "\nConcomitant Medications\n" }

Instruct patients to inform their healthcare provider of any other medications they are currently taking with Micafungin in Sodium Chloride Injection, including over-the-counter medications.

{ "type": "p", "children": [], "text": "Instruct patients to inform their healthcare provider of any other medications they are currently taking with Micafungin in Sodium Chloride Injection, including over-the-counter medications." }

High Sodium Load

{ "type": "p", "children": [], "text": "\nHigh Sodium Load\n" }

Advise patients to inform their healthcare provider if they are on a salt-restricted diet or have congestive heart failure as increased blood sodium can occur in people who receive Micafungin in Sodium Chloride Injection [see Warnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": "Advise patients to inform their healthcare provider if they are on a salt-restricted diet or have congestive heart failure as increased blood sodium can occur in people who receive Micafungin in Sodium Chloride Injection [see Warnings and Precautions (5.6)]." }

Baxter Logo

{ "type": "p", "children": [], "text": "\nBaxter Logo\n" }

Manufactured by:

{ "type": "p", "children": [], "text": "Manufactured by:" }

Baxter Healthcare Corporation

{ "type": "p", "children": [], "text": "Baxter Healthcare Corporation" }

Deerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Deerfield, IL 60015 USA" }

Product of USA

{ "type": "p", "children": [], "text": "Product of USA" }

Baxter and Galaxy are registered trademarks of Baxter International Inc.

{ "type": "p", "children": [], "text": "Baxter and Galaxy are registered trademarks of Baxter International Inc." }

07-19-06-083

{ "type": "p", "children": [], "text": "07-19-06-083" }

{ "type": "", "children": [], "text": "" }

NDC 0338-9051-01

{ "type": "p", "children": [], "text": "NDC 0338-9051-01" }

Micafunginin 0.9% Sodium Chloride Injection50 mg / 50 mL (1 mg / mL)

{ "type": "p", "children": [], "text": "\nMicafunginin 0.9% Sodium Chloride Injection50 mg / 50 mL (1 mg / mL)\n" }

50 mgTOTAL

{ "type": "p", "children": [], "text": "\n50 mgTOTAL\n" }

50 mL Single-Dose GALAXY containerDiscard unused portion For Intravenous Infusion Only

{ "type": "p", "children": [], "text": "\n50 mL Single-Dose GALAXY containerDiscard unused portion\n\nFor Intravenous Infusion Only\n" }

Rx onlySterile Nonpyrogenic

{ "type": "p", "children": [], "text": "\nRx onlySterile Nonpyrogenic\n" }

Cautions: Do not add supplemental medication or additives.Must not be used in series connections. Check for minute leaks and solutionclarity.

{ "type": "p", "children": [], "text": "Cautions: Do not add supplemental medication or additives.Must not be used in series connections. Check for minute leaks and solutionclarity." }

Each 50 mL bag contains: 50 mg of Micafungin Sodium (equivalent to 50.87 mg ofMicafungin Sodium); 36 mg Citric Acid, Anhydrous; 450 mg Sodium Chloride,92 mg Sodium Citrate, Dihydrate; and Water for Injection.

{ "type": "p", "children": [], "text": "Each 50 mL bag contains: 50 mg of Micafungin Sodium (equivalent to 50.87 mg ofMicafungin Sodium); 36 mg Citric Acid, Anhydrous; 450 mg Sodium Chloride,92 mg Sodium Citrate, Dihydrate; and Water for Injection." }

Dosage: See prescribing information.

{ "type": "p", "children": [], "text": "Dosage: See prescribing information." }

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton toprotect from light. Do Not Freeze.

{ "type": "p", "children": [], "text": "\nStore refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton toprotect from light. Do Not Freeze.\n" }

If needed, may store at room temperature up to 25°C (77°F) up to 30 days inthe original carton. Discard after 30 days if stored at room temperature.

{ "type": "p", "children": [], "text": "If needed, may store at room temperature up to 25°C (77°F) up to 30 days inthe original carton. Discard after 30 days if stored at room temperature." }

Baxter Logo

{ "type": "p", "children": [], "text": "\nBaxter Logo\n" }

Baxter and Galaxy are registered trademarks of Baxter International Inc. Baxter Healthcare Corporation, Deerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Baxter and Galaxy are registered trademarks of Baxter International Inc.\nBaxter Healthcare Corporation, Deerfield, IL 60015 USA" }

Code 2G3434 PL 2501 Plastic

{ "type": "p", "children": [], "text": "\nCode 2G3434\nPL 2501 Plastic" }

Product of USA07-34-00-1662

{ "type": "p", "children": [], "text": "Product of USA07-34-00-1662" }

BAR CODEPOSITION ONLY UPCA-A

{ "type": "p", "children": [], "text": "BAR CODEPOSITION ONLY UPCA-A" }

XXXXXXXXXXXX

{ "type": "p", "children": [], "text": "XXXXXXXXXXXX" }

{ "type": "", "children": [], "text": "" }

NDC 0338-9053-01

{ "type": "p", "children": [], "text": "NDC 0338-9053-01" }

Micafunginin 0.9% Sodium Chloride Injection100 mg / 100 mL (1 mg / mL)

{ "type": "p", "children": [], "text": "\nMicafunginin 0.9% Sodium Chloride Injection100 mg / 100 mL (1 mg / mL)\n" }

100 mgTOTAL

{ "type": "p", "children": [], "text": "\n100 mgTOTAL\n" }

100 mL Single-Dose GALAXY containerDiscard unused portion For Intravenous Infusion Only

{ "type": "p", "children": [], "text": "\n100 mL Single-Dose GALAXY containerDiscard unused portion\n\nFor Intravenous Infusion Only\n" }

Rx onlySterile Nonpyrogenic

{ "type": "p", "children": [], "text": "\nRx onlySterile Nonpyrogenic\n" }

Cautions: Do not add supplemental medication or additives.Must not be used in series connections. Check for minute leaksand solution clarity.

{ "type": "p", "children": [], "text": "Cautions: Do not add supplemental medication or additives.Must not be used in series connections. Check for minute leaksand solution clarity." }

Each mL contains: 100 mg of Micafungin (equivalentto 101.73 mg of Micafungin Sodium); 72 mg Citric Acid,Anhydrous; 900 mg Sodium Chloride; 184 mg Sodium Citrate,Dihydrate; and Water for Injection.

{ "type": "p", "children": [], "text": "Each mL contains: 100 mg of Micafungin (equivalentto 101.73 mg of Micafungin Sodium); 72 mg Citric Acid,Anhydrous; 900 mg Sodium Chloride; 184 mg Sodium Citrate,Dihydrate; and Water for Injection." }

Dosage: See prescribing information.

{ "type": "p", "children": [], "text": "Dosage: See prescribing information." }

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do Not Freeze.

{ "type": "p", "children": [], "text": "\nStore refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do Not Freeze.\n" }

If needed, may store at room temperature up to 25°C (77°F) up to 30 days in the original carton. Discard after 30 days if stored atroom temperature.

{ "type": "p", "children": [], "text": "If needed, may store at room temperature up to 25°C (77°F) up to 30 days in the original carton. Discard after 30 days if stored atroom temperature." }

Baxter Logo

{ "type": "p", "children": [], "text": "\nBaxter Logo\n" }

Baxter and Galaxy are registered trademarks ofBaxter International Inc. Baxter Healthcare Corporation, Deerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Baxter and Galaxy are registered trademarks ofBaxter International Inc.\nBaxter Healthcare Corporation,\nDeerfield, IL 60015 USA" }

Code 2G3435 PL 2501 Plastic

{ "type": "p", "children": [], "text": "\nCode 2G3435\nPL 2501 Plastic" }

Product of USA07-34-00-1663

{ "type": "p", "children": [], "text": "Product of USA07-34-00-1663" }

BAR CODEPOSITION ONLY UPCA-A

{ "type": "p", "children": [], "text": "BAR CODEPOSITION ONLY UPCA-A" }

XXXXXXXXXXXX

{ "type": "p", "children": [], "text": "XXXXXXXXXXXX" }

{ "type": "", "children": [], "text": "" }

NDC 0338-9055-01

{ "type": "p", "children": [], "text": "NDC 0338-9055-01" }

Micafungin in 0.9% Sodium Chloride Injection150 mg / 150 mL (1 mg / mL)

{ "type": "p", "children": [], "text": "\nMicafungin\n\nin 0.9% Sodium Chloride Injection150 mg / 150 mL (1 mg / mL)\n" }

150mgTOTAL

{ "type": "p", "children": [], "text": "\n150mgTOTAL\n" }

150 mL Single-Dose GALAXY containerDiscard unused portion For Intravenous Infusion Only

{ "type": "p", "children": [], "text": "\n150 mL Single-Dose GALAXY containerDiscard unused portion\n\nFor Intravenous Infusion Only\n" }

Rx onlySterile Nonpyrogenic

{ "type": "p", "children": [], "text": "\nRx onlySterile Nonpyrogenic\n" }

Cautions: Do not add supplemental medication or additives.Must not be used in series connections. Check for minute leaksand solution clarity.

{ "type": "p", "children": [], "text": "Cautions: Do not add supplemental medication or additives.Must not be used in series connections. Check for minute leaksand solution clarity." }

Each mL contains: 150 mg of Micafungin (equivalentto 152.60 mg of Micafungin Sodium); 108 mg Citric Acid,Anhydrous; 1350 mg Sodium Chloride; 276 mg Sodium Citrate,Dihydrate; and Water for Injection.

{ "type": "p", "children": [], "text": "Each mL contains: 150 mg of Micafungin (equivalentto 152.60 mg of Micafungin Sodium); 108 mg Citric Acid,Anhydrous; 1350 mg Sodium Chloride; 276 mg Sodium Citrate,Dihydrate; and Water for Injection." }

Dosage: See prescribing information.

{ "type": "p", "children": [], "text": "Dosage: See prescribing information." }

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do Not Freeze.

{ "type": "p", "children": [], "text": "\nStore refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do Not Freeze.\n" }

If needed, may store at room temperature up to 25°F (77°F) upto 30 days in the original carton. Discard after 30 days if stored atroom temperature.

{ "type": "p", "children": [], "text": "If needed, may store at room temperature up to 25°F (77°F) upto 30 days in the original carton. Discard after 30 days if stored atroom temperature." }

Baxter Logo

{ "type": "p", "children": [], "text": "\nBaxter Logo\n" }

Baxter and Galaxy are registered trademarks ofBaxter International Inc. Baxter Healthcare Corporation, Deerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Baxter and Galaxy are registered trademarks ofBaxter International Inc.\nBaxter Healthcare Corporation,\nDeerfield, IL 60015 USA" }

Code 2G3433 PL 2501 Plastic

{ "type": "p", "children": [], "text": "\nCode 2G3433\nPL 2501 Plastic" }

Product of USA07-34-00-1664

{ "type": "p", "children": [], "text": "Product of USA07-34-00-1664" }

BAR CODEPOSITION ONLY UPCA-A

{ "type": "p", "children": [], "text": "BAR CODEPOSITION ONLY UPCA-A" }

XXXXXXXXXXXX

{ "type": "p", "children": [], "text": "XXXXXXXXXXXX" }

{ "type": "", "children": [], "text": "" }

For Intravenous OnlyMicafunginin 0.9% Sodium Chloride Injection

{ "type": "p", "children": [], "text": "\nFor Intravenous OnlyMicafunginin 0.9% Sodium Chloride Injection\n" }

50 mg per 50 mL (1 mg / mL)

{ "type": "p", "children": [], "text": "\n50 mg per 50 mL (1 mg / mL)\n" }

For Intravenous OnlyMicafunginin 0.9% Sodium Chloride Injection

{ "type": "p", "children": [], "text": "\nFor Intravenous OnlyMicafunginin 0.9% Sodium Chloride Injection\n" }

50 mg per 50 mL (1 mg / mL)

{ "type": "p", "children": [], "text": "\n50 mg per 50 mL (1 mg / mL)\n" }

NDC 0338-9051-01

{ "type": "p", "children": [], "text": "NDC 0338-9051-01" }

Sterile, Nonpyrogenic

{ "type": "p", "children": [], "text": "Sterile, Nonpyrogenic" }

Micafunginin 0.9% Sodium Chloride Injection50 mg / 50 mL (1 mg / mL)

{ "type": "p", "children": [], "text": "\nMicafunginin 0.9% Sodium Chloride Injection50 mg / 50 mL (1 mg / mL)\n" }

50 mgTOTAL

{ "type": "p", "children": [], "text": "\n50 mgTOTAL\n" }

UNVARNISHED AREA FOR ON-LINEPRINTING OF LOT & EXP

{ "type": "p", "children": [], "text": "UNVARNISHED AREA FOR ON-LINEPRINTING OF LOT & EXP" }

FPO UPC-A Barcode085412XXXXXX

{ "type": "p", "children": [], "text": "FPO UPC-A Barcode085412XXXXXX" }

Each 50 mL bag contains: 50 mg of Micafungin (equivalent to 50.87 mg of Micafungin Sodium);36 mg Citric Acid, Anhydrous; 450 mg Sodium Chloride; 92 mg Sodium Citrate, Dihydrate;and Water for Injection.

{ "type": "p", "children": [], "text": "Each 50 mL bag contains: 50 mg of Micafungin (equivalent to 50.87 mg of Micafungin Sodium);36 mg Citric Acid, Anhydrous; 450 mg Sodium Chloride; 92 mg Sodium Citrate, Dihydrate;and Water for Injection." }

Dosage: For Intravenous Infusion Only. See prescribing information.

{ "type": "p", "children": [], "text": "\nDosage: For Intravenous Infusion Only. See prescribing information." }

Caution: Do not add supplemental medication or additives.

{ "type": "p", "children": [], "text": "\nCaution: Do not add supplemental medication or additives." }

RX only

{ "type": "p", "children": [], "text": "\nRX only\n" }

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.Do Not Freeze

{ "type": "p", "children": [], "text": "\nStore refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.Do Not Freeze \n" }

If needed, may store at room temperature up to 25°C (77°F) up to 30 days in the original carton.Once stored at room temperature, do not place back in the refrigerator.Discard after 30 days if stored at room temperature

{ "type": "p", "children": [], "text": "If needed, may store at room temperature up to 25°C (77°F) up to 30 days in the original carton.Once stored at room temperature, do not place back in the refrigerator.Discard after 30 days if stored at room temperature\n" }

Discard 30 days after storing at room temperature. Discard after:(Month) (Day) (Year)(to be completed by dispensing pharmacist)

{ "type": "p", "children": [], "text": "Discard 30 days after storing at room temperature. Discard after:(Month) (Day) (Year)(to be completed by dispensing pharmacist)" }

Baxter and Galaxy are registered trademarks of Baxter International Inc. Baxter Healthcare Corporation Deerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Baxter and Galaxy are registered trademarks of Baxter International Inc.\nBaxter Healthcare Corporation\nDeerfield, IL 60015 USA" }

Product of USA 07-01-00-0593

{ "type": "p", "children": [], "text": "Product of USA\n07-01-00-0593\n" }

For Intravenous Infusion OnlyMicafunginin 0.9% Sodium Chloride Injection

{ "type": "p", "children": [], "text": "\nFor Intravenous Infusion OnlyMicafunginin 0.9% Sodium Chloride Injection\n" }

50 mg per 50 mL (1 mg / mL)

{ "type": "p", "children": [], "text": "\n50 mg per 50 mL (1 mg / mL)\n" }

For Intravenous Infusion OnlyMicafunginin 0.9% Sodium Chloride Injection

{ "type": "p", "children": [], "text": "\nFor Intravenous Infusion OnlyMicafunginin 0.9% Sodium Chloride Injection\n" }

50 mg per 50 mL (1 mg / mL)

{ "type": "p", "children": [], "text": "\n50 mg per 50 mL (1 mg / mL)\n" }

NDC 0338-9051-01

{ "type": "p", "children": [], "text": "\nNDC 0338-9051-01\n" }

Code 2G3434

{ "type": "p", "children": [], "text": "Code 2G3434" }

Micafunginin 0.9% Sodium Chloride Injection50 mg / 50 mL (1 mg / 1 mL)

{ "type": "p", "children": [], "text": "\nMicafunginin 0.9% Sodium Chloride Injection50 mg / 50 mL (1 mg / 1 mL)\n" }

50 mgTOTAL

{ "type": "p", "children": [], "text": "\n50 mgTOTAL\n" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

For Intravenous Infusion Only

{ "type": "p", "children": [], "text": "\nFor Intravenous Infusion Only\n" }

1 Single-Dose GALAXY ContainerDiscard unused portion

{ "type": "p", "children": [], "text": "1 Single-Dose GALAXY ContainerDiscard unused portion" }

USE CARTON TO PROECT CONTENTSFROM LIGHT UNTIL ADMINISTRATION

{ "type": "p", "children": [], "text": "USE CARTON TO PROECT CONTENTSFROM LIGHT UNTIL ADMINISTRATION" }

Baxter Logo

{ "type": "p", "children": [], "text": "\nBaxter Logo\n" }

{ "type": "", "children": [], "text": "" }

For Intravenous OnlyMicafunginin 0.9% Sodium Chloride Injection

{ "type": "p", "children": [], "text": "\nFor Intravenous OnlyMicafunginin 0.9% Sodium Chloride Injection\n" }

100 mg per 100 mL (1 mg / mL)

{ "type": "p", "children": [], "text": "\n100 mg per 100 mL (1 mg / mL)\n" }

For Intravenous OnlyMicafunginin 0.9% Sodium Chloride Injection

{ "type": "p", "children": [], "text": "\nFor Intravenous OnlyMicafunginin 0.9% Sodium Chloride Injection\n" }

100 mg per 100 mL (1 mg / mL)

{ "type": "p", "children": [], "text": "\n100 mg per 100 mL (1 mg / mL)\n" }

NDC 0338-9053-01

{ "type": "p", "children": [], "text": "NDC 0338-9053-01" }

Sterile, Nonpyrogenic

{ "type": "p", "children": [], "text": "Sterile, Nonpyrogenic" }

Micafunginin 0.9% Sodium Chloride Injection100 mg / 100 mL (1 mg / mL)

{ "type": "p", "children": [], "text": "\nMicafunginin 0.9% Sodium Chloride Injection100 mg / 100 mL (1 mg / mL)\n" }

100 mgTOTAL

{ "type": "p", "children": [], "text": "\n100 mgTOTAL\n" }

UNVARNISHED AREA FOR ON-LINEPRINTING OF LOT & EXP

{ "type": "p", "children": [], "text": "UNVARNISHED AREA FOR ON-LINEPRINTING OF LOT & EXP" }

FPO UPC-A Barcode085412XXXXXX

{ "type": "p", "children": [], "text": "FPO UPC-A Barcode085412XXXXXX" }

Each 100 mL bag contains: 100 mg of Micafungin (equivalent to 101.73 mg of Micafungin Sodium);72 mg Citric Acid, Anhydrous; 900 mg Sodium Chloride; 184 mg Sodium Citrate, Dihydrate;and Water for Injection.

{ "type": "p", "children": [], "text": "Each 100 mL bag contains: 100 mg of Micafungin (equivalent to 101.73 mg of Micafungin Sodium);72 mg Citric Acid, Anhydrous; 900 mg Sodium Chloride; 184 mg Sodium Citrate, Dihydrate;and Water for Injection." }

Dosage: For Intravenous Infusion Only. See prescribing information.

{ "type": "p", "children": [], "text": "\nDosage: For Intravenous Infusion Only. See prescribing information." }

Caution: Do not add supplemental medication or additives.

{ "type": "p", "children": [], "text": "\nCaution: Do not add supplemental medication or additives." }

RX only

{ "type": "p", "children": [], "text": "\nRX only\n" }

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.Do Not Freeze

{ "type": "p", "children": [], "text": "\nStore refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.Do Not Freeze \n" }

If needed, may store at room temperature up to 25°C (77°F) up to 30 days in the original carton.Once stored at room temperature, do not place back in the refrigerator.Discard after 30 days if stored at room temperature

{ "type": "p", "children": [], "text": "If needed, may store at room temperature up to 25°C (77°F) up to 30 days in the original carton.Once stored at room temperature, do not place back in the refrigerator.Discard after 30 days if stored at room temperature\n" }

Discard 30 days after storing at room temperature. Discard after:(Month) (Day) (Year)(to be completed by dispensing pharmacist)

{ "type": "p", "children": [], "text": "Discard 30 days after storing at room temperature. Discard after:(Month) (Day) (Year)(to be completed by dispensing pharmacist)" }

Baxter and Galaxy are registered trademarks of Baxter International Inc. Baxter Healthcare Corporation Deerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Baxter and Galaxy are registered trademarks of Baxter International Inc.\nBaxter Healthcare Corporation\nDeerfield, IL 60015 USA" }

Product of USA 07-01-00-0613

{ "type": "p", "children": [], "text": "Product of USA\n07-01-00-0613\n" }

For Intravenous Infusion OnlyMicafunginin 0.9% Sodium Chloride Injection

{ "type": "p", "children": [], "text": "\nFor Intravenous Infusion OnlyMicafunginin 0.9% Sodium Chloride Injection\n" }

100 mg per 100 mL (1 mg / mL)

{ "type": "p", "children": [], "text": "\n100 mg per 100 mL (1 mg / mL)\n" }

For Intravenous Infusion OnlyMicafunginin 0.9% Sodium Chloride Injection

{ "type": "p", "children": [], "text": "\nFor Intravenous Infusion OnlyMicafunginin 0.9% Sodium Chloride Injection\n" }

100 mg per 100 mL (1 mg / mL)

{ "type": "p", "children": [], "text": "\n100 mg per 100 mL (1 mg / mL)\n" }

NDC 0338-9053-01

{ "type": "p", "children": [], "text": "\nNDC 0338-9053-01\n" }

Code 2G3435

{ "type": "p", "children": [], "text": "Code 2G3435" }

Micafunginin 0.9% Sodium Chloride Injection100 mg / 100 mL (1 mg / 1 mL)

{ "type": "p", "children": [], "text": "\nMicafunginin 0.9% Sodium Chloride Injection100 mg / 100 mL (1 mg / 1 mL)\n" }

100 mgTOTAL

{ "type": "p", "children": [], "text": "\n100 mgTOTAL\n" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

For Intravenous Infusion Only

{ "type": "p", "children": [], "text": "\nFor Intravenous Infusion Only\n" }

1 Single-Dose GALAXY ContainerDiscard unused portion

{ "type": "p", "children": [], "text": "1 Single-Dose GALAXY ContainerDiscard unused portion" }

USE CARTON TO PROECT CONTENTSFROM LIGHT UNTIL ADMINISTRATION

{ "type": "p", "children": [], "text": "USE CARTON TO PROECT CONTENTSFROM LIGHT UNTIL ADMINISTRATION" }

Baxter Logo

{ "type": "p", "children": [], "text": "\nBaxter Logo\n" }

{ "type": "", "children": [], "text": "" }

For Intravenous OnlyMicafunginin 0.9% Sodium Chloride Injection

{ "type": "p", "children": [], "text": "\nFor Intravenous OnlyMicafunginin 0.9% Sodium Chloride Injection\n" }

150 mg per 150 mL (1 mg / mL)

{ "type": "p", "children": [], "text": "\n150 mg per 150 mL (1 mg / mL)\n" }

For Intravenous OnlyMicafunginin 0.9% Sodium Chloride Injection

{ "type": "p", "children": [], "text": "\nFor Intravenous OnlyMicafunginin 0.9% Sodium Chloride Injection\n" }

150 mg per 150 mL (1 mg / mL)

{ "type": "p", "children": [], "text": "\n150 mg per 150 mL (1 mg / mL)\n" }

NDC 0338-9055-01

{ "type": "p", "children": [], "text": "NDC 0338-9055-01" }

Sterile, Nonpyrogenic

{ "type": "p", "children": [], "text": "Sterile, Nonpyrogenic" }

Micafunginin 0.9% Sodium Chloride Injection150 mg / 150 mL (1 mg / mL)

{ "type": "p", "children": [], "text": "\nMicafunginin 0.9% Sodium Chloride Injection150 mg / 150 mL (1 mg / mL)\n" }

150 mgTOTAL

{ "type": "p", "children": [], "text": "\n150 mgTOTAL\n" }

UNVARNISHED AREA FOR ON-LINEPRINTING OF LOT & EXP

{ "type": "p", "children": [], "text": "UNVARNISHED AREA FOR ON-LINEPRINTING OF LOT & EXP" }

FPO UPC-A Barcode085412XXXXXX

{ "type": "p", "children": [], "text": "FPO UPC-A Barcode085412XXXXXX" }

Each 150 mL bag contains: 150 mg of Micafungin (equivalent to 152.60 mg of MicafunginSodium); 108 mg Citric Acid, Anhydrous; 1350 mg Sodium Chloride; 276 mg Sodium Citrate,Dihydrate; and Water for Injection.

{ "type": "p", "children": [], "text": "Each 150 mL bag contains: 150 mg of Micafungin (equivalent to 152.60 mg of MicafunginSodium); 108 mg Citric Acid, Anhydrous; 1350 mg Sodium Chloride; 276 mg Sodium Citrate,Dihydrate; and Water for Injection." }

Dosage: For Intravenous Infusion Only. See prescribing information.

{ "type": "p", "children": [], "text": "\nDosage: For Intravenous Infusion Only. See prescribing information." }

Caution: Do not add supplemental medication or additives.

{ "type": "p", "children": [], "text": "\nCaution: Do not add supplemental medication or additives." }

RX only

{ "type": "p", "children": [], "text": "\nRX only\n" }

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.Do Not Freeze

{ "type": "p", "children": [], "text": "\nStore refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.Do Not Freeze \n" }

If needed, may store at room temperature up to 25°C (77°F) up to 30 days in the original carton.Once stored at room temperature, do not place back in the refrigerator.Discard after 30 days if stored at room temperature

{ "type": "p", "children": [], "text": "If needed, may store at room temperature up to 25°C (77°F) up to 30 days in the original carton.Once stored at room temperature, do not place back in the refrigerator.Discard after 30 days if stored at room temperature\n" }

Discard 30 days after storing at room temperature. Discard after:(Month) (Day) (Year)(to be completed by dispensing pharmacist)

{ "type": "p", "children": [], "text": "Discard 30 days after storing at room temperature. Discard after:(Month) (Day) (Year)(to be completed by dispensing pharmacist)" }

Baxter and Galaxy are registered trademarks of Baxter International Inc. Baxter Healthcare Corporation Deerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Baxter and Galaxy are registered trademarks of Baxter International Inc.\nBaxter Healthcare Corporation\nDeerfield, IL 60015 USA" }

Product of USA 07-01-00-0614

{ "type": "p", "children": [], "text": "Product of USA\n07-01-00-0614\n" }

For Intravenous Infusion OnlyMicafunginin 0.9% Sodium Chloride Injection

{ "type": "p", "children": [], "text": "\nFor Intravenous Infusion OnlyMicafunginin 0.9% Sodium Chloride Injection\n" }

150 mg per 150 mL (1 mg / mL)

{ "type": "p", "children": [], "text": "\n150 mg per 150 mL (1 mg / mL)\n" }

For Intravenous Infusion OnlyMicafunginin 0.9% Sodium Chloride Injection

{ "type": "p", "children": [], "text": "\nFor Intravenous Infusion OnlyMicafunginin 0.9% Sodium Chloride Injection\n" }

150 mg per 150 mL (1 mg / mL)

{ "type": "p", "children": [], "text": "\n150 mg per 150 mL (1 mg / mL)\n" }

NDC 0338-9055-01

{ "type": "p", "children": [], "text": "\nNDC 0338-9055-01\n" }

Code 2G3433

{ "type": "p", "children": [], "text": "Code 2G3433" }

Micafunginin 0.9% Sodium Chloride Injection150 mg / 150 mL (1 mg / 1 mL)

{ "type": "p", "children": [], "text": "\nMicafunginin 0.9% Sodium Chloride Injection150 mg / 150 mL (1 mg / 1 mL)\n" }

150 mgTOTAL

{ "type": "p", "children": [], "text": "\n150 mgTOTAL\n" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

For Intravenous Infusion Only

{ "type": "p", "children": [], "text": "\nFor Intravenous Infusion Only\n" }

1 Single-Dose GALAXY ContainerDiscard unused portion

{ "type": "p", "children": [], "text": "1 Single-Dose GALAXY ContainerDiscard unused portion" }

USE CARTON TO PROECT CONTENTSFROM LIGHT UNTIL ADMINISTRATION

{ "type": "p", "children": [], "text": "USE CARTON TO PROECT CONTENTSFROM LIGHT UNTIL ADMINISTRATION" }

Baxter Logo

{ "type": "p", "children": [], "text": "\nBaxter Logo\n" }

Micafungin for injection is indicated for:

{ "type": "p", "children": [], "text": "\nMicafungin for injection is indicated for:" }

{ "type": "ul", "children": [ "Treatment of Candidemia, Acute Disseminated Candidiasis, CandidaPeritonitis and Abscesses in adult and pediatric patients 4 months of age and older [see Clinical Studies (14.1) and Use in Specific Populations (8.4)].\n", "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)].", "Treatment of Esophageal Candidiasis in adult and pediatric patients 4 months of age and older [see Clinical Studies (14.2)].\n", "Prophylaxis of CandidaInfections in adult and pediatric patients 4 months of age and older undergoing hematopoietic stem cell transplantation [see Clinical Studies (14.3)].\n" ], "text": "" }

Limitations of Use

{ "type": "p", "children": [], "text": "\nLimitations of Use\n" }

{ "type": "ul", "children": [ "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)]. \n", "Micafungin has not been adequately studied in patients with endocarditis, osteomyelitis and meningoencephalitis due to Candida.\n", "The efficacy of micafungin against infections caused by fungi other than Candidahas not been established." ], "text": "" }

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

<div class="scrollingtable"><table class="Noautorules" width="543"> <caption> <span> Table 1 Micafungin Dosage in Adult Patients </span> </caption> <col width="283"/> <col width="260"/> <tfoot> <tr> <td align="left" colspan="2"> <p class="First Footnote"> <span class="Sup">*</span> In patients treated successfully for candidemia and other <span class="Italics">Candida</span> infections, the mean duration of treatment was 15 days (range 10 days to 47 days).</p> </td> </tr> <tr> <td align="left" colspan="2"> <p class="First Footnote"> <span class="Sup">‡</span> In patients treated successfully for esophageal candidiasis, the mean duration of treatment was 15 days (range 10 days to 30 days).</p> </td> </tr> <tr> <td align="left" colspan="2"> <p class="First Footnote"> <span class="Sup">§</span> 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).</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold"> Indication</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Recommended Reconstituted Dose Once Daily</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Treatment of Candidemia, Acute Disseminated Candidiasis, <span class="Italics">Candida </span> Peritonitis and Abscesses<span class="Sup">* </span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> 100 mg</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Treatment of Esophageal Candidiasis<span class="Sup">‡</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> 150 mg</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Prophylaxis of <span class="Italics">Candida </span> Infections in HSCT Recipients<span class="Sup">§</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> 50 mg</span> <br/> </td> </tr> </tbody> </table></div>

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

<div class="scrollingtable"><table class="Noautorules" width="543"> <caption> <span> Table 2 Micafungin Dosage in Pediatric Patients (4 Months of Age and Older) </span> </caption> <col width="140"/> <col width="199"/> <col width="204"/> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" rowspan="2"><span class="Bold"> Indication</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" colspan="2"><span class="Bold"> Dosage for Pediatric Patients 4 Months of Age and Older</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Rrule"><span class="Bold"> 30 kg or less</span> <br/> </td><td align="left" class="Botrule Rrule"><span class="Bold"> Greater than 30 kg</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Treatment of Candidemia, Acute Disseminated Candidiasis, <span class="Italics">Candida </span> Peritonitis and Abscesses <br/> </td><td align="center" class="Botrule Rrule" colspan="2"> 2 mg/kg once daily (maximum daily dose 100 mg)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Treatment of Esophageal Candidiasis<br/> </td><td align="center" class="Botrule Rrule"> 3 mg/kg once daily<br/> </td><td align="center" class="Botrule Rrule"> 2.5 mg/kg once daily (maximum daily dose 150 mg)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Prophylaxis of <span class="Italics">Candida </span> Infections in HSCT Recipients<br/> </td><td align="center" class="Botrule Rrule" colspan="2"> 1 mg/kg once daily (maximum daily dose 50 mg)<br/> </td> </tr> </tbody> </table></div>

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 (8.4), Clinical Pharmacology (12.3) and Microbiology (12.4)].

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:

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:

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 (5.5)].

 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.

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 (5.5)].

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)].

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:

{ "type": "p", "children": [], "text": "\nMicafungin 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:" }

{ "type": "ul", "children": [ "50 mg single-dose vial", "100 mg single-dose vial" ], "text": "" }

Micafungin is contraindicated in persons with known hypersensitivity to micafungin, any component of micafungin or other echinocandins.

{ "type": "p", "children": [], "text": "\nMicafungin is contraindicated in persons with known hypersensitivity to micafungin, any component of micafungin or other echinocandins." }

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.

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.

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.

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.

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 (2.3)].

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 (2.3) and  Adverse Reactions (6.1)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of micafungin cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.

The overall safety of micafungin was assessed in 520 healthy volunteers and 3,417 adult and pediatric patients who received single or multiple doses of micafungin across 50 clinical trials, including the invasive candidiasis, esophageal candidiasis and prophylaxis trials. The doses of micafungin administered included doses above and below the recommended doses [see Dosage and Administration (2.1, 2.2)] and ranged from 0.75 mg/kg to 15 mg/kg in pediatric patients and 12.5 mg to 150 mg/day or greater in adults.

Clinical Trials Experience in Adults

In clinical trials with micafungin, 2,497/2,748 (91%) adult patients experienced at least one adverse reaction.

Candidemia and Other Candida Infections

In a randomized, double-blind trial for the treatment of candidemia and other Candida infections, adverse reactions occurred in 183/200 (92%) and 171/193 (89%) patients in the micafungin 100 mg/day and caspofungin (70 mg loading dose followed by 50 mg/day dose) treatment groups, respectively. Selected adverse reactions occurring in 5% or more of the patients and more frequently in the micafungin treatment group, are shown in Table 3.

<div class="scrollingtable"><table class="Noautorules" width="555"> <caption> <span> Table 3 Selected<span class="Sup">*</span> Adverse Reactions in Adult Patients with Candidemia and Other Candida Infections </span> </caption> <col width="207"/> <col width="168"/> <col width="180"/> <tfoot> <tr> <td align="left" colspan="3"> <p class="First Footnote">Patient base: all randomized patients who received at least 1 dose of trial drug.</p> </td> </tr> <tr> <td align="left" colspan="3"> <p class="First Footnote"> <span class="Sup">*</span> During IV treatment + 3 days.</p> </td> </tr> <tr> <td align="left" colspan="3"> <p class="First Footnote"> <span class="Sup">†</span> Within a system organ class, patients may experience more than 1 adverse reaction.</p> </td> </tr> <tr> <td align="left" colspan="3"> <p class="First Footnote"> <span class="Sup">§</span> 70 mg loading dose on day 1 followed by 50 mg/day thereafter (caspofungin).</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold"> Adverse Reactions by System Organ Class</span><span class="Sup">†</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Micafungin</span> <br/> <span class="Bold"> 100 mg</span> <br/> <span class="Bold"> n (%)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Caspofungin</span><span class="Sup">§</span> <br/> <span class="Bold"> n (%)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold"> Number of Patients</span> <br/> </td><td align="center" class="Botrule Rrule"> 200<br/> </td><td align="center" class="Botrule Rrule"> 193<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold"> Gastrointestinal Disorders</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> 81 (41)</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> 76 (39)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Diarrhea<br/> </td><td align="center" class="Botrule Rrule"> 15 (8)<br/> </td><td align="center" class="Botrule Rrule"> 14 (7)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Vomiting<br/> </td><td align="center" class="Botrule Rrule"> 18 (9)<br/> </td><td align="center" class="Botrule Rrule"> 16 (8)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold"> Metabolism and Nutrition Disorders</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> 77 (39)</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> 73 (38)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Hypoglycemia<br/> </td><td align="center" class="Botrule Rrule"> 12 (6)<br/> </td><td align="center" class="Botrule Rrule"> 9 (5)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Hyperkalemia<br/> </td><td align="center" class="Botrule Rrule"> 10 (5)<br/> </td><td align="center" class="Botrule Rrule"> 5 (3)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold"> General Disorders/Administration Site Conditions</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> 59 (30)</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> 51 (26)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold"> Investigations</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> 36 (18)</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> 37 (19)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Blood Alkaline Phosphatase Increased<br/> </td><td align="center" class="Botrule Rrule"> 11 (6)<br/> </td><td align="center" class="Botrule Rrule"> 8 (4)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold"> Cardiac Disorders</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> 35 (18)</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> 36 (19)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Atrial Fibrillation<br/> </td><td align="center" class="Botrule Rrule"> 5 (3)<br/> </td><td align="center" class="Botrule Rrule"> 0<br/> </td> </tr> </tbody> </table></div>

In a second, supportive, randomized, double-blind trial for the treatment of candidemia and other Candida infections, adverse reactions occurred in 245/264 (93%) and 250/265 (94%) adult and pediatric patients in the micafungin (100 mg/day) and amphotericin B liposome (3 mg/kg/day) treatment groups, respectively. In this trial, the following adverse reactions were reported in patients at least 16 years of age in the micafungin and amphotericin B liposome treatment groups, respectively: nausea (10% vs. 8%), diarrhea (11% vs. 11%), vomiting (13% vs. 9%), abnormal liver tests (4% vs. 3%), increased aspartate aminotransferase (3% vs. 2%) and increased blood alkaline phosphatase (3% vs. 2%).

Esophageal Candidiasis

In a randomized, double-blind study for treatment of esophageal candidiasis, a total of 202/260 (78%) patients who received micafungin 150 mg/day and 186/258 (72%) patients who received intravenous fluconazole 200 mg/day experienced an adverse reaction. Adverse reactions resulting in discontinuation were reported in 17 (7%) micafungin-treated patients; and in 12 (5%) fluconazole-treated patients. Selected treatment-emergent adverse reactions occurring in 5% or more of the patients and more frequently in the micafungin group, are shown in Table 4.

<div class="scrollingtable"><table class="Noautorules" width="582"> <caption> <span> Table 4 Selected<span class="Sup">*</span> Adverse Reactions in Adult Patients with Esophageal Candidiasis </span> </caption> <col width="228"/> <col width="174"/> <col width="180"/> <tfoot> <tr> <td align="left" colspan="3"> <p class="First Footnote">Patient base: all randomized patients who received at least 1 dose of trial drug.</p> </td> </tr> <tr> <td align="left" colspan="3"> <p class="First Footnote"> <span class="Sup">*</span>During treatment + 3 days.</p> </td> </tr> <tr> <td align="left" colspan="3"> <p class="First Footnote"> <span class="Sup">†</span> Within a system organ class, patients may experience more than 1 adverse reaction.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold"> Adverse Reactions by System Organ Class</span><span class="Sup">†</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Micafungin</span> <br/> <span class="Bold"> 150 mg/day </span> <br/> <span class="Bold"> n (%)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Fluconazole</span> <br/> <span class="Bold"> 200 mg/day </span> <br/> <span class="Bold"> n (%)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Number of Patients</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 260<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 258<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Gastrointestinal Disorders</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 84 (32)</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 93 (36)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Diarrhea<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 27 (10)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 29 (11)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Nausea<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 20 (8)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 23 (9)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Vomiting<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 17 (7)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 17 (7)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> General Disorders/Administration Site Conditions</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 52 (20)</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 45 (17)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Pyrexia<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 34 (13)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 21 (8)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Nervous System Disorders</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 42 (16)</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 40 (16)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Headache<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 22 (9)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 20 (8)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Vascular Disorders</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 54 (21)</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 21 (8)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Phlebitis<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 49 (19)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 13 (5)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Skin and Subcutaneous Tissue Disorders</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 36 (14)</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 26 (10)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Rash<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 14 (5)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 6 (2)<br/> </td> </tr> </tbody> </table></div>

Prophylaxis of Candida Infections in Hematopoietic Stem Cell Transplant Recipients

A double-blind trial was conducted in a total of 882 patients scheduled to undergo an autologous or allogeneic hematopoietic stem cell transplant. The median duration of treatment was 18 days (range 1 day to 51 days) in both treatment arms.

All adult patients who received micafungin (382) or fluconazole (409) experienced at least one adverse reaction during the study. Treatment-emergent adverse reactions resulting in micafungin discontinuation were reported in 15 (4%) adult patients; while those resulting in fluconazole discontinuation were reported in 32 (8%). Selected adverse reactions reported in 15% or more of adult patients and more frequently in the micafungin treatment arm, are shown in Table 5.

<div class="scrollingtable"><table class="Noautorules" width="576"> <caption> <span> Table 5 Selected Adverse Reactions in Adult Patients During Prophylaxis of Candida Infection in Hematopoietic Stem Cell Transplant Recipients </span> </caption> <col width="258"/> <col width="162"/> <col width="156"/> <tfoot> <tr> <td align="left" colspan="3"> <p class="First Footnote">Patient base: all randomized adult patients who received at least 1 dose of trial drug.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold"> System Organ Class</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Micafungin 50 mg/day </span> <br/> <span class="Bold"> n (%)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Fluconazole 400 mg/day </span> <br/> <span class="Bold"> n (%)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Number of Patients</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 382<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 409<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Gastrointestinal Disorders</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 377 (99)</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 404 (99)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Diarrhea<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 294 (77)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 327 (80)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Nausea<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 270 (71)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 290 (71)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Vomiting<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 252 (66)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 274 (67)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Abdominal Pain<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 100 (26)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 93 (23)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Blood and Lymphatic System Disorders</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 368 (96)</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 385 (94)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Neutropenia<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 288 (75)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 297 (73)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Thrombocytopenia<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 286 (75)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 280 (69)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Skin and Subcutaneous Tissue Disorders</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 257 (67)</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 275 (67)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Rash<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 95 (25)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 91 (22)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Nervous System Disorders</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 250 (65)</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 254 (62)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Headache<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 169 (44)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 154 (38)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Psychiatric Disorders</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 233 (61)</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 235 (58)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Insomnia<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 142 (37)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 140 (34)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Anxiety<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 84 (22)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 87 (21)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Cardiac Disorders</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 133 (35)</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold"> 138 (34)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> Tachycardia<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 99 (26)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 91 (22)<br/> </td> </tr> </tbody> </table></div>

Other selected adverse reactions reported at less than 5% in adult clinical trials are listed below:

Clinical Trials Experience in Pediatric Patients

The safety of micafungin was assessed in 593 pediatric patients, 425 of whom were 4 months through 16 years of age and 168 of whom were 3 days to less than 4 months of age who received at least one dose of micafungin across 15 clinical trials.

Of the 425 pediatric patients, 4 months through 16 years of age enrolled in 11 clinical trials, 235 (55%) were male, 290 (68%) were white, with the following age distribution: 62 (15%) 4 months to <2 years, 108 (25%) 2 to 5 years, 140 (33%) 6 to 11 years, and 115 (27%) 12 to 16 years of age. The mean treatment duration was 26.1 days. A total of 246 patients received at least one dose of micafungin ranging from 2 to 10 mg/kg. Overall, 388/425 (91%) patients experienced at least one adverse reaction. Adverse reactions occurring in ≥15% or more of micafungin-treated pediatric patients 4 months of age and older are: vomiting (32%), diarrhea (24%), pyrexia (24%), hypokalemia (22%), nausea (21%), mucosal inflammation (19%), thrombocytopenia (19%), abdominal pain (18%), headache (15%), and hypertension (15%).

Two randomized, double-blind active-controlled trials included pediatric patients. In the invasive candidiasis/candidemia trial, the efficacy and safety of micafungin (2 mg/kg/day for patients weighing 40 kg or less and 100 mg/day for patients weighing greater than 40 kg) was compared to amphotericin B liposome (3 mg/kg/day) in 112 pediatric patients. Treatment-emergent adverse reactions occurred in 51/56 (91%) of patients in the micafungin group and 52/56 (93%) of patients in the amphotericin B liposome group. Treatment-emergent adverse reactions resulting in drug discontinuation were reported in 2 (4%) micafungin-treated pediatric patients and in 9 (16%) amphotericin B liposome-treated pediatric patients.

The prophylaxis study in patients undergoing HSCT investigated the efficacy of micafungin (1 mg/kg/day for patients weighing 50 kg or less and 50 mg/day for patients weighing greater than 50 kg) as compared to fluconazole (8 mg/kg/day for patients weighing 50 kg or less and 400 mg/day for patients weighing greater than 50 kg). All 91 pediatric patients experienced at least one treatment-emergent adverse reaction. Three (7%) pediatric patients discontinued micafungin due to adverse reaction, while one (2%) patient discontinued fluconazole.

Selected adverse reactions, occurring in 15% or more of the patients and more frequently in a micafungin group, for the two comparative trials are shown in Table 6.

<div class="scrollingtable"><table class="Noautorules" width="0"> <caption> <span> Table 6 Selected Adverse Reactions in Pediatric Patients with Candidemia and Other Candida Infections (C/IC) and in Hematopoietic Stem-Cell Recipients During Prophylaxis of Candida Infections </span> </caption> <col width="185"/> <col width="108"/> <col width="126"/> <col width="93"/> <col width="101"/> <tfoot> <tr> <td align="left" colspan="5"> <p class="First Footnote"> <span class="Bold"><span class="Sup">*</span></span> Study population included 20 pediatric patients younger than 4 months of age (10 in each arm)</p> </td> </tr> <tr> <td align="left" colspan="5"> <p class="First Footnote"> <span class="Sup">†</span> Within a system organ class, patients may experience more than 1 adverse reaction.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" rowspan="2"><span class="Bold"> Adverse Reactions</span><span class="Sup">†</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" colspan="2"><span class="Bold"> C/IC<span class="Sup">*</span></span> <br/> </td><td align="center" class="Botrule Rrule Toprule" colspan="2"><span class="Bold"> Prophylaxis</span> <br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule"><span class="Bold"> Micafungin</span> <br/> <span class="Bold"> n = 56</span> <br/> <span class="Bold"> n (%)</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> Amphotericin B</span> <br/> <span class="Bold"> liposome</span> <br/> <span class="Bold"> n = 56 </span> <br/> <span class="Bold"> n (%)</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> Micafungin</span> <br/> <span class="Bold"> n = 43</span> <br/> <span class="Bold"> n (%)</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> Fluconazole</span> <br/> <span class="Bold"> n = 48</span> <br/> <span class="Bold"> n (%)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold"> Gastrointestinal disorders</span> <br/> </td><td align="center" class="Botrule Rrule"> 22 (40)<br/> </td><td align="center" class="Botrule Rrule"> 18 (32)<br/> </td><td align="center" class="Botrule Rrule"> 43 (100)<br/> </td><td align="center" class="Botrule Rrule"> 45 (94)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Vomiting<br/> </td><td align="center" class="Botrule Rrule"> 10 (18)<br/> </td><td align="center" class="Botrule Rrule"> 8 (14)<br/> </td><td align="center" class="Botrule Rrule"> 28 (65)<br/> </td><td align="center" class="Botrule Rrule"> 32 (67)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Diarrhea<br/> </td><td align="center" class="Botrule Rrule"> 4 (7)<br/> </td><td align="center" class="Botrule Rrule"> 5 (9)<br/> </td><td align="center" class="Botrule Rrule"> 22 (51)<br/> </td><td align="center" class="Botrule Rrule"> 31 (65)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Nausea<br/> </td><td align="center" class="Botrule Rrule"> 4 (7)<br/> </td><td align="center" class="Botrule Rrule"> 4 (7)<br/> </td><td align="center" class="Botrule Rrule"> 30 (70)<br/> </td><td align="center" class="Botrule Rrule"> 25 (52)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Abdominal pain<br/> </td><td align="center" class="Botrule Rrule"> 2 (4)<br/> </td><td align="center" class="Botrule Rrule"> 2 (4)<br/> </td><td align="center" class="Botrule Rrule"> 15 (35)<br/> </td><td align="center" class="Botrule Rrule"> 12 (25)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Abdominal distension<br/> </td><td align="center" class="Botrule Rrule"> 1 (2)<br/> </td><td align="center" class="Botrule Rrule"> 1 (2)<br/> </td><td align="center" class="Botrule Rrule"> 8 (19)<br/> </td><td align="center" class="Botrule Rrule"> 6 (13)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold"> General disorders and administration site conditions</span> <br/> </td><td align="center" class="Botrule Rrule"> 14 (25)<br/> </td><td align="center" class="Botrule Rrule"> 14 (25)<br/> </td><td align="center" class="Botrule Rrule"> 41 (95)<br/> </td><td align="center" class="Botrule Rrule"> 46 (96)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Pyrexia<br/> </td><td align="center" class="Botrule Rrule"> 5 (9)<br/> </td><td align="center" class="Botrule Rrule"> 9 (16)<br/> </td><td align="center" class="Botrule Rrule"> 26 (61)<br/> </td><td align="center" class="Botrule Rrule"> 31 (65)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Infusion-related reaction<br/> </td><td align="center" class="Botrule Rrule"> 0<br/> </td><td align="center" class="Botrule Rrule"> 3 (5)<br/> </td><td align="center" class="Botrule Rrule"> 7 (16)<br/> </td><td align="center" class="Botrule Rrule"> 4 (8)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold"> Skin and subcutaneous tissue disorders</span> <br/> </td><td align="center" class="Botrule Rrule"> 11 (20)<br/> </td><td align="center" class="Botrule Rrule"> 8 (14)<br/> </td><td align="center" class="Botrule Rrule"> 33 (77)<br/> </td><td align="center" class="Botrule Rrule"> 38 (79)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Pruritus<br/> </td><td align="center" class="Botrule Rrule"> 0<br/> </td><td align="center" class="Botrule Rrule"> 1 (2)<br/> </td><td align="center" class="Botrule Rrule"> 14 (33)<br/> </td><td align="center" class="Botrule Rrule"> 15 (31)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Rash<br/> </td><td align="center" class="Botrule Rrule"> 1 (2)<br/> </td><td align="center" class="Botrule Rrule"> 1 (2)<br/> </td><td align="center" class="Botrule Rrule"> 13 (30)<br/> </td><td align="center" class="Botrule Rrule"> 13 (27)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Urticaria<br/> </td><td align="center" class="Botrule Rrule"> 0<br/> </td><td align="center" class="Botrule Rrule"> 1 (2)<br/> </td><td align="center" class="Botrule Rrule"> 8 (19)<br/> </td><td align="center" class="Botrule Rrule"> 4 (8)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold"> Respiratory, thoracic and mediastinal disorders</span> <br/> </td><td align="center" class="Botrule Rrule"> 9 (16)<br/> </td><td align="center" class="Botrule Rrule"> 13 (23)<br/> </td><td align="center" class="Botrule Rrule"> 30 (70)<br/> </td><td align="center" class="Botrule Rrule"> 33 (69)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Epistaxis<br/> </td><td align="center" class="Botrule Rrule"> 0<br/> </td><td align="center" class="Botrule Rrule"> 0<br/> </td><td align="center" class="Botrule Rrule"> 4 (9)<br/> </td><td align="center" class="Botrule Rrule"> 8 (17)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold"> Blood and lymphatic system disorders</span> <br/> </td><td align="center" class="Botrule Rrule"> 17 (30)<br/> </td><td align="center" class="Botrule Rrule"> 13 (23)<br/> </td><td align="center" class="Botrule Rrule"> 40 (93)<br/> </td><td align="center" class="Botrule Rrule"> 44 (92)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Thrombocytopenia<br/> </td><td align="center" class="Botrule Rrule"> 5 (9)<br/> </td><td align="center" class="Botrule Rrule"> 3 (5)<br/> </td><td align="center" class="Botrule Rrule"> 31 (72)<br/> </td><td align="center" class="Botrule Rrule"> 37 (77)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Neutropenia<br/> </td><td align="center" class="Botrule Rrule"> 3 (5)<br/> </td><td align="center" class="Botrule Rrule"> 4 (7)<br/> </td><td align="center" class="Botrule Rrule"> 33 (77)<br/> </td><td align="center" class="Botrule Rrule"> 34 (71)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Anemia<br/> </td><td align="center" class="Botrule Rrule"> 10 (18)<br/> </td><td align="center" class="Botrule Rrule"> 6 (11)<br/> </td><td align="center" class="Botrule Rrule"> 22 (51)<br/> </td><td align="center" class="Botrule Rrule"> 24 (50)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Febrile neutropenia<br/> </td><td align="center" class="Botrule Rrule"> 0<br/> </td><td align="center" class="Botrule Rrule"> 0<br/> </td><td align="center" class="Botrule Rrule"> 7 (16)<br/> </td><td align="center" class="Botrule Rrule"> 7 (15)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold"> Investigations</span> <br/> </td><td align="center" class="Botrule Rrule"> 12 (21)<br/> </td><td align="center" class="Botrule Rrule"> 8 (14)<br/> </td><td align="center" class="Botrule Rrule"> 24 (56)<br/> </td><td align="center" class="Botrule Rrule"> 25 (52)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Alanine aminotransferase increased<br/> </td><td align="center" class="Botrule Rrule"> 0<br/> </td><td align="center" class="Botrule Rrule"> 0<br/> </td><td align="center" class="Botrule Rrule"> 7 (16)<br/> </td><td align="center" class="Botrule Rrule"> 1 (2)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Urine output decreased<br/> </td><td align="center" class="Botrule Rrule"> 0<br/> </td><td align="center" class="Botrule Rrule"> 0<br/> </td><td align="center" class="Botrule Rrule"> 10 (23)<br/> </td><td align="center" class="Botrule Rrule"> 8 (17)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold"> Cardiac disorders</span> <br/> </td><td align="center" class="Botrule Rrule"> 7 (13)<br/> </td><td align="center" class="Botrule Rrule"> 3 (5)<br/> </td><td align="center" class="Botrule Rrule"> 10 (23)<br/> </td><td align="center" class="Botrule Rrule"> 17 (35)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Tachycardia<br/> </td><td align="center" class="Botrule Rrule"> 2 (4)<br/> </td><td align="center" class="Botrule Rrule"> 1 (2)<br/> </td><td align="center" class="Botrule Rrule"> 7 (16)<br/> </td><td align="center" class="Botrule Rrule"> 12 (25)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold"> Renal and urinary disorders</span> <br/> </td><td align="center" class="Botrule Rrule"> 4 (7)<br/> </td><td align="center" class="Botrule Rrule"> 4 (7)<br/> </td><td align="center" class="Botrule Rrule"> 16 (37)<br/> </td><td align="center" class="Botrule Rrule"> 15 (31)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Hematuria<br/> </td><td align="center" class="Botrule Rrule"> 0<br/> </td><td align="center" class="Botrule Rrule"> 0<br/> </td><td align="center" class="Botrule Rrule"> 10 (23)<br/> </td><td align="center" class="Botrule Rrule"> 7 (15)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"><span class="Bold"> Psychiatric disorders </span> <br/> </td><td align="center" class="Botrule Rrule"> 3 (5)<br/> </td><td align="center" class="Botrule Rrule"> 1 (2)<br/> <br/> </td><td align="center" class="Botrule Rrule"> 20 (47)<br/> </td><td align="center" class="Botrule Rrule"> 9 (19)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Anxiety <br/> </td><td align="center" class="Botrule Rrule"> 0<br/> </td><td align="center" class="Botrule Rrule"> 0<br/> </td><td align="center" class="Botrule Rrule"> 10 (23)<br/> </td><td align="center" class="Botrule Rrule"> 3 (6)<br/> </td> </tr> </tbody> </table></div>

Other clinically significant adverse reactions reported at less than 15% in pediatric clinical trials are listed below:

Clinical Trials Experience in Pediatric Patients Younger than 4 Months of Age

The safety of Micafungin was assessed in 168 pediatric patients younger than 4 months of age who received varying doses of micafungin in 9 clinical trials. The mean treatment duration was 16.6 days. A total of 59 patients received micafungin at doses ≤4 mg/kg/day and 109 patients received micafungin doses >4 mg/kg/day [5 to 15 mg/kg/day (approximately 1.3 to 3.8 times the recommended dosage in pediatric patients less than 4 months old)].

The adverse reaction profile of micafungin in pediatric patients younger than 4 months of age was generally comparable to that of pediatric patients 4 months of age and older and adults. The most frequent adverse reactions (≥15%) in pediatric patients younger than 4 months old receiving a micafungin dose of approximately 4 mg/kg/day included hypokalemia (25%), thrombocytopenia (25%), acidosis (20%), sepsis (20%), anemia (15%), oxygen saturation decreased (15%), and vomiting (15%). No new safety signals were seen in patients who received 5 to 15 mg/kg/day [see Use in Specific Populations (8.4)].

Additional clinically significant adverse reactions reported in less than 15% of pediatric patients younger than 4 months of age who received approximately 4 mg/kg/day are listed below:

The following adverse reactions have been identified during post-approval use of micafungin for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

CYP3A4, CYP2C9 and CYP2C19 Inhibitors

Co-administration of micafungin with cyclosporine, itraconazole, voriconazole and fluconazole did not alter the pharmacokinetics of micafungin.

CYP2C19 and CYP3A4 Inducer

Co-administration of micafungin with rifampin and ritonavir did not alter the pharmacokinetics of micafungin.

Co-administration of Micafungin with Other Drugs

Co-administration of micafungin with mycophenolate mofetil (MMF), amphotericin B, tacrolimus, prednisolone, sirolimus and nifedipine did not alter the pharmacokinetics of micafungin.

CYP3A4 Substrates

There was no effect of single or multiple doses of micafungin on cyclosporine, tacrolimus, prednisolone, voriconazole and fluconazole pharmacokinetics.

Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state micafungin compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state micafungin compared with nifedipine alone. Itraconazole AUC and Cmax were increased by 22% and 11%, respectively. Patients receiving sirolimus, nifedipine and itraconazole in combination with micafungin should be monitored for sirolimus, nifedipine and itraconazole toxicity and the sirolimus, nifedipine and itraconazole dosage should be reduced if necessary.

UDP-Glycosyltransferase Substrate

Co-administration of mycophenolate mofetil (MMF) with micafungin did not alter the pharmacokinetics of MMF.

Risk Summary

Based on findings from animal studies, micafungin may cause fetal harm when administered to a pregnant woman (see Data). There is insufficient human data on the use of micafungin in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, intravenous administration of micafungin sodium to pregnant rabbits during organogenesis at doses four times the maximum recommended human dose resulted in visceral abnormalities and increased abortion (see Data). Advise pregnant women of the risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In an embryo-fetal toxicity study in pregnant rabbits, intravenous administration of micafungin sodium during organogenesis (days 6 to 18 of gestation) resulted in fetal visceral abnormalities and abortion at 32 mg/kg, a dose equivalent to four times the recommended human dose based on body surface area comparisons. Visceral abnormalities included abnormal lobation of the lung, levocardia, retrocaval ureter, anomalous right subclavian artery and dilatation of the ureter.

Risk Summary

There are no data on the presence of micafungin in human milk, the effects on the breast-fed infant or the effects on milk production. Micafungin was present in the milk of lactating rats following intravenous administration. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for micafungin and any potential adverse effects on the breast-fed child from micafungin or from the underlying maternal condition.

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:

A total of 418 subjects in clinical studies of micafungin were 65 years of age and older and 124 subjects were 75 years of age and older. No overall differences in safety and effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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

Micafungin does not require dose adjustment in patients with renal impairment. Supplementary dosing should not be required following hemodialysis [see Clinical Pharmacology (12.3)].

Dose adjustment of micafungin is not required in patients with mild, moderate or severe hepatic impairment [see Clinical Pharmacology (12.3)].

No dose adjustment of micafungin 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 19% in Japanese subjects compared to blacks, due to smaller body weight.

There has been no evidence of either psychological or physical dependence or withdrawal or rebound effects with micafungin.

{ "type": "p", "children": [], "text": "\nThere has been no evidence of either psychological or physical dependence or withdrawal or rebound effects with micafungin." }

Micafungin is highly protein bound and, therefore, is not dialyzable. No cases of micafungin overdosage have been reported. Repeated daily doses up to 8 mg/kg (maximum total dose of 896 mg) in adult patients, up to 6 mg/kg in pediatric patients 4 months of age and older, and up to 15 mg/kg in pediatric patients younger than 4 months of age have been administered in clinical trials with no reported dose-limiting toxicity [see Adverse Reactions (6.1) and Use in Specific Populations (8.4)].

{ "type": "p", "children": [], "text": "\nMicafungin is highly protein bound and, therefore, is not dialyzable. No cases of micafungin overdosage have been reported. Repeated daily doses up to 8 mg/kg (maximum total dose of 896 mg) in adult patients, up to 6 mg/kg in pediatric patients 4 months of age and older, and up to 15 mg/kg in pediatric patients younger than 4 months of age have been administered in clinical trials with no reported dose-limiting toxicity [see Adverse Reactions (6.1) and Use in Specific Populations (8.4)].\n" }

Micafungin for injection, USP is a sterile, lyophilized product for intravenous (IV) infusion that contains micafungin sodium, USP. Micafungin sodium, USP 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-beta-D-glucan, an integral component of the fungal cell wall.

{ "type": "p", "children": [], "text": "\nMicafungin for injection, USP is a sterile, lyophilized product for intravenous (IV) infusion that contains micafungin sodium, USP. Micafungin sodium, USP 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-beta-D-glucan, an integral component of the fungal cell wall." }

Each single-dose vial contains 50 mg micafungin (equivalent to 50.86 mg micafungin sodium, USP) or 100 mg micafungin (equivalent to 101.73 mg micafungin sodium, USP), 200 mg lactose monohydrate, with citric acid anhydrous and/or sodium hydroxide (used for pH adjustment). Micafungin for injection, USP must be diluted with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP [see Dosage and Administration (2)]. Following reconstitution with 0.9% Sodium Chloride Injection, USP, the resulting pH of the solution is between 5 to 7.

{ "type": "p", "children": [], "text": "Each single-dose vial contains 50 mg micafungin (equivalent to 50.86 mg micafungin sodium, USP) or 100 mg micafungin (equivalent to 101.73 mg micafungin sodium, USP), 200 mg lactose monohydrate, with citric acid anhydrous and/or sodium hydroxide (used for pH adjustment). Micafungin for injection, USP must be diluted with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP [see Dosage and Administration (2)]. Following reconstitution with 0.9% Sodium Chloride Injection, USP, the resulting pH of the solution is between 5 to 7." }

Micafungin sodium, USP is chemically designated as:

{ "type": "p", "children": [], "text": "Micafungin sodium, USP is chemically designated as:" }

Pneumocandin A0,1-[(4R,5R)-4,5-dihydroxy-N2-[4-[5-[4-(pentyloxy) phenyl]-3-isoxazolyl]benzoyl]-L-ornithine]-4-[(4S)-4-hydroxy-4-[4-hydroxy-3-(sulfooxy)phenyl]-L-threonine]-, monosodium salt.

{ "type": "p", "children": [], "text": "Pneumocandin A0,1-[(4R,5R)-4,5-dihydroxy-N2-[4-[5-[4-(pentyloxy) phenyl]-3-isoxazolyl]benzoyl]-L-ornithine]-4-[(4S)-4-hydroxy-4-[4-hydroxy-3-(sulfooxy)phenyl]-L-threonine]-, monosodium salt." }

The chemical structure of micafungin sodium, USP is:

{ "type": "p", "children": [], "text": "The chemical structure of micafungin sodium, USP is:" }

The molecular formula is C56H70N9NaO23S and the molecular weight is 1292.3.

{ "type": "p", "children": [], "text": "\nThe molecular formula is C56H70N9NaO23S and the molecular weight is 1292.3." }

Micafungin sodium, USP is a light-sensitive, hygroscopic white powder that is freely soluble in dimethyl sulfoxide, soluble in dimethyl formamide and water, sparingly soluble in methanol and slightly soluble to practically insoluble in acetone, methylethylketone, methylisobutylketone, ethanol, isopropanol, ethyl acetate, isopropyl acetate, acetonitrile, toluene, heptane and tetrahydrofuran.

{ "type": "p", "children": [], "text": "Micafungin sodium, USP is a light-sensitive, hygroscopic white powder that is freely soluble in dimethyl sulfoxide, soluble in dimethyl formamide and water, sparingly soluble in methanol and slightly soluble to practically insoluble in acetone, methylethylketone, methylisobutylketone, ethanol, isopropanol, ethyl acetate, isopropyl acetate, acetonitrile, toluene, heptane and tetrahydrofuran." }

Micafungin is a member of the echinocandin class of antifungal agents [see Microbiology (12.4)].

The pharmacodynamics of micafungin related to hematogenous Candida meningoencephalitis are described in other sections of the prescribing information [see Use in Specific Populations (8.4) and Microbiology (12.4)].

Adults

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. Typically, 85% of the steady-state concentration is achieved after three daily micafungin doses.

Steady-state pharmacokinetic parameters in relevant patient populations after repeated daily administration are presented in Table 7.

<div class="scrollingtable"><table class="Noautorules" width="0"> <caption> <span> Table 7 Pharmacokinetic Parameters of Micafungin in Adult Patients </span> </caption> <col width="89"/> <col width="31"/> <col width="47"/> <col width="84"/> <col width="136"/> <col width="57"/> <col width="103"/> <tfoot> <tr> <td align="left" colspan="7"> <p class="First Footnote"> <span class="Sup">*</span> AUC<span class="Sub">0-infinity</span> is presented for Day 1; AUC<span class="Sub">0-24</span> is presented for steady-state.</p> </td> </tr> <tr> <td align="left" colspan="7"> <p class="First Footnote"> <span class="Sup">†</span> candidemia or other <span class="Italics">Candida</span> infections.</p> </td> </tr> <tr> <td align="left" colspan="7"> <p class="First Footnote"> <span class="Sup">‡</span> human immunodeficiency virus.</p> </td> </tr> <tr> <td align="left" colspan="7"> <p class="First Footnote"> <span class="Sup">§</span> esophageal candidiasis.</p> </td> </tr> <tr> <td align="left" colspan="7"> <p class="First Footnote"> <span class="Sup">¶ </span>hematopoietic stem cell transplant.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" rowspan="2"><span class="Bold"> Population</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" rowspan="2"><span class="Bold"> n</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" rowspan="2"><span class="Bold"> Dose</span> <br/> <span class="Bold"> (mg)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" colspan="4"><span class="Bold"> Pharmacokinetic Parameters</span> <br/> <span class="Bold"> (Mean ± Standard Deviation)</span> <br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule"><span class="Bold"> C<span class="Sub">max</span> (mcg/mL)</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> AUC<span class="Sub">0-24</span><span class="Sup">*</span></span> <br/> <span class="Bold"> (mcg·h/mL)</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> t<span class="Sub">½ </span>(h)</span> <br/> </td><td align="center" class="Botrule Rrule"><span class="Bold"> Cl (mL/min/kg)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Patients with IC<span class="Sup">†</span> <br/> [Day 1] <br/> [Steady-State]<br/> </td><td align="center" class="Botrule Rrule"> 20<br/> 20<br/> </td><td align="center" class="Botrule Rrule"> 100<br/> 100<br/> </td><td align="center" class="Botrule Rrule"> 5.7 ± 2.2<br/> 10.1 ± 4.4<br/> </td><td align="center" class="Botrule Rrule"> 83 ± 51<br/> 97 ± 29<br/> </td><td align="center" class="Botrule Rrule"> 14.5 ± 7<br/> 13.4 ± 2<br/> </td><td align="center" class="Botrule Rrule"> 0.359 ± 0.179<br/> 0.298 ± 0.115<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> HIV<span class="Sup">‡</span>- Positive <br/> Patients with EC<span class="Sup">§ </span> <br/> [Day 1] <br/> [Day 14 or 21] <br/> </td><td align="center" class="Botrule Rrule"> 20<br/> 20<br/> 14<br/> 20<br/> 20<br/> 14<br/> </td><td align="center" class="Botrule Rrule"> 50<br/> 100<br/> 150<br/> 50<br/> 100<br/> 150<br/> </td><td align="center" class="Botrule Rrule"> 4.1 ± 1.4<br/> 8 ± 2.4<br/> 11.6 ± 3.1<br/> 5.1 ± 1<br/> 10.1 ± 2.6<br/> 16.4 ± 6.5<br/> </td><td align="center" class="Botrule Rrule"> 36 ± 9<br/> 108 ± 31<br/> 151 ± 45<br/> 54 ± 13<br/> 115 ± 25<br/> 167 ± 40<br/> </td><td align="center" class="Botrule Rrule"> 14.9 ± 4.3<br/> 13.8 ± 3<br/> 14.1 ± 2.6<br/> 15.6 ± 2.8<br/> 16.9 ± 4.4<br/> 15.2 ± 2.2<br/> </td><td align="center" class="Botrule Rrule"> 0.321 ± 0.098<br/> 0.327 ± 0.093<br/> 0.340 ± 0.092<br/> 0.300 ± 0.063<br/> 0.301 ± 0.086<br/> 0.297 ± 0.081<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> HSCT<span class="Sup">¶ </span>Recipients <br/> [Day 7]<br/> </td><td align="center" class="Botrule Rrule"> 8<br/> 10<br/> 8<br/> 8<br/> </td><td align="center" class="Botrule Rrule"><span class="Italics">per kg</span> <br/> 3<br/> 4<br/> 6<br/> 8<br/> </td><td align="center" class="Botrule Rrule"> 21.1 ± 2.84<br/> 29.2 ± 6.2<br/> 38.4 ± 6.9<br/> 60.8 ± 26.9<br/> </td><td align="center" class="Botrule Rrule"> 234 ± 34<br/> 339 ± 72<br/> 479 ± 157<br/> 663 ± 212<br/> </td><td align="center" class="Botrule Rrule"> 14 ± 1.4<br/> 14.2 ± 3.2<br/> 14.9 ± 2.6<br/> 17.2 ± 2.3<br/> </td><td align="center" class="Botrule Rrule"> 0.214 ± 0.031<br/> 0.204 ± 0.036<br/> 0.224 ± 0.064<br/> 0.223 ± 0.081<br/> </td> </tr> </tbody> </table></div>

Pediatric Patients 4 Months of Age and Older

Micafungin pharmacokinetics in 229 pediatric patients 4 months through 16 years of age were characterized using population pharmacokinetics. Micafungin exposure was dose proportional across the dose and age range studied.

<div class="scrollingtable"><table class="Noautorules" width="0"> <caption> <span> Table 8 Summary (Mean +/- Standard Deviation) of Micafungin Pharmacokinetics in Pediatric Patients 4 Months of Age and Older (Steady-State) </span> </caption> <col width="65"/> <col width="42"/> <col width="58"/> <col width="102"/> <col width="136"/> <col width="90"/> <col width="111"/> <tfoot> <tr> <td align="left" colspan="7"> <p class="First Footnote"> <span class="Sup">*</span> Or the equivalent if receiving the adult dose (50 mg, 100 mg or 150 mg).</p> </td> </tr> <tr> <td align="left" colspan="7"> <p class="First Footnote"> <span class="Sup">†</span> Derived from simulations from the population PK model.</p> </td> </tr> <tr> <td align="left" colspan="7"> <p class="First Footnote"> <span class="Sup">‡</span> Derived from the population PK model.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold"> Body weight group</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> N</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Dose</span><span class="Sup">*</span> <br/> <span class="Bold"> mg/kg</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> C<span class="Sub">max.SS</span></span><span class="Sup">†</span> <br/> <span class="Bold"> (mcg/mL)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> AUC.<span class="Sub">SS</span></span><span class="Sup">†</span> <br/> <span class="Bold"> (mcg·h/mL)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> t<span class="Sub">½</span></span><span class="Sup">‡ </span><span class="Bold"> (h)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> CL</span><span class="Sup">‡</span> <br/> <span class="Bold"> (mL/min/kg)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="3"> 30 kg or less<br/> </td><td align="center" class="Botrule Rrule" rowspan="3"> 149<br/> </td><td align="center" class="Botrule Rrule"> 1<br/> </td><td align="center" class="Botrule Rrule"> 7.1 +/- 4.7<br/> </td><td align="center" class="Botrule Rrule"> 55 +/- 16<br/> </td><td align="center" class="Botrule Rrule" rowspan="3"> 12.5 +/- 4.6<br/> </td><td align="center" class="Botrule Rrule" rowspan="3"> 0.328 +/- 0.091<br/> <br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule"> 2<br/> </td><td align="center" class="Botrule Rrule"> 14.2 +/- 9.3<br/> </td><td align="center" class="Botrule Rrule"> 109 +/- 31<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule"> 3<br/> </td><td align="center" class="Botrule Rrule"> 21.3 +/- 14<br/> </td><td align="center" class="Botrule Rrule"> 164 +/- 47<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" rowspan="3"> Greater than 30 kg<br/> </td><td align="center" class="Botrule Rrule" rowspan="3"> 80<br/> </td><td align="center" class="Botrule Rrule"> 1<br/> </td><td align="center" class="Botrule Rrule"> 8.7 +/- 5.6<br/> </td><td align="center" class="Botrule Rrule"> 67 +/- 17<br/> </td><td align="center" class="Botrule Rrule" rowspan="3"> 13.6 +/- 8.8<br/> <br/> </td><td align="center" class="Botrule Rrule" rowspan="3"> 0.241 +/- 0.061<br/> <br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule"> 2<br/> </td><td align="center" class="Botrule Rrule"> 17.5 +/- 11.2<br/> </td><td align="center" class="Botrule Rrule"> 134 +/- 33<br/> </td> </tr> <tr> <td align="center" class="Botrule Rrule"> 2.5<br/> </td><td align="center" class="Botrule Rrule"> 23 +/- 14.5<br/> </td><td align="center" class="Botrule Rrule"> 176 +/- 42<br/> </td> </tr> </tbody> </table></div>

Pediatric Patients Younger than 4 Months of Age

Micafungin pharmacokinetic data in 103 pediatric patients less than 4 months of age were assessed using population pharmacokinetics. Predicted micafungin AUC estimates were dose proportional across the dose regimens and age ranges studied. The body weight-normalized micafungin clearance in pediatric patients less than 4 months of age is higher than the body weight-normalized micafungin clearance in older pediatric patients greater than 4 months of age and adults. Administration of 4 mg/kg once daily micafungin to pediatric patients less than 4 months of age produces a mean (SD) steady-state AUC of 131 (50) mcg·h/mL, which is comparable to the steady-state AUC in pediatric patients 4 months of age and older administered micafungin 2 mg/kg/day and adults administered 100 mg once daily.

Specific Populations

Adult Patients with Renal Impairment

Micafungin does not require dose adjustment in patients with renal impairment. A single 1 hour infusion of 100 mg micafungin was administered to 9 adult subjects with severe renal impairment (creatinine clearance less than 30 mL/min) and to 9 age-, gender- and weight-matched subjects with normal renal function (creatinine clearance greater than 80 mL/min). The maximum concentration (Cmax) 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.

Adult Patients with Hepatic Impairment

Distribution

The mean ± standard deviation volume of distribution of micafungin at terminal phase was 0.39 L/kg ± 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 (greater than 99%) protein bound in vitro, independent of plasma concentrations over the range of 10 mcg/mL 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.

Micafungin is neither a substrate nor an inhibitor of P-glycoprotein.

Metabolism

Micafungin is metabolized to M-1 (catechol form) by arylsulfatase, with further metabolism to M-2 (methoxy form) by catechol-O-methyltransferase. 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% of the administered dose).

Mechanism of Action

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

Activity in Animal Models of Candidiasis

Activity of micafungin has been demonstrated in both mucosal and disseminated murine and rabbit models of candidiasis. Micafungin administered to immunocompetent or immunosuppressed mice or rabbits with disseminated candidiasis prolonged survival (mice) and/or decreased the fungal burden in different organs including brain in a dose-dependent manner (mice and rabbits). Overall, antifungal activity of micafungin was demonstrated in the brain and eye tissues of nonneutropenic rabbits with HCME infected with a micafungin-sensitive strain of C. albicans; however, the activity varied in different central nervous system and ocular compartments. In the cerebrum, culture negativity was achieved at a micafungin dose regimen of 32 mg/kg once daily for 7 days; whereas, in spinal cord, vitreous humor and choroid, culture negativity was achieved at micafungin dose regimens of 24 mg/kg to 32 mg/kg once daily. Compared to untreated animals, micafungin dose regimens between 8 mg/kg and 24 mg/kg once daily reduced fungal burden in the cerebrum and cerebellum. When cerebrum, cerebellum and spinal cord data were combined, a decrease in fungal burden relative to untreated controls was evident at micafungin dose regimens between 16 mg/kg and 32 mg/kg once daily [see Use in Specific Populations (8.4)].

Resistance

There have been reports of clinical failures in patients receiving micafungin therapy due to the development of drug resistance. Some of these reports have identified specific mutations in the FKS protein component of the glucan synthase enzyme that are associated with higher MICs and breakthrough infection.

Antimicrobial Activity

Micafungin has been shown to be active against most isolates of the following Candida species, both in vitro and in clinical infections [see Indications and Usage (1)]:

Candida albicans

Candida glabrata

Candida guilliermondii

Candida krusei

Candida parapsilosis

Candida tropicalis

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

Hepatic carcinomas and adenomas were observed in a 6 month intravenous toxicology study with an 18 month recovery period of micafungin sodium in rats designed to assess the reversibility of hepatocellular lesions.

Rats administered micafungin sodium for 3 months at 32 mg/kg/day (corresponding to 8 times the highest recommended human dose [150 mg/day], based on AUC comparisons), exhibited colored patches/zones, multinucleated hepatocytes and altered hepatocellular foci after 1 month or 3 month recovery periods and adenomas were observed after a 21 month recovery period. Rats administered micafungin sodium at the same dose for 6 months exhibited adenomas after a 12 month recovery period; after an 18 month recovery period, an increased incidence of adenomas was observed and, additionally, carcinomas were detected. A lower dose of micafungin sodium (equivalent to 5 times the human AUC) in the 6 month rat study resulted in a lower incidence of adenomas and carcinomas following 18 months recovery. The duration of micafungin dosing in these rat studies (3 months or 6 months) exceeds the usual duration of micafungin dosing in patients, which is typically less than 1 month for treatment of esophageal candidiasis, but dosing may exceed 1 month for Candida prophylaxis.

Although the increase in carcinomas in the 6 month rat study did not reach statistical significance, the persistence of altered hepatocellular foci subsequent to micafungin dosing and the presence of adenomas and carcinomas in the recovery periods suggest a causal relationship between micafungin sodium, altered hepatocellular foci and hepatic neoplasms. Whole-life carcinogenicity studies of micafungin in animals have not been conducted and it is not known whether the hepatic neoplasms observed in treated rats also occur in other species or if there is a dose threshold for this effect.

Micafungin sodium was not mutagenic or clastogenic when evaluated in a standard battery of in vitro and in vivo tests (i.e., bacterial reversion - S. typhimurium, E. coli; chromosomal aberration; intravenous mouse micronucleus).

Male rats treated intravenously with micafungin sodium for 9 weeks showed vacuolation of the epididymal ductal epithelial cells at or above 10 mg/kg (about 0.6 times the recommended clinical dose for esophageal candidiasis, based on body surface area comparisons). Higher doses (about twice the recommended clinical dose, based on body surface area comparisons) resulted in higher epididymis weights and reduced numbers of sperm cells. In a 39 week intravenous study in dogs, seminiferous tubular atrophy and decreased sperm in the epididymis were observed at 10 mg/kg and 32 mg/kg, doses equal to about 2 times and 7 times the recommended clinical dose, based on body surface area comparisons. There was no impairment of fertility in animal studies with micafungin sodium.

High doses of micafungin sodium (5 times to 8 times the highest recommended human dose, based on AUC comparisons) have been associated with irreversible changes to the liver when administered for 3 months or 6 months and these changes may be indicative of pre-malignant processes [see Nonclinical Toxicology (13.1)].

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.

<div class="scrollingtable"><table class="Noautorules" width="552"> <caption> <span> Table 9 Efficacy Analysis: Treatment Success in Patients in Study 03-0-192 with Candidemia and Other Candida Infections </span> </caption> <col width="282"/> <col width="126"/> <col width="144"/> <tfoot> <tr> <td align="left" colspan="3"> <p class="First Footnote"> <span class="Sup">*</span> 70 mg loading dose on day 1 followed by 50 mg/day thereafter (caspofungin).</p> </td> </tr> <tr> <td align="left" colspan="3"> <p class="First Footnote"> <span class="Sup">†</span> All patients who received at least one dose of study medication and had documented invasive candidiasis or candidemia. Patients with <span class="Italics">Candida </span> endocarditis were excluded from the analyses.</p> </td> </tr> <tr> <td align="left" colspan="3"> <p class="First Footnote"> <span class="Sup">‡</span> A patient may have had greater than 1 organ of dissemination.</p> </td> </tr> <tr> <td align="left" colspan="3"> <p class="First Footnote"> <span class="Sup">§</span> A patient may have had greater than 1 baseline infection species.</p> </td> </tr> <tr> <td align="left" colspan="3"> <p class="First Footnote"> <span class="Sup">¶</span> All patients who had a culture-confirmed relapse or required systemic antifungal therapy in the post-treatment period for a suspected or proven</p> </td> </tr> <tr> <td align="left" colspan="3"> <p class="First Footnote"> <span class="Italics">Candida</span> infection. Also includes patients who died or were not assessed in follow-up.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Micafungin</span> <br/> <span class="Bold"> 100 mg/day</span> <br/> <span class="Bold"> n (%)</span> <br/> <span class="Bold"> % treatment difference</span> <br/> <span class="Bold"> (95% CI)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Caspofungin</span> <br/> <span class="Bold"> 70/50 mg/day</span><span class="Sup">*</span> <br/> <span class="Bold"> n (%)</span> <br/> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Treatment Success at End of IV Therapy</span><span class="Sup">†</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 135/191 (70.7)<br/> 7.4<br/> (-2, 16.3)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 119/188 (63.3)<br/> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Success in Patients with Neutropenia at Baseline</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 14/22 (63.6)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 5/11 (45.5)<br/> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Success by Site of Infection </span> <br/> <span class="Bold"> Candidemia</span> <br/> <span class="Bold"> Abscess </span> <br/> <span class="Bold"> Acute Disseminated</span><span class="Sup">‡ </span> <br/> Endophthalmitis<br/> Chorioretinitis<br/> Skin <br/> Kidney <br/> Pancreas <br/> Peritoneum <br/> Lung/Skin <br/> Lung/Spleen <br/> Liver <br/> Intraabdominal abscess <br/> <span class="Bold"> Chronic Disseminated </span> <br/> <span class="Bold"> Peritonitis</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 116/163 (71.2)<br/> 4/5 (80)<br/> 6/13 (46.2)<br/> 1/3<br/> 0/3<br/> 1/1<br/> 2/2<br/> 1/1<br/> 1/1<br/> 0/1<br/> 0/1<br/> 0<br/> 0<br/> 0/1<br/> 4/6 (66.7)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> <br/> 103/161 (64)<br/> 5/9 (55.6)<br/> 5/9 (55.6)<br/> 1/1<br/> 0<br/> 0<br/> 1/1<br/> 0<br/> 0<br/> 0<br/> 0<br/> 0/2<br/> 3/5<br/> 0<br/> 2/5 (40)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Success by Organism<span class="Sup">§</span></span> <br/> <span class="Italics">C. albicans</span> <br/> <span class="Italics">C. glabrata</span> <br/> <span class="Italics">C. tropicalis</span> <br/> <span class="Italics">C. parapsilosis</span> <br/> <span class="Italics">C. krusei</span> <br/> <span class="Italics">C. guilliermondii</span> <br/> <span class="Italics">C. lusitaniae</span> <br/> </td><td align="center" class="Botrule Rrule" valign="top"> 57/81 (70.4)<br/> 16/23 (69.6)<br/> 17/27 (63)<br/> 21/28 (75)<br/> 5/8 (62.5)<br/> 1/2<br/> 2/3 (66.7)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> <br/> 45/73 (61.6)<br/> 19/31 (61.3)<br/> 22/29 (75.9)<br/> 22/39 (56.4)<br/> 2/3 (66.7)<br/> 0/1<br/> 2/2<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Relapse through 6 Weeks<span class="Sup">¶ </span></span> <br/> Overall <br/> Culture-confirmed relapse <br/> Required systemic antifungal therapy<br/> Died during follow-up <br/> Not assessed <br/> </td><td align="center" class="Botrule Rrule" valign="top"> <br/> 49/135 (36.3)<br/> 5<br/> 11<br/> 17<br/> 16<br/> </td><td align="center" class="Botrule Rrule" valign="top"> <br/> 44/119 (37)<br/> 4<br/> 5<br/> 16<br/> 19<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold"> Overall study mortality </span> <br/> Mortality during IV therapy<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 58/200 (29)<br/> 28/200 (14)<br/> </td><td align="center" class="Botrule Rrule" valign="top"> 51/193 (26.4)<br/> 27/193 (14)<br/> </td> </tr> </tbody> </table></div>

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.

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.

<div class="scrollingtable"><table class="Noautorules" width="569"> <caption> <span> Table 10 Endoscopic, Clinical and Mycological Outcomes for Esophageal Candidiasis at End-of-Treatment </span> </caption> <col width="161"/> <col width="129"/> <col width="123"/> <col width="156"/> <tfoot> <tr> <td align="left" colspan="4"> <p class="First Footnote"> <span class="Sup">*</span> 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.</p> </td> </tr> <tr> <td align="left" colspan="4"> <p class="First Footnote"> <span class="Sup">†</span> Calculated as micafungin – fluconazole.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold"> Treatment Outcome</span><span class="Sup">*</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Micafungin</span> <br/> <span class="Bold"> 150 mg/day </span> <br/> <span class="Bold"> n = 260</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Fluconazole</span> <br/> <span class="Bold"> 200 mg/day </span> <br/> <span class="Bold"> n = 258</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> % Difference</span><span class="Sup">†</span><span class="Bold"> (95% CI)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Endoscopic Cure<br/> </td><td align="center" class="Botrule Rrule"> 228 (87.7%)<br/> </td><td align="center" class="Botrule Rrule"> 227 (88%)<br/> </td><td align="center" class="Botrule Rrule"> -0.3% (-5.9, +5.3)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Clinical Cure<br/> </td><td align="center" class="Botrule Rrule"> 239 (91.9%)<br/> </td><td align="center" class="Botrule Rrule"> 237 (91.9%)<br/> </td><td align="center" class="Botrule Rrule"> 0.06% (-4.6, +4.8)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Overall Therapeutic Cure<br/> </td><td align="center" class="Botrule Rrule"> 223 (85.8%)<br/> </td><td align="center" class="Botrule Rrule"> 220 (85.3%)<br/> </td><td align="center" class="Botrule Rrule"> 0.5% (-5.6, +6.6)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Mycological Eradication<br/> </td><td align="center" class="Botrule Rrule"> 141/189 (74.6%)<br/> </td><td align="center" class="Botrule Rrule"> 149/192 (77.6%)<br/> </td><td align="center" class="Botrule Rrule"> -3% (-11.6, +5.6)<br/> </td> </tr> </tbody> </table></div>

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.

<div class="scrollingtable"><table class="Noautorules" width="552"> <caption> <span> 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 </span> </caption> <col width="168"/> <col width="138"/> <col width="120"/> <col width="126"/> <tfoot> <tr> <td align="left" colspan="4"> <p class="First Footnote"> <span class="Sup">*</span>Calculated as micafungin – fluconazole; N = number of patients with overall therapeutic cure (both clinical and endoscopic cure at end-of-treatment);</p> </td> </tr> <tr> <td align="left" colspan="4"> <p class="First Footnote"> <span class="Sup">†</span> Relapse included patients who died or were lost to follow-up and those who received systemic anti-fungal therapy in the post-treatment period.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold"> Relapse </span> <br/> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Micafungin</span> <br/> <span class="Bold"> 150 mg/day </span> <br/> <span class="Bold"> n = 223</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> Fluconazole</span> <br/> <span class="Bold"> 200 mg/day </span> <br/> <span class="Bold"> n = 220</span> <br/> </td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold"> % Difference</span><span class="Sup">*</span><span class="Bold"> (95% CI)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Relapse<span class="Sup">†</span> at Week 2<br/> </td><td align="center" class="Botrule Rrule"> 40 (17.9%)<br/> </td><td align="center" class="Botrule Rrule"> 30 (13.6%)<br/> </td><td align="center" class="Botrule Rrule"> 4.3% (-2.5, 11.1)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Relapse<span class="Sup">†</span> through Week 4 (cumulative)<br/> </td><td align="center" class="Botrule Rrule"> 73 (32.7%)<br/> </td><td align="center" class="Botrule Rrule"> 62 (28.2%)<br/> </td><td align="center" class="Botrule Rrule"> 4.6% (-4, 13.1)<br/> </td> </tr> </tbody> </table></div>

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]).

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/mm3 or 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.

<div class="scrollingtable"><table class="Noautorules" width="558"> <caption> <span> Table 12 Results from Clinical Study of Prophylaxis of Candida Infections in Hematopoietic Stem Cell Transplant Recipients </span> </caption> <col width="282"/> <col width="150"/> <col width="126"/> <tfoot> <tr> <td align="left" colspan="3"> <p class="First Footnote"> <span class="Sup">*</span> Difference (micafungin – fluconazole): + 7% [95% CI=1.5, 12.5].</p> </td> </tr> <tr> <td align="left" colspan="3"> <p class="First Footnote"> <span class="Sup">†</span> Through end-of-study (4 weeks post-therapy).</p> </td> </tr> <tr> <td align="left" colspan="3"> <p class="First Footnote"> <span class="Sup">‡</span> Through end-of-therapy.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold"> Outcome of Prophylaxis</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Micafungin</span> <br/> <span class="Bold"> 50 mg/day (n = 425)</span> <br/> </td><td align="center" class="Botrule Rrule Toprule"><span class="Bold"> Fluconazole</span> <br/> <span class="Bold"> 400 mg/day</span> <br/> <span class="Bold"> (n = 457)</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Success<span class="Sup">*</span> <br/> </td><td align="center" class="Botrule Rrule"> 343 (80.7%)<br/> </td><td align="center" class="Botrule Rrule"> 337 (73.7%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Failure:<br/> </td><td align="center" class="Botrule Rrule"> 82 (19.3%)<br/> </td><td align="center" class="Botrule Rrule"> 120 (26.3%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> All Deaths<span class="Sup">†</span> <br/> Proven/probable fungal infection prior to death <br/> </td><td align="center" class="Botrule Rrule"> 18 (4.2%)<br/> 1 (0.2%)<br/> </td><td align="center" class="Botrule Rrule"> 26 (5.7%)<br/> 3 (0.7%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Proven/probable fungal infection (not resulting in death)<span class="Sup">†</span> <br/> </td><td align="center" class="Botrule Rrule"> 6 (1.4%)<br/> </td><td align="center" class="Botrule Rrule"> 8 (1.8%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Suspected fungal infection<span class="Sup">‡</span> <br/> </td><td align="center" class="Botrule Rrule"> 53 (12.5%)<br/> </td><td align="center" class="Botrule Rrule"> 83 (18.2%)<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> Lost to follow-up <br/> </td><td align="center" class="Botrule Rrule"> 5 (1.2%)<br/> </td><td align="center" class="Botrule Rrule"> 3 (0.7%)<br/> </td> </tr> </tbody> </table></div>

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

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<div class="scrollingtable"><table class="Noautorules" width="541"> <col width="147"/> <col width="225"/> <col width="169"/> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold"> Strength</span> <br/> <span class="Bold"> (mg of micafungin)</span> <br/> </td><td align="left" class="Botrule Rrule Toprule"><span class="Bold"> Pack Size</span> <br/> </td><td align="left" class="Botrule Rrule Toprule"><span class="Bold"> Carton NDC</span> <br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> 50 mg/vial<br/> </td><td align="left" class="Botrule Rrule"> Carton of 10 Single-dose vials sealed with blue flip-off cap<br/> (NDC Number: 70710-1724-1)<br/> </td><td align="left" class="Botrule Rrule"> 70710-1724-6<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> 100 mg/vial<br/> </td><td align="left" class="Botrule Rrule"> Carton of 10 Single-dose vials sealed with red flip-off cap<br/> (NDC Number: 70710-1725-1)<br/> </td><td align="left" class="Botrule Rrule"> 70710-1725-6<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> 50 mg/vial<br/> </td><td align="left" class="Botrule Rrule"> Carton of Single-dose vials sealed with blue flip-off cap<br/> (NDC Number: 70710-1724-1)<br/> </td><td align="left" class="Botrule Rrule"> 70710-1724-1<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> 100 mg/vial<br/> </td><td align="left" class="Botrule Rrule"> Carton of Single-dose vials sealed with red flip-off cap<br/> (NDC Number: 70710-1725-1)<br/> </td><td align="left" class="Botrule Rrule"> 70710-1725-1<br/> </td> </tr> </tbody> </table></div>

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Storage

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Unopened vials of lyophilized material must be stored at room temperature, 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

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Store the reconstituted product at 25°C (77°F) [see Dosage and Administration (2.4)].

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Store the diluted solution at 25°C (77°F) [see Dosage and Administration (2.4)].

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Protect from light.

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Hypersensitivity

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Inform patients about the serious adverse effects of micafungin including hypersensitivity reactions e.g., anaphylaxis and anaphylactoid reactions including shock.

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Hepatic

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Inform patients about the serious adverse effects of micafungin including hepatic effects e.g., abnormal liver tests, hepatic impairment, hepatitis or worsening hepatic failure.

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Hematologic

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Inform patients about the serious adverse effects of micafungin including hematological effects e.g., acute intravascular hemolysis, hemolytic anemia and hemoglobinuria.

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Renal

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Inform patients about the serious adverse effects of micafungin including renal effects e.g., elevations in BUN and creatinine, renal impairment or acute renal failure.

{ "type": "p", "children": [], "text": "Inform patients about the serious adverse effects of micafungin including renal effects e.g., elevations in BUN and creatinine, renal impairment or acute renal failure." }

Embryo-Fetal Toxicity

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Advise pregnant women and females of reproductive potential of the potential risk of micafungin to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.

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Concomitant Medications

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Instruct patients to inform their healthcare provider of any other medications they are currently taking with micafungin, including over-the-counter medications.

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Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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Please address medical inquiries to, MedicalAffairs@zydususa.com or Tel.: 1-877-993-8779.

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Manufactured by:

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Zydus Lifesciences Ltd.

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Vadodara, India

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Distributed by:

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Zydus Pharmaceuticals (USA) Inc.

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Pennington, NJ 08534

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Rev: 08/24

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NDC 70710-1724-6

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Micafungin for Injection

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50 mg/vial

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For Intravenous Infusion Only

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10 x 50 mg Single-Dose Vials

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Rx only

{ "type": "p", "children": [], "text": "Rx only" }

NDC 70710-1725-6

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Micafungin for Injection

{ "type": "p", "children": [], "text": "Micafungin for Injection" }

100 mg/vial

{ "type": "p", "children": [], "text": "100 mg/vial" }

For Intravenous Infusion Only

{ "type": "p", "children": [], "text": "For Intravenous Infusion Only" }

10 x 100 mg Single-Dose Vials

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Rx only

{ "type": "p", "children": [], "text": "Rx only" }

NDC 70710-1724-1

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Micafungin for Injection

{ "type": "p", "children": [], "text": "Micafungin for Injection" }

50 mg/vial

{ "type": "p", "children": [], "text": "50 mg/vial" }

For Intravenous Infusion Only

{ "type": "p", "children": [], "text": "For Intravenous Infusion Only" }

50 mg Single-Dose Vials

{ "type": "p", "children": [], "text": "50 mg Single-Dose Vials" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

NDC 70710-1725-1

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Micafungin for Injection

{ "type": "p", "children": [], "text": "Micafungin for Injection" }

100 mg/vial

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For Intravenous Infusion Only

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100 mg Single-Dose Vials

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Rx only

{ "type": "p", "children": [], "text": "Rx only" }