FDA label 48123b08-5cab-4639-b379-157369f2e5ec

WARNINGS NEUTREXIN (TRIMETREXATE GLUCURONATE FOR INJECTION) MUST BE USED WITH CONCURRENT LEUCOVORIN (LEUCOVORIN PROTECTION) TO AVOID POTENTIALLY SERIOUS OR LIFE-THREATENING TOXICITIES (SEE PRECAUTIONS AND DOSAGE AND ADMINISTRATION).

WARNINGS Neutrexin (trimetrexate glucuronate for injection) must be used with concurrent leucovorin to avoid potentially serious or life-threatening complications including bone marrow suppression, oral and gastrointestinal mucosal ulceration, and renal and hepatic dysfunction. Leucovorin therapy must extend for 72 hours past the last dose of Neutrexin. Patients should be informed that failure to take the recommended dose and duration of leucovorin can lead to fatal toxicity. Patients should be closely monitored for the development of serious hematologic adverse reactions (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ). Neutrexin can cause fetal harm when administered to a pregnant woman. Trimetrexate has been shown to be fetotoxic and teratogenic in rats and rabbits. Rats administered 1.5 and 2.5 mg/kg/day intravenously on gestational days 6-15 showed substantial postimplantation loss and severe inhibition of maternal weight gain. Trimetrexate administered intravenously to rats at 0.5 and 1.0 mg/kg/day on gestational days 6-15 retarded normal fetal development and was teratogenic. Rabbits administered trimetrexate intravenously at daily doses of 2.5 and 5.0 mg/kg/day on gestational days 6-18 resulted in significant maternal and fetal toxicity. In rabbits, trimetrexate at 0.1 mg/kg/day was teratogenic in the absence of significant maternal toxicity. These effects were observed using doses 1/20 to 1/2 the equivalent human therapeutic dose based on a mg/m 2 basis. Teratogenic effects included skeletal, visceral, ocular, and cardiovascular abnormalities. If Neutrexin is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

ADVERSE REACTIONS Because many patients who participated in clinical trials of Neutrexin (trimetrexate glucuronate for injection) had complications of advanced HIV disease, it is difficult to distinguish adverse events caused by Neutrexin from those resulting from underlying medical conditions. Table 3 lists the adverse events that occurred in ≥ 1% of the patients who participated in the Comparative Study of Neutrexin plus leucovorin versus TMP/SMX. TABLE 3 NEUTREXIN COMPARATIVE TRIAL Comparison of Adverse Events Reported for ≥ 1% of Patients Adverse Events Number and Percent (%) of Patients with Adverse Events TMTX/LV (n = 109) TMP/SMX (n = 111) Non-Laboratory Adverse Events: Fever 9 (8.3) 14 (12.6) Rash/Pruritus 6 (5.5) 14 (12.6) Nausea/Vomiting 5 (4.6) Statistically significant difference between treatment groups (Chi-square: p=0.022) 15 (13.5) Confusion 3 (2.8) 3 (2.7) Fatigue 2 (1.8) 0 (0.0) Hematologic Toxicity: Thrombocytopenia ( < 75,000/mm 3 ) 33 (30.3) 37 (33.3) Anemia (Hgb <8 g/dL) 11 (10.1) 17 (15.3) Neutropenia ( < 1000/mm 3 ) 8 (7.3) 10 (9.0) Hepatotoxicity: Increased AST (>5 x ULN ULN = Upper limit of normal range ) 15 (13.8) 10 (9.0) Increased ALT (>5 x ULN) 12 (11.0) 13 (11.7) Increased Alkaline Phosphatase (>5 x ULN) 5 (4.6) 3 (2.7) Increased Bilirubin (2.5 x ULN) 2 (1.8) 1 (0.9) Renal: Increased Serum Creatinine (>3 x ULN) 1 (0.9) 2 (1.8) Electrolyte Imbalance: Hyponatremia 5 (4.6) 10 (9.0) Hypocalcemia 2 (1.8) 0 (0.0) No. of Patients With at Least one Adverse Event Patients could have reported more than one adverse event; therefore, the sum of adverse events exceeds the number of patients 58 (53.2) 60 (54.1) Laboratory toxicities were generally manageable with dose modification of trimetrexate/leucovorin (see DOSAGE AND ADMINISTRATION ). Table 4 lists the adverse events resulting in discontinuation of study therapy in the Neutrexin Comparative Study with TMP/SMX. Twenty-nine percent of the patients on the TMP/SMX arm discontinued therapy due to adverse events compared to 10% of the patients treated with TMTX/LV (p < 0.001). TABLE 4 NEUTREXIN COMPARATIVE TRIAL Adverse Events Resulting in Discontinuation of Therapy Adverse Events Number and Percent (%) of Patients Discontinued for Adverse Events Patients could discontinue therapy due to more than one toxicity; therefore the sum exceeds number of patients who discontinued due to toxicity TMTX/LV (n = 109) TMP/SMX (n = 111) Non-Laboratory Adverse Events: Rash/Pruritus 3 (2.8) 5 (4.5) Fever 2 (1.8) 4 (3.6) Nausea/Vomiting 1 (0.9) 8 (7.2) Neurologic Toxicity 1 (0.9) Patient discontinued TMTX/LV due to seizure, though causal relationship could not be established. 2 (1.8) Hematologic Toxicity: Neutropenia ( < 1000/mm 3 ) 4 (3.7) 6 (5.4) Thrombocytopenia ( < 75,000/mm 3 ) 0 (0.0) 4 (3.6) Anemia (Hgb <8 g/dL) 0 (0.0) 4 (3.6) Hepatotoxicity: Increased AST (>5 x ULN ULN = Upper limit of normal range ) 3 (2.8) 9 (8.1) Increased ALT (>5 x ULN) 1 (0.9) 4 (3.6) Increased Alkaline Phosphatase (>5 x ULN) 0 (0.0) 1 (0.9) Electrolyte Imbalance: Hyponatremia 0 (0.0) 3 (2.7) No. of Patients Discontinuing Therapy Due to an Adverse Event 11 (10.1) Statistically significant difference between treatment groups (Chi-square: p < 0.001) 32 (28.8) Hematologic toxicity was the principal dose-limiting side effect.

<table ID="_RefID_6B20D3E6-5E72-4D5F-A219-C9A5B3A22" width="100%"><caption>TABLE 3 NEUTREXIN COMPARATIVE TRIAL Comparison of Adverse Events Reported for &#x2265; 1% of Patients</caption><col width="42%"/><col width="8%"/><col width="31%"/><col width="7%"/><col width="10%"/><tbody><tr><td align="justify" rowspan="2" styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Events</content></paragraph></td><td align="justify" colspan="4" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Number and Percent (%) of Patients with Adverse Events</content></paragraph></td></tr><tr><td colspan="2" styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">TMTX/LV</content></paragraph><paragraph><content styleCode="bold">(n = 109)</content></paragraph></td><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">TMP/SMX</content></paragraph><paragraph><content styleCode="bold">(n = 111)</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Non-Laboratory Adverse Events:</content></paragraph></td><td styleCode="Lrule Botrule " valign="middle"/><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="middle"/></tr><tr><td styleCode="Lrule Botrule " valign="middle"><paragraph> Fever</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="middle"><paragraph>9</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="middle"><paragraph>(8.3)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>(12.6)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="middle"><paragraph> Rash/Pruritus</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="middle"><paragraph>6</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="middle"><paragraph>(5.5)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>(12.6)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="middle"><paragraph> Nausea/Vomiting</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="middle"><paragraph>5</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="middle"><paragraph>(4.6)<footnote ID="_RefID-1E03A5F5-5424-4E6D-9BE1-BB1DECE8D"> Statistically significant difference between treatment groups (Chi-square: p=0.022)</footnote></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>(13.5)<footnoteRef IDREF="_RefID-1E03A5F5-5424-4E6D-9BE1-BB1DECE8D"/> </paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="middle"><paragraph> Confusion</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="middle"><paragraph>3</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="middle"><paragraph>(2.8)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>(2.7)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="middle"><paragraph> Fatigue</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="middle"><paragraph>2</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="middle"><paragraph>(1.8)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>(0.0)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Hematologic Toxicity:</content></paragraph></td><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Thrombocytopenia (<content styleCode="underline">&lt;</content>75,000/mm³)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>33</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(30.3)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>37</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(33.3)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Anemia (Hgb &lt;8 g/dL)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(10.1)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(15.3)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Neutropenia (<content styleCode="underline">&lt;</content>1000/mm³)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(7.3)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(9.0)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Hepatotoxicity:</content></paragraph></td><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Lrule Botrule " valign="middle"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Increased AST (&gt;5 x ULN<footnote ID="_RefID-347E1ECC-39E1-432E-BC98-A1AE9137A"> ULN = Upper limit of normal range</footnote>)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(13.8)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="middle"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(9.0)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Increased ALT (&gt;5 x ULN)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(11.0)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="middle"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(11.7)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Increased Alkaline Phosphatase (&gt;5 x ULN)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(4.6)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="middle"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(2.7)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Increased Bilirubin (2.5 x ULN)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(1.8)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="middle"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(0.9)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Renal:</content></paragraph></td><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Increased Serum Creatinine (&gt;3 x ULN)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(0.9)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(1.8)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Electrolyte Imbalance:</content></paragraph></td><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Hyponatremia</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(4.6)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(9.0)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Hypocalcemia</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(1.8)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(0.0)</paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph><content styleCode="bold">No. of Patients With at Least one Adverse Event</content><footnote ID="_RefID-139E9AF1-0F87-405D-B92E-69BC0A3A0"> Patients could have reported more than one adverse event; therefore, the sum of adverse events exceeds the number of patients</footnote><content styleCode="bold"> </content></paragraph></td><td align="justify" styleCode="Botrule Lrule " valign="top"><paragraph><content styleCode="bold">58</content></paragraph></td><td align="justify" styleCode="Botrule Lrule " valign="top"><paragraph><content styleCode="bold">(53.2)</content></paragraph></td><td align="justify" styleCode="Botrule Lrule " valign="top"><paragraph><content styleCode="bold">60</content></paragraph></td><td align="justify" styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">(54.1)</content></paragraph></td></tr></tbody></table>

<table ID="_RefID_BEF1D05F-1ECB-4284-889F-8364F4115" width="100%"><caption>TABLE 4 NEUTREXIN COMPARATIVE TRIAL Adverse Events Resulting in Discontinuation of Therapy </caption><col width="42%"/><col width="6%"/><col width="33%"/><col width="6%"/><col width="11%"/><tbody><tr><td align="justify" rowspan="2" styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Events</content></paragraph></td><td colspan="4" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Number and Percent (%) of Patients Discontinued for Adverse Events</content><footnote ID="_RefID-9A670244-75CF-4BA1-99DD-3EE1FD94F">Patients could discontinue therapy due to more than one toxicity; therefore the sum exceeds number of patients who discontinued due to toxicity</footnote></paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">TMTX/LV</content></paragraph><paragraph><content styleCode="bold">(n = 109)</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">TMP/SMX</content></paragraph><paragraph><content styleCode="bold">(n = 111)</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Non-Laboratory Adverse Events:</content></paragraph></td><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Rash/Pruritus</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(2.8)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(4.5)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Fever</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(1.8)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(3.6)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Nausea/Vomiting</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(0.9)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(7.2)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Neurologic Toxicity</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(0.9)<footnote ID="_RefID-5963A7A1-ECF6-4AAE-A127-296423A1F">Patient discontinued TMTX/LV due to seizure, though causal relationship could not be established.</footnote></paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(1.8)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Hematologic Toxicity:</content></paragraph></td><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Neutropenia (<content styleCode="underline">&lt;</content>1000/mm³)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(3.7)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(5.4)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Thrombocytopenia (<content styleCode="underline">&lt;</content>75,000/mm³)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(0.0)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(3.6)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Anemia (Hgb &lt;8 g/dL)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(0.0)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(3.6)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Hepatotoxicity:</content></paragraph></td><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Increased AST (&gt;5 x ULN<footnote ID="_RefID-EE707585-C24D-463E-A4C0-4AB3250C5">ULN = Upper limit of normal range</footnote>)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(2.8)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(8.1)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Increased ALT (&gt;5 x ULN)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(0.9)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(3.6)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Increased Alkaline Phosphatase (&gt;5 x ULN)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(0.0)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(0.9)</paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Electrolyte Imbalance:</content></paragraph></td><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph> Hyponatremia</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>(0.0)</paragraph></td><td align="center" styleCode="Lrule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>(2.7)</paragraph></td></tr><tr><td styleCode="Botrule Lrule " valign="top"><paragraph><content styleCode="bold">No. of Patients Discontinuing Therapy Due to an Adverse Event</content><footnoteRef IDREF="_RefID-9A670244-75CF-4BA1-99DD-3EE1FD94F"/></paragraph></td><td align="justify" styleCode="Botrule Lrule " valign="top"><paragraph><content styleCode="bold">11</content></paragraph></td><td align="justify" styleCode="Botrule Lrule " valign="top"><paragraph><content styleCode="bold">(10.1)</content><footnote ID="_RefID-9E4356FE-3B4C-42D3-822F-024617548">Statistically significant difference between treatment groups (Chi-square: p &lt; 0.001)</footnote></paragraph></td><td align="justify" styleCode="Botrule Lrule " valign="top"><paragraph><content styleCode="bold">32</content></paragraph></td><td align="justify" styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">(28.8)</content><footnoteRef IDREF="_RefID-9E4356FE-3B4C-42D3-822F-024617548"/></paragraph></td></tr></tbody></table>