Micafungin

Hypersensitivity Reactions: Anaphylaxis and anaphylactoid reactions (including shock) have been observed. Discontinue micafungin for injection and administer appropriate treatment. (5.1) Hematological Effects: Isolated cases of acute intravascular hemolysis, hemolytic anemia and hemoglobinuria have been reported. Monitor rate of hemolysis. Discontinue if severe. (5.2) Hepatic Effects: Abnormalities in liver tests; isolated cases of hepatic impairment, hepatitis, and hepatic failure have been observed. Monitor hepatic function. Discontinue if severe dysfunction occurs. (5.3) Renal Effects: Elevations in BUN and creatinine; isolated cases of renal impairment or acute renal failure have been reported. Monitor renal function. (5.4) Infusion and Injection Site Reactions can occur including rash, pruritus, facial swelling, and vasodilatation. Monitor infusion closely, slow infusion rate if necessary. (2.5, 5.5) 5.1 Hypersensitivity Reactions 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 for injection infusion should be discontinued and appropriate treatment administered. 5.2 Hematological Effects 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 for injection therapy should be monitored closely for evidence of worsening of these conditions and evaluated for the risk/benefit of continuing micafungin for injection therapy. 5.3 Hepatic Effects Laboratory abnormalities in liver function tests have been seen in healthy volunteers and patients treated with micafungin for injection. In some patients with serious underlying conditions who were receiving micafungin for injection 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 for injection therapy should be monitored for evidence of worsening hepatic function and evaluated for the risk/benefit of continuing micafungin for injection therapy. 5.4 Renal Effects Elevations in BUN and creatinine, and isolated cases of significant renal impairment or acute renal failure have been reported in patients who received micafungin 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 for injection therapy should be monitored for evidence of worsening renal function. 5.5 Infusion and Injection Site Reactions 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 (2.3)] . 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 Dosage and Administration (2.3) and Adverse Reactions (6.1)] .

5.1 Hypersensitivity Reactions 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 for injection infusion should be discontinued and appropriate treatment administered.

5.2 Hematological Effects 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 for injection therapy should be monitored closely for evidence of worsening of these conditions and evaluated for the risk/benefit of continuing micafungin for injection therapy.

5.3 Hepatic Effects Laboratory abnormalities in liver function tests have been seen in healthy volunteers and patients treated with micafungin for injection. In some patients with serious underlying conditions who were receiving micafungin for injection 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 for injection therapy should be monitored for evidence of worsening hepatic function and evaluated for the risk/benefit of continuing micafungin for injection therapy.

<table border="1" cellpadding="0" cellspacing="0" width="100%"><tbody><tr><td><paragraph><content styleCode="bold">Adverse Reactions by System Organ Class ^&#x2020;</content></paragraph></td><td><paragraph><content styleCode="bold">Micafungin for Injection</content></paragraph><paragraph><content styleCode="bold">150 mg/day </content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td><td><paragraph><content styleCode="bold">Fluconazole </content></paragraph><paragraph><content styleCode="bold">200 mg/day </content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Number of Patients</content></paragraph></td><td><paragraph>260</paragraph></td><td><paragraph>258</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td><td><paragraph><content styleCode="bold">84 (32)</content></paragraph></td><td><paragraph><content styleCode="bold">93 (36)</content></paragraph></td></tr><tr><td><paragraph>Diarrhea</paragraph></td><td><paragraph>27 (10)</paragraph></td><td><paragraph>29 (11)</paragraph></td></tr><tr><td><paragraph>Nausea</paragraph></td><td><paragraph>20 (8)</paragraph></td><td><paragraph>23 (9)</paragraph></td></tr><tr><td><paragraph>Vomiting</paragraph></td><td><paragraph>17 (7)</paragraph></td><td><paragraph>17 (7)</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">General Disorders/Administration Site Conditions</content></paragraph></td><td><paragraph><content styleCode="bold">52 (20)</content></paragraph></td><td><paragraph><content styleCode="bold">45 (17)</content></paragraph></td></tr><tr><td><paragraph>Pyrexia</paragraph></td><td><paragraph>34 (13)</paragraph></td><td><paragraph>21 (8)</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Nervous System Disorders</content></paragraph></td><td><paragraph><content styleCode="bold">42 (16)</content></paragraph></td><td><paragraph><content styleCode="bold">40 (16)</content></paragraph></td></tr><tr><td><paragraph>Headache</paragraph></td><td><paragraph>22 (9)</paragraph></td><td><paragraph>20 (8)</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Vascular Disorders</content></paragraph></td><td><paragraph><content styleCode="bold">54 (21)</content></paragraph></td><td><paragraph><content styleCode="bold">21 (8)</content></paragraph></td></tr><tr><td><paragraph>Phlebitis</paragraph></td><td><paragraph>49 (19)</paragraph></td><td><paragraph>13 (5)</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></paragraph></td><td><paragraph><content styleCode="bold">36 (14)</content></paragraph></td><td><paragraph><content styleCode="bold">26 (10)</content></paragraph></td></tr><tr><td><paragraph>Rash</paragraph></td><td><paragraph>14 (5)</paragraph></td><td><paragraph>6 (2)</paragraph></td></tr></tbody></table>

<table border="1" cellpadding="0" cellspacing="0" width="100.0%"><tbody><tr><td><paragraph><content styleCode="bold">System Organ Class</content></paragraph></td><td><paragraph><content styleCode="bold">Micafungin for Injection</content></paragraph><paragraph><content styleCode="bold">50 mg/day</content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td><td><paragraph><content styleCode="bold">Fluconazole </content></paragraph><paragraph><content styleCode="bold">400 mg/day</content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Number of Patients</content></paragraph></td><td><paragraph>382</paragraph></td><td><paragraph>409</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td><td><paragraph><content styleCode="bold">377 (99)</content></paragraph></td><td><paragraph><content styleCode="bold">404 (99)</content></paragraph></td></tr><tr><td><paragraph>Diarrhea</paragraph></td><td><paragraph>294 (77)</paragraph></td><td><paragraph>327 (80)</paragraph></td></tr><tr><td><paragraph>Nausea</paragraph></td><td><paragraph>270 (71)</paragraph></td><td><paragraph>290 (71)</paragraph></td></tr><tr><td><paragraph>Vomiting</paragraph></td><td><paragraph>252 (66)</paragraph></td><td><paragraph>274 (67)</paragraph></td></tr><tr><td><paragraph>Abdominal Pain</paragraph></td><td><paragraph>100 (26)</paragraph></td><td><paragraph>93 (23)</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Blood and Lymphatic System Disorders</content></paragraph></td><td><paragraph><content styleCode="bold">368 (96)</content></paragraph></td><td><paragraph><content styleCode="bold">385 (94)</content></paragraph></td></tr><tr><td><paragraph>Neutropenia</paragraph></td><td><paragraph>288 (75)</paragraph></td><td><paragraph>297 (73)</paragraph></td></tr><tr><td><paragraph>Thrombocytopenia</paragraph></td><td><paragraph>286 (75)</paragraph></td><td><paragraph>280 (69)</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></paragraph></td><td><paragraph><content styleCode="bold">257 (67)</content></paragraph></td><td><paragraph><content styleCode="bold">275 (67)</content></paragraph></td></tr><tr><td><paragraph>Rash</paragraph></td><td><paragraph>95 (25)</paragraph></td><td><paragraph>91 (22)</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Nervous System Disorders</content></paragraph></td><td><paragraph><content styleCode="bold">250 (65)</content></paragraph></td><td><paragraph><content styleCode="bold">254 (62)</content></paragraph></td></tr><tr><td><paragraph>Headache</paragraph></td><td><paragraph>169 (44)</paragraph></td><td><paragraph>154 (38)</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td><td><paragraph><content styleCode="bold">233 (61)</content></paragraph></td><td><paragraph><content styleCode="bold">235 (58)</content></paragraph></td></tr><tr><td><paragraph>Insomnia</paragraph></td><td><paragraph>142 (37)</paragraph></td><td><paragraph>140 (34)</paragraph></td></tr><tr><td><paragraph>Anxiety</paragraph></td><td><paragraph>84 (22)</paragraph></td><td><paragraph>87 (21)</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Cardiac Disorders</content></paragraph></td><td><paragraph><content styleCode="bold">133 (35)</content></paragraph></td><td><paragraph><content styleCode="bold">138 (34)</content></paragraph></td></tr><tr><td><paragraph>Tachycardia</paragraph></td><td><paragraph>99 (26)</paragraph></td><td><paragraph>91 (22)</paragraph></td></tr></tbody></table>

<table border="1" cellpadding="0" cellspacing="0" width="100.0%"><tbody><tr><td rowspan="2"><paragraph><content styleCode="bold">Adverse Reactions ^*</content></paragraph></td><td colspan="2"><paragraph><content styleCode="bold">C/IC ^&#x2020;</content></paragraph></td><td colspan="2"><paragraph><content styleCode="bold">Prophylaxis</content></paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Micafungin for Injection</content></paragraph><paragraph><content styleCode="bold">n = 56</content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td><td><paragraph><content styleCode="bold">Amphotericin B liposome</content></paragraph><paragraph><content styleCode="bold">n = 56</content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td><td><paragraph><content styleCode="bold">Micafungin for Injection</content></paragraph><paragraph><content styleCode="bold">n = 43</content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td><td><paragraph><content styleCode="bold">Fluconazole</content></paragraph><paragraph><content styleCode="bold">n = 48</content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Gastrointestinal disorders </content></paragraph></td><td><paragraph>22 (40)</paragraph></td><td><paragraph>18 (32)</paragraph></td><td><paragraph>43 (100)</paragraph></td><td><paragraph>45 (94)</paragraph></td></tr><tr><td><paragraph>Vomiting</paragraph></td><td><paragraph>10 (18)</paragraph></td><td><paragraph>8 (14)</paragraph></td><td><paragraph>28 (65)</paragraph></td><td><paragraph>32 (67)</paragraph></td></tr><tr><td><paragraph>Diarrhea</paragraph></td><td><paragraph>4 (7)</paragraph></td><td><paragraph>5 (9)</paragraph></td><td><paragraph>22 (51)</paragraph></td><td><paragraph>31 (65)</paragraph></td></tr><tr><td><paragraph>Nausea</paragraph></td><td><paragraph>4 (7)</paragraph></td><td><paragraph>4 (7)</paragraph></td><td><paragraph>30 (70)</paragraph></td><td><paragraph>25 (52)</paragraph></td></tr><tr><td><paragraph>Abdominal pain</paragraph></td><td><paragraph>2 (4)</paragraph></td><td><paragraph>2 (4)</paragraph></td><td><paragraph>15 (35)</paragraph></td><td><paragraph>12 (25)</paragraph></td></tr><tr><td><paragraph>Abdominal distension</paragraph></td><td><paragraph>1 (2)</paragraph></td><td><paragraph>1 (2)</paragraph></td><td><paragraph>8 (19)</paragraph></td><td><paragraph>6 (13)</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">General disorders and administration site conditions </content></paragraph></td><td><paragraph>14 (25)</paragraph></td><td><paragraph>14 (25)</paragraph></td><td><paragraph>41 (95)</paragraph></td><td><paragraph>46 (96)</paragraph></td></tr><tr><td><paragraph>Pyrexia</paragraph></td><td><paragraph>5 (9)</paragraph></td><td><paragraph>9 (16)</paragraph></td><td><paragraph>26 (61)</paragraph></td><td><paragraph>31 (65)</paragraph></td></tr><tr><td><paragraph>Infusion-related reaction</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>3 (5)</paragraph></td><td><paragraph>7 (16)</paragraph></td><td><paragraph>4 (8)</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Skin and subcutaneous tissue disorders </content></paragraph></td><td><paragraph>11 (20)</paragraph></td><td><paragraph>8 (14)</paragraph></td><td><paragraph>33 (77)</paragraph></td><td><paragraph>38 (79)</paragraph></td></tr><tr><td><paragraph>Pruritus</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>1 (2)</paragraph></td><td><paragraph>14 (33)</paragraph></td><td><paragraph>15 (31)</paragraph></td></tr><tr><td><paragraph>Rash</paragraph></td><td><paragraph>1 (2)</paragraph></td><td><paragraph>1 (2)</paragraph></td><td><paragraph>13 (30)</paragraph></td><td><paragraph>13 (27)</paragraph></td></tr><tr><td><paragraph>Urticaria</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>1 (2)</paragraph></td><td><paragraph>8 (19)</paragraph></td><td><paragraph>4 (8)</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Respiratory, thoracic and mediastinal disorders </content></paragraph></td><td><paragraph>9 (16)</paragraph></td><td><paragraph>13 (23)</paragraph></td><td><paragraph>30 (70)</paragraph></td><td><paragraph>33 (69)</paragraph></td></tr><tr><td><paragraph>Epistaxis</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>4 (9)</paragraph></td><td><paragraph>8 (17)</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Blood and lymphatic system disorders </content></paragraph></td><td><paragraph>17 (30)</paragraph></td><td><paragraph>13 (23)</paragraph></td><td><paragraph>40 (93)</paragraph></td><td><paragraph>44 (92)</paragraph></td></tr><tr><td><paragraph>Thrombocytopenia</paragraph></td><td><paragraph>5 (9)</paragraph></td><td><paragraph>3 (5)</paragraph></td><td><paragraph>31 (72)</paragraph></td><td><paragraph>37 (77)</paragraph></td></tr><tr><td><paragraph>Neutropenia</paragraph></td><td><paragraph>3 (5)</paragraph></td><td><paragraph>4 (7)</paragraph></td><td><paragraph>33 (77)</paragraph></td><td><paragraph>34 (71)</paragraph></td></tr><tr><td><paragraph>Anemia</paragraph></td><td><paragraph>10 (18)</paragraph></td><td><paragraph>6 (11)</paragraph></td><td><paragraph>22 (51)</paragraph></td><td><paragraph>24 (50)</paragraph></td></tr><tr><td><paragraph>Febrile neutropenia</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>7 (16)</paragraph></td><td><paragraph>7 (15)</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Investigations </content></paragraph></td><td><paragraph>12 (21)</paragraph></td><td><paragraph>8 (14)</paragraph></td><td><paragraph>24 (56)</paragraph></td><td><paragraph>25 (52)</paragraph></td></tr><tr><td><paragraph>Alanine aminotransferase increased</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>7 (16)</paragraph></td><td><paragraph>1 (2)</paragraph></td></tr><tr><td><paragraph>Urine output decreased</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>10 (23)</paragraph></td><td><paragraph>8 (17)</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Cardiac disorders </content></paragraph></td><td><paragraph>7 (13)</paragraph></td><td><paragraph>3 (5)</paragraph></td><td><paragraph>10 (23)</paragraph></td><td><paragraph>17 (35)</paragraph></td></tr><tr><td><paragraph>Tachycardia</paragraph></td><td><paragraph>2 (4)</paragraph></td><td><paragraph>1 (2)</paragraph></td><td><paragraph>7 (16)</paragraph></td><td><paragraph>12 (25)</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Renal and urinary disorders </content></paragraph></td><td><paragraph>4 (7)</paragraph></td><td><paragraph>4 (7)</paragraph></td><td><paragraph>16 (37)</paragraph></td><td><paragraph>15 (31)</paragraph></td></tr><tr><td><paragraph>Hematuria</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>10 (23)</paragraph></td><td><paragraph>7 (15)</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Psychiatric disorders </content></paragraph></td><td><paragraph>3 (5)</paragraph></td><td><paragraph>1 (2)</paragraph></td><td><paragraph>20 (47)</paragraph></td><td><paragraph>9 (19)</paragraph></td></tr><tr><td><paragraph>Anxiety</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>10 (23)</paragraph></td><td><paragraph>3 (6)</paragraph></td></tr></tbody></table>

<table border="1" cellpadding="0" cellspacing="0" width="100.0%"><tbody><tr><td><paragraph><content styleCode="bold">Adverse Reactions by System Organ Class ^&#x2020;</content></paragraph></td><td><paragraph><content styleCode="bold">Micafungin for Injection</content></paragraph><paragraph><content styleCode="bold">100 mg</content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td><td><paragraph><content styleCode="bold">Caspofungin ^&#x2021;</content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Number of Patients</content></paragraph></td><td><paragraph>200</paragraph></td><td><paragraph>193</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td><td><paragraph><content styleCode="bold">81 (41)</content></paragraph></td><td><paragraph><content styleCode="bold">76 (39)</content></paragraph></td></tr><tr><td><paragraph>Diarrhea</paragraph></td><td><paragraph>15 (8)</paragraph></td><td><paragraph>14 (7)</paragraph></td></tr><tr><td><paragraph>Vomiting</paragraph></td><td><paragraph>18 (9)</paragraph></td><td><paragraph>16 (8)</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Metabolism and Nutrition Disorders</content></paragraph></td><td><paragraph><content styleCode="bold">77 (39)</content></paragraph></td><td><paragraph><content styleCode="bold">73 (38)</content></paragraph></td></tr><tr><td><paragraph>Hypoglycemia</paragraph></td><td><paragraph>12 (6)</paragraph></td><td><paragraph>9 (5)</paragraph></td></tr><tr><td><paragraph>Hyperkalemia</paragraph></td><td><paragraph>10 (5)</paragraph></td><td><paragraph>5 (3)</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">General Disorders/Administration Site Conditions</content></paragraph></td><td><paragraph><content styleCode="bold">59 (30)</content></paragraph></td><td><paragraph><content styleCode="bold">51 (26)</content></paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Investigations</content></paragraph></td><td><paragraph><content styleCode="bold">36 (18) </content></paragraph></td><td><paragraph><content styleCode="bold">37 (19) </content></paragraph></td></tr><tr><td><paragraph>Blood Alkaline Phosphatase Increased</paragraph></td><td><paragraph>11 (6)</paragraph></td><td><paragraph>8 (4)</paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Cardiac Disorders</content></paragraph></td><td><paragraph><content styleCode="bold">35 (18)</content></paragraph></td><td><paragraph><content styleCode="bold">36 (19)</content></paragraph></td></tr><tr><td><paragraph>Atrial Fibrillation</paragraph></td><td><paragraph>5 (3)</paragraph></td><td><paragraph>0</paragraph></td></tr></tbody></table>