FDA label 63833656-7192-485f-bf97-9797a2e7fffa

WARNING: CHEMICAL ARACHNOIDITIS Chemical arachnoiditis, a syndrome manifested primarily by nausea, vomiting, headache and fever, was a common adverse event in all clinical studies. If left untreated, chemical arachnoiditis may be fatal. Patients receiving DepoCyt should be treated concurrently with dexamethasone to mitigate the symptoms of chemical arachnoiditis. [ see Warnings and Precautions ( 5.1 , 5.2 ) ] WARNING: CHEMICAL ARACHNOIDITIS ADVERSE REACTIONS See full prescribing information for complete boxed warning Chemical arachnoiditis, a syndrome manifested primarily by nausea, vomiting, headache and fever, was a common adverse event in all clinical studies. If left untreated, chemical arachnoiditis may be fatal. Patients receiving DepoCyt should be treated concurrently with dexamethasone to mitigate the symptoms of chemical arachnoiditis. ( 5.1 , 5.2 ))

5 WARNINGS AND PRECAUTIONS Neurotoxicity: Myelopathy and other neurologic toxicity may occur. Reduce the dose or discontinue DepoCyt. ( 5.2 ) Embryo-fetal Toxicity: May cause fetal harm. Advise women of potential harm to a fetus and to avoid pregnancy if receiving DepoCyt. ( 5.4 ) 5.1 Chemical Arachnoiditis Chemical arachnoiditis, a syndrome manifested primarily by nausea, vomiting, headache and fever, has been a common adverse event in all studies. If chemical arachnoiditis is suspected, exclude other inflammatory, infectious, or neoplastic conditions. If left untreated, chemical arachnoiditis may be fatal. The incidence and severity of chemical arachnoiditis can be reduced by coadministration of dexamethasone. Patients receiving DepoCyt should be treated concurrently with dexamethasone to mitigate the symptoms of chemical arachnoiditis [ see Dosage and Administration ( 2 ) ]. Toxic effects may be related to a single dose or to cumulative administration. Because toxic effects can occur at any time during therapy (although they are most likely to occur within 5 days of drug administration), patients receiving intrathecal therapy with DepoCyt should be monitored continuously for the development of neurotoxicity. If patients develop neurotoxicity, reduce subsequent doses of DepoCyt. If neurotoxicity persists, discontinue DepoCyt [ see Warnings and Precautions ( 5.3 ) ] Hydrocephalus has also been reported, possibly precipitated by arachnoiditis. Arachnoiditis is an expected and well-documented side effect of both neoplastic meningitis and of intrathecal chemotherapy. The incidence of severe and life-threatening arachnoiditis in patients receiving DepoCyt was 19% (48/257) in all patients and 30% (10/33) in patients with lymphomatous meningitis. In the early dose-finding study, chemical arachnoiditis was observed in 100% of cycles without dexamethasone prophylaxis. When concurrent dexamethasone was administered, chemical arachnoiditis was observed in 33% of cycles. 5.2 Neurotoxicity Intrathecal administration of cytarabine may cause myelopathy and other neurologic toxicity and can rarely lead to a permanent neurologic deficit. Administration of intrathecal cytarabine in combination with other chemotherapeutic agents or with cranial/spinal irradiation may increase this risk of neurotoxicity. Blockage to CSF flow may result in increased free cytarabine concentrations in the CSF and an increased risk of neurotoxicity. Therefore, as with any intrathecal cytotoxic therapy, consideration should be given to the need for assessment of CSF flow before treatment is started. Following intrathecal administration of DepoCyt, central nervous system toxicity, including persistent extreme somnolence, hemiplegia, visual disturbances including blindness which may be total and permanent, deafness and cranial nerve palsies have been reported. Symptoms and signs of peripheral neuropathy, such as pain, numbness, paresthesia, weakness, and impaired bowel and bladder control have also been observed. In some cases, a combination of neurological signs and symptoms has been reported as Cauda Equina Syndrome. If patients develop neurotoxicity, reduce subsequent doses of DepoCyt or discontinue DepoCyt Headache, nausea, and fever are expected in early signs of neurotoxicity. 5.3 Transient Elevations in CSF Protein and CSF White Blood Cells Transient elevations in CSF protein and white blood cell counts have been observed in patients following DepoCyt administration. 5.4 Embryo-fetal Toxicity Cytarabine, the active component of DepoCyt, can cause fetal harm if a pregnant woman is exposed to the drug systemically. The systemic exposure of cytarabine following intrathecal administration of DepoCyt is negligible. Cytarabine was teratogenic in mice and rats. Cytarabine was embryotoxic in mice when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to a fetus. [See Use in Specific Populations, Sec. 8.1 ]

6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail in other sections of the label : Chemical Arachnoiditis [see Warnings and Precautions ( 5.1 )] Neurotoxicity [see Warnings and Precautions ( 5.2 )] Transient elevations in CSF protein and CSF white blood cells [see Warnings and Precautions ( 5.3 )] Most common adverse reactions (incidence ≥20%) are headache, arachnoiditis, confusion, abnormal gait , convulsions, weakness, pyrexia, fatigue, nausea, vomiting , constipation, and back pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sigma-Tau Pharmaceuticals, Inc. at 1-888-393-4584 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Most Frequently Reported Reactions After intrathecal administration of cytarabine the most frequently reported reactions (≥ 10%) are headache NOS, nausea, vomiting NOS, arachnoiditis, weakness, confusion, pyrexia, fatigue, constipation, back pain, gait abnormal NOS, convulsions NOS, dizziness NOS, lethargy, pain in limb, insomnia, urinary tract infection NOS, neck pain, death NOS, pain, memory impairment, dehydration, anemia NOS, diarrhea NOS, appetite decreased NOS, thrombocytopenia, edema peripheral, arthralgia, neck stiffness, vision blurred, muscle weakness, neutropenia, hypoesthesia, agitation, and dyspnea NOS. 6.2 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The toxicity database consists of the observations made during Phase 1-4 studies. The most common adverse reactions in all patients and in patients with lymphoma are shown in Table 1 . The incidences of symptoms possibly reflecting meningeal irritation are shown in Table 2 . Table 1. Incidence of adverse reactions occurring in > 10% of patients in all Phase 1-4 adult study patients and in patients with lymphomatous meningitis receiving DepoCyt 50 mg or an active comparator Lymphoma System Organ Class / Preferred Term All DepoCyt (N=257) DepoCyt (N=33) Ara-C (N=28) Nervous System Disorders Headache NOS 144 (56%) 17 (52%) 9 (32%) Arachnoiditis 108 (42%) 14 (42%) 10 (36%) Confusion 86 (33%) 12 (36%) 3 (11%) Gait abnormal NOS 60 (23%) 7 (21 %) 8 (29%) Convulsions NOS 52 (20%) 7 (21%) 1 (4%) Dizziness NOS 47 (18%) 7 (21%) 6 (21%) Memory impairment 36 (14%) 4 (12%) 1 (4%) Hypoesthesia 26 (10%) 4 (12%) 3 (11%) Tremor 22 (9%) 5 (15%) 5 (18%) Peripheral neuropathy NOS 9 (4%) 4 (12%) 1 (4%) Syncope 8 (3%) 0 (0%) 3 (11%) Neuropathy NOS 7 (3%) 3 (9%) 3 (11%) Peripheral sensory neuropathy 7 (3%) 2 (6%) 3 (11%) Reflexes abnormal 7 (3%) 0 (0%) 3 (11%) General Disorders and Administration Site Conditions Weakness 103 (40%) 13 (39%) 15 (54%) Pyrexia 81 (32%) 15 (45%) 12 (43%) Fatigue 64 (25%) 9 (27%) 13 (46%) Lethargy 41 (16%) 4 (12%) 4 (14%) Death NOS 35 (14%) 9 (27%) 5 (18%) Pain NOS 35 (14%) 3 (9%) 5 (18%) Edema peripheral 27 (11 %) 6 (18%) 7 (25%) Fall 12 (5%) 0 (0%) 3 (11%) Mucosal inflammation NOS 8 (3%) 4 (12%) 2 (7%) Edema NOS 6 (2%) 1 (3%) 6 (21%) Gastrointestinal Disorders Nausea 117 (46%) 11 (33%) 15 (54%) Vomiting NOS 112 (44%) 11 (33%) 9 (32%) Constipation 64 (25%) 8 (24%) 7 (25%) Diarrhea NOS 31 (12%) 9 (27%) 9 (32%) Abdominal pain NOS 22 (9%) 5 (15%) 4 (14%) Dysphagia 20 (8%) 3 (9%) 3 (11%) Hemorrhoids 8 (3%) 0 (0%) 3 (11%) Musculoskeletal and Connective Tissue Disorders Back pain 61 (24%) 7 (21%) 5 (18%) Pain in limb 39 (15%) 4 (12%) 8 (29%) Neck pain 36 (14%) 5 (15%) 3 (11%) Arthralgia 29 (11%) 3 (9%) 4 (14%) Neck stiffness 28 (11%) 2 (6%) 4 (14%) Muscle weakness NOS 25 (10%) 5 (15%) 2 (7%) Psychiatric Disorders Insomnia 35 (14%) 6 (18%) 7 (25%) Agitation 26 (10%) 5 (15%) 2 (7%) Depression 21 (8%) 6 (18%) 4 (14%) Anxiety 17 (7%) 1 (3%) 3 (11%) Infections and Infestations Urinary tract infection NOS 35 (14%) 6 (18%) 5 (18%) Pneumonia NOS 16 (6%) 2 (6%) 3 (11%) Metabolism and Nutrition Disorders Dehydration 33 (13%) 6 (18%) 3 (11%) Appetite decreased NOS 29 (11%) 4 (12%) 3 (11%) Hyponatremia 18 (7%) 4 (12%) 1 (4%) Hypokalemia 17 (7%) 5 (15%) 2 (7%) Hyperglycemia 15 (6%) 4 (12%) 2 (7%) Anorexia 14 (5%) 1 (3%) 5 (18%) Investigations Platelet count decreased 8 (3%) 0 (0%) 3 (11%) Renal and Urinary Disorders Incontinence NOS 19 (7%) 3 (9%) 5 (18%) Urinary retention 14 (5%) 0 (0%) 3 (11%) Respiratory, Thoracic and Mediastinal Disorders Dyspnea NOS 25 (10%) 4 (12%) 6 (21%) Cough 17 (7%) 3 (9%) 6 (21%) Eye Disorders Vision blurred 29 (11%) 4 (12%) 4 (14%) Blood and Lymphatic Disorders Anemia NOS 31 (12%) 6 (18%) 5 (18%) Thrombocytopenia 27 (11%) 8 (24%) 9 (32%) Neutropenia 26 (10%) 12 (36%) 7 (25%) Skin and Subcutaneous Tissue Disorders Contusion 6 (2%) 1 (3%) 3 (11%) Pruritus NOS 6 (2%) 0 (0%) 4 (14%) Sweating increased 6 (2%) 1 (3%) 3 (11%) Vascular Disorders Hypotension NOS 21 (8%) 6 (18%) 2 (7%) Hypertension NOS 15 (6%) 5 (15%) 1 (4%) Ear and Labyrinth Disorders Hypacusis 15 (6%) 6 (18%) 3 (11%) Cardiac Disorders Tachycardia NOS 22 (9%) 0 (0%) 5 (18%) Neoplasms Benign, Malignant and Unspecified (Incl Cysts and Polyps) Diffuse Large B-Cell Lymphoma NOS 1 (0%) 1 (3%) 3 (11%) Table 2. Incidence of adverse reactions possibly reflecting meningeal irritation occurring in > 10% of all studied adult patients receiving DepoCyt 50 mg or an active comparator* * Hydrocephalus acquired, CSF pleocytosis and meningism occurred in ≤ 10% of all studied adult patients receiving DepoCyt or an active comparator System Organ Class / Preferred Term DepoCyt (N=257) MTX (N=78) Ara-C (N=28) Nervous System Disorders Headache NOS 145 (56%) 33 (42%) 9 (32%) Arachnoiditis 108 (42%) 15 (19%) 10 (36%) Convulsions NOS 56 (22%) 11 (14%) 1 (4%) Gastrointestinal Disorders Nausea 117 (46%) 24 (31%) 15 (54%) Vomiting NOS 112 (44%) 22 (28%) 9 (32%) Musculoskeletal and Connective Tissue Disorders Back pain 61 (24%) 15 (19%) 5 (18%) Neck pain 36 (14%) 6 (8%) 3 (11%) Neck stiffness 28 (11%) 1 (1%) 4 (14%) General Disorders and Administration Site Conditions Pyrexia 81 (32%) 15 (19%) 12 (43%) During the clinical studies, 2 deaths related to DepoCyt were reported. One patient at the 125 mg dose level died of encephalopathy 36 hours after receiving an intraventricular dose of DepoCyt. This patient, however, was also receiving concomitant whole brain irradiation and had previously received intraventricular methotrexate. The other patient received DepoCyt, 50 mg by the intraventricular route and developed focal seizures progressing to status epilepticus. This patient died approximately 8 weeks after the last dose of study medication. In the controlled lymphoma study, the patient incidence of seizures was higher in the DepoCyt group (4/17, 23.5%) than in the cytarabine group (1/16, 6.3%). The death of 1 additional patient was considered “possibly” related to DepoCyt. He was a 63-year-old with extensive lymphoma involving the nasopharynx, brain, and meninges with multiple neurologic deficits who died of apparent disease progression 4 days after his second dose of DepoCyt.

<table width="900" styleCode="Noautorules" ID="table1"> <caption>Table 1. Incidence of adverse reactions occurring in &gt; 10% of patients in all Phase 1-4 adult study patients and in patients with lymphomatous meningitis receiving DepoCyt 50 mg or an active comparator </caption> <col width="40%" align="left"/> <col width="10%" align="center"/> <col width="10%" align="left"/> <col width="10%" align="center"/> <col width="10%" align="left"/> <col width="10%" align="center"/> <col width="10%" align="left"/> <tbody> <tr> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td align="center" colspan="4" styleCode="toprule Botrule">Lymphoma</td> </tr> <tr> <td styleCode="left" valign="bottom">System Organ Class / Preferred Term</td> <td valign="bottom" colspan="2">All DepoCyt (N=257)</td> <td valign="bottom" colspan="2">DepoCyt (N=33)</td> <td valign="bottom" colspan="2">Ara-C (N=28)</td> </tr> <tr> <td styleCode="bold toprule">Nervous System Disorders</td> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> </tr> <tr> <td> Headache NOS</td> <td>144</td> <td>(56%)</td> <td>17</td> <td>(52%)</td> <td>9</td> <td>(32%)</td> </tr> <tr> <td> Arachnoiditis</td> <td>108</td> <td>(42%)</td> <td>14</td> <td>(42%)</td> <td>10</td> <td>(36%)</td> </tr> <tr> <td> Confusion</td> <td>86</td> <td>(33%)</td> <td>12</td> <td>(36%)</td> <td>3</td> <td>(11%)</td> </tr> <tr> <td> Gait abnormal NOS</td> <td>60</td> <td>(23%)</td> <td>7</td> <td>(21 %)</td> <td>8</td> <td>(29%)</td> </tr> <tr> <td> Convulsions NOS</td> <td>52</td> <td>(20%)</td> <td>7</td> <td>(21%)</td> <td>1</td> <td>(4%)</td> </tr> <tr> <td> Dizziness NOS</td> <td>47</td> <td>(18%)</td> <td>7</td> <td>(21%)</td> <td>6</td> <td>(21%)</td> </tr> <tr> <td> Memory impairment</td> <td>36</td> <td>(14%)</td> <td>4</td> <td>(12%)</td> <td>1</td> <td>(4%)</td> </tr> <tr> <td> Hypoesthesia</td> <td>26</td> <td>(10%)</td> <td>4</td> <td>(12%)</td> <td>3</td> <td>(11%)</td> </tr> <tr> <td> Tremor</td> <td>22</td> <td>(9%)</td> <td>5</td> <td>(15%)</td> <td>5</td> <td>(18%)</td> </tr> <tr> <td> Peripheral neuropathy NOS</td> <td>9</td> <td>(4%)</td> <td>4</td> <td>(12%)</td> <td>1</td> <td>(4%)</td> </tr> <tr> <td> Syncope</td> <td>8</td> <td>(3%)</td> <td>0</td> <td>(0%)</td> <td>3</td> <td>(11%)</td> </tr> <tr> <td> Neuropathy NOS</td> <td>7</td> <td>(3%)</td> <td>3</td> <td>(9%)</td> <td>3</td> <td>(11%)</td> </tr> <tr> <td> Peripheral sensory neuropathy</td> <td>7</td> <td>(3%)</td> <td>2</td> <td>(6%)</td> <td>3</td> <td>(11%)</td> </tr> <tr> <td styleCode="Botrule"> Reflexes abnormal</td> <td styleCode="Botrule">7</td> <td styleCode="Botrule">(3%)</td> <td styleCode="Botrule">0</td> <td styleCode="Botrule">(0%)</td> <td styleCode="Botrule">3</td> <td styleCode="Botrule">(11%)</td> </tr> <tr> <td styleCode="bold toprule">General Disorders and Administration Site Conditions</td> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> </tr> <tr> <td> Weakness</td> <td>103</td> <td>(40%)</td> <td>13</td> <td>(39%)</td> <td>15</td> <td>(54%)</td> </tr> <tr> <td> Pyrexia</td> <td>81</td> <td>(32%)</td> <td>15</td> <td>(45%)</td> <td>12</td> <td>(43%)</td> </tr> <tr> <td> Fatigue</td> <td>64</td> <td>(25%)</td> <td>9</td> <td>(27%)</td> <td>13</td> <td>(46%)</td> </tr> <tr> <td> Lethargy</td> <td>41</td> <td>(16%)</td> <td>4</td> <td>(12%)</td> <td>4</td> <td>(14%)</td> </tr> <tr> <td> Death NOS</td> <td>35</td> <td>(14%)</td> <td>9</td> <td>(27%)</td> <td>5</td> <td>(18%)</td> </tr> <tr> <td> Pain NOS</td> <td>35</td> <td>(14%)</td> <td>3</td> <td>(9%)</td> <td>5</td> <td>(18%)</td> </tr> <tr> <td> Edema peripheral</td> <td>27</td> <td>(11 %)</td> <td>6</td> <td>(18%)</td> <td>7</td> <td>(25%)</td> </tr> <tr> <td> Fall</td> <td>12</td> <td>(5%)</td> <td>0</td> <td>(0%)</td> <td>3</td> <td>(11%)</td> </tr> <tr> <td> Mucosal inflammation NOS</td> <td>8</td> <td>(3%)</td> <td>4</td> <td>(12%)</td> <td>2</td> <td>(7%)</td> </tr> <tr> <td> Edema NOS</td> <td>6</td> <td>(2%)</td> <td>1</td> <td>(3%)</td> <td>6</td> <td>(21%)</td> </tr> <tr> <td styleCode="bold toprule">Gastrointestinal Disorders</td> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> </tr> <tr> <td> Nausea</td> <td>117</td> <td>(46%)</td> <td>11</td> <td>(33%)</td> <td>15</td> <td>(54%)</td> </tr> <tr> <td> Vomiting NOS</td> <td>112</td> <td>(44%)</td> <td>11</td> <td>(33%)</td> <td>9</td> <td>(32%)</td> </tr> <tr> <td> Constipation</td> <td>64</td> <td>(25%)</td> <td>8</td> <td>(24%)</td> <td>7</td> <td>(25%)</td> </tr> <tr> <td> Diarrhea NOS</td> <td>31</td> <td>(12%)</td> <td>9</td> <td>(27%)</td> <td>9</td> <td>(32%)</td> </tr> <tr> <td> Abdominal pain NOS</td> <td>22</td> <td>(9%)</td> <td>5</td> <td>(15%)</td> <td>4</td> <td>(14%)</td> </tr> <tr> <td> Dysphagia</td> <td>20</td> <td>(8%)</td> <td>3</td> <td>(9%)</td> <td>3</td> <td>(11%)</td> </tr> <tr> <td> Hemorrhoids</td> <td>8</td> <td>(3%)</td> <td>0</td> <td>(0%)</td> <td>3</td> <td>(11%)</td> </tr> <tr> <td styleCode="bold toprule">Musculoskeletal and Connective Tissue Disorders</td> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> </tr> <tr> <td> Back pain</td> <td>61</td> <td>(24%)</td> <td>7</td> <td>(21%)</td> <td>5</td> <td>(18%)</td> </tr> <tr> <td> Pain in limb</td> <td>39</td> <td>(15%)</td> <td>4</td> <td>(12%)</td> <td>8</td> <td>(29%)</td> </tr> <tr> <td> Neck pain</td> <td>36</td> <td>(14%)</td> <td>5</td> <td>(15%)</td> <td>3</td> <td>(11%)</td> </tr> <tr> <td> Arthralgia</td> <td>29</td> <td>(11%)</td> <td>3</td> <td>(9%)</td> <td>4</td> <td>(14%)</td> </tr> <tr> <td> Neck stiffness</td> <td>28</td> <td>(11%)</td> <td>2</td> <td>(6%)</td> <td>4</td> <td>(14%)</td> </tr> <tr> <td> Muscle weakness NOS</td> <td>25</td> <td>(10%)</td> <td>5</td> <td>(15%)</td> <td>2</td> <td>(7%)</td> </tr> <tr> <td styleCode="bold toprule">Psychiatric Disorders</td> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> </tr> <tr> <td> Insomnia</td> <td>35</td> <td>(14%)</td> <td>6</td> <td>(18%)</td> <td>7</td> <td>(25%)</td> </tr> <tr> <td> Agitation</td> <td>26</td> <td>(10%)</td> <td>5</td> <td>(15%)</td> <td>2</td> <td>(7%)</td> </tr> <tr> <td> Depression</td> <td>21</td> <td>(8%)</td> <td>6</td> <td>(18%)</td> <td>4</td> <td>(14%)</td> </tr> <tr> <td> Anxiety</td> <td>17</td> <td>(7%)</td> <td>1</td> <td>(3%)</td> <td>3</td> <td>(11%)</td> </tr> <tr> <td styleCode="bold toprule">Infections and Infestations</td> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> </tr> <tr> <td> Urinary tract infection NOS</td> <td>35</td> <td>(14%)</td> <td>6</td> <td>(18%)</td> <td>5</td> <td>(18%)</td> </tr> <tr> <td> Pneumonia NOS</td> <td>16</td> <td>(6%)</td> <td>2</td> <td>(6%)</td> <td>3</td> <td>(11%)</td> </tr> <tr> <td styleCode="bold toprule">Metabolism and Nutrition Disorders</td> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> </tr> <tr> <td> Dehydration</td> <td>33</td> <td>(13%)</td> <td>6</td> <td>(18%)</td> <td>3</td> <td>(11%)</td> </tr> <tr> <td> Appetite decreased NOS</td> <td>29</td> <td>(11%)</td> <td>4</td> <td>(12%)</td> <td>3</td> <td>(11%)</td> </tr> <tr> <td> Hyponatremia</td> <td>18</td> <td>(7%)</td> <td>4</td> <td>(12%)</td> <td>1</td> <td>(4%)</td> </tr> <tr> <td> Hypokalemia</td> <td>17</td> <td>(7%)</td> <td>5</td> <td>(15%)</td> <td>2</td> <td>(7%)</td> </tr> <tr> <td> Hyperglycemia</td> <td>15</td> <td>(6%)</td> <td>4</td> <td>(12%)</td> <td>2</td> <td>(7%)</td> </tr> <tr> <td> Anorexia</td> <td>14</td> <td>(5%)</td> <td>1</td> <td>(3%)</td> <td>5</td> <td>(18%)</td> </tr> <tr> <td styleCode="bold toprule">Investigations</td> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> </tr> <tr> <td> Platelet count decreased</td> <td>8</td> <td>(3%)</td> <td>0</td> <td>(0%)</td> <td>3</td> <td>(11%)</td> </tr> <tr> <td styleCode="bold toprule">Renal and Urinary Disorders</td> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> </tr> <tr> <td> Incontinence NOS</td> <td>19</td> <td>(7%)</td> <td>3</td> <td>(9%)</td> <td>5</td> <td>(18%)</td> </tr> <tr> <td> Urinary retention</td> <td>14</td> <td>(5%)</td> <td>0</td> <td>(0%)</td> <td>3</td> <td>(11%)</td> </tr> <tr> <td styleCode="bold toprule">Respiratory, Thoracic and Mediastinal Disorders</td> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> </tr> <tr> <td> Dyspnea NOS</td> <td>25</td> <td>(10%)</td> <td>4</td> <td>(12%)</td> <td>6</td> <td>(21%)</td> </tr> <tr> <td> Cough</td> <td>17</td> <td>(7%)</td> <td>3</td> <td>(9%)</td> <td>6</td> <td>(21%)</td> </tr> <tr> <td styleCode="bold toprule">Eye Disorders</td> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> </tr> <tr> <td> Vision blurred</td> <td>29</td> <td>(11%)</td> <td>4</td> <td>(12%)</td> <td>4</td> <td>(14%)</td> </tr> <tr> <td styleCode="bold toprule">Blood and Lymphatic Disorders</td> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> </tr> <tr> <td> Anemia NOS</td> <td>31</td> <td>(12%)</td> <td>6</td> <td>(18%)</td> <td>5</td> <td>(18%)</td> </tr> <tr> <td> Thrombocytopenia</td> <td>27</td> <td>(11%)</td> <td>8</td> <td>(24%)</td> <td>9</td> <td>(32%)</td> </tr> <tr> <td> Neutropenia</td> <td>26</td> <td>(10%)</td> <td>12</td> <td>(36%)</td> <td>7</td> <td>(25%)</td> </tr> <tr> <td styleCode="bold toprule">Skin and Subcutaneous Tissue Disorders</td> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> </tr> <tr> <td> Contusion</td> <td>6</td> <td>(2%)</td> <td>1</td> <td>(3%)</td> <td>3</td> <td>(11%)</td> </tr> <tr> <td> Pruritus NOS</td> <td>6</td> <td>(2%)</td> <td>0</td> <td>(0%)</td> <td>4</td> <td>(14%)</td> </tr> <tr> <td> Sweating increased</td> <td>6</td> <td>(2%)</td> <td>1</td> <td>(3%)</td> <td>3</td> <td>(11%)</td> </tr> <tr> <td styleCode="bold toprule">Vascular Disorders</td> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> </tr> <tr> <td> Hypotension NOS</td> <td>21</td> <td>(8%)</td> <td>6</td> <td>(18%)</td> <td>2</td> <td>(7%)</td> </tr> <tr> <td> Hypertension NOS</td> <td>15</td> <td>(6%)</td> <td>5</td> <td>(15%)</td> <td>1</td> <td>(4%)</td> </tr> <tr> <td styleCode="bold toprule">Ear and Labyrinth Disorders</td> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> </tr> <tr> <td> Hypacusis</td> <td>15</td> <td>(6%)</td> <td>6</td> <td>(18%)</td> <td>3</td> <td>(11%)</td> </tr> <tr> <td styleCode="bold toprule">Cardiac Disorders</td> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> </tr> <tr> <td> Tachycardia NOS</td> <td>22</td> <td>(9%)</td> <td>0</td> <td>(0%)</td> <td>5</td> <td>(18%)</td> </tr> <tr> <td styleCode="bold toprule">Neoplasms Benign, Malignant and Unspecified (Incl Cysts and Polyps)</td> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> <td styleCode="toprule"/> </tr> <tr> <td styleCode="Botrule"> Diffuse Large B-Cell Lymphoma NOS</td> <td styleCode="Botrule">1</td> <td styleCode="Botrule">(0%)</td> <td styleCode="Botrule">1</td> <td styleCode="Botrule">(3%)</td> <td styleCode="Botrule">3</td> <td styleCode="Botrule">(11%)</td> </tr> </tbody> </table>

<table width="900" styleCode="Noautorules" ID="table2"> <caption>Table 2. Incidence of adverse reactions possibly reflecting meningeal irritation occurring in &gt; 10% of all studied adult patients receiving DepoCyt 50 mg or an active comparator*</caption> <col width="40%" align="left"/> <col width="10%" align="center"/> <col width="10%" align="left"/> <col width="10%" align="center"/> <col width="10%" align="left"/> <col width="10%" align="center"/> <col width="10%" align="left"/> <tfoot> <tr> <td colspan="7" styleCode="Toprule">* Hydrocephalus acquired, CSF pleocytosis and meningism occurred in &#x2264; 10% of all studied adult patients receiving DepoCyt or an active comparator</td> </tr> </tfoot> <tbody> <tr> <td styleCode="left Toprule Botrule" valign="middle">System Organ Class / Preferred Term</td> <td valign="bottom" colspan="2" styleCode="Toprule Botrule">DepoCyt (N=257)</td> <td valign="bottom" colspan="2" styleCode="Toprule Botrule">MTX (N=78)</td> <td valign="bottom" colspan="2" styleCode="Toprule Botrule">Ara-C (N=28)</td> </tr> <tr> <td styleCode="bold toprule Botrule">Nervous System Disorders</td> <td styleCode="toprule Botrule"/> <td styleCode="toprule Botrule"/> <td styleCode="toprule Botrule"/> <td styleCode="toprule Botrule"/> <td styleCode="toprule Botrule"/> <td styleCode="toprule Botrule"/> </tr> <tr> <td> Headache NOS</td> <td>145</td> <td>(56%)</td> <td>33</td> <td>(42%)</td> <td>9</td> <td>(32%)</td> </tr> <tr> <td> Arachnoiditis</td> <td>108</td> <td>(42%)</td> <td>15</td> <td>(19%)</td> <td>10</td> <td>(36%)</td> </tr> <tr> <td> Convulsions NOS</td> <td>56</td> <td>(22%)</td> <td>11</td> <td>(14%)</td> <td>1</td> <td>(4%)</td> </tr> <tr> <td styleCode="bold toprule Botrule">Gastrointestinal Disorders</td> <td styleCode="toprule Botrule"/> <td styleCode="toprule Botrule"/> <td styleCode="toprule Botrule"/> <td styleCode="toprule Botrule"/> <td styleCode="toprule Botrule"/> <td styleCode="toprule Botrule"/> </tr> <tr> <td> Nausea</td> <td>117</td> <td>(46%)</td> <td>24</td> <td>(31%)</td> <td>15</td> <td>(54%)</td> </tr> <tr> <td> Vomiting NOS</td> <td>112</td> <td>(44%)</td> <td>22</td> <td>(28%)</td> <td>9</td> <td>(32%)</td> </tr> <tr> <td styleCode="bold toprule Botrule">Musculoskeletal and Connective Tissue Disorders</td> <td styleCode="toprule Botrule"/> <td styleCode="toprule Botrule"/> <td styleCode="toprule Botrule"/> <td styleCode="toprule Botrule"/> <td styleCode="toprule Botrule"/> <td styleCode="toprule Botrule"/> </tr> <tr> <td> Back pain</td> <td>61</td> <td>(24%)</td> <td>15</td> <td>(19%)</td> <td>5</td> <td>(18%)</td> </tr> <tr> <td> Neck pain</td> <td>36</td> <td>(14%)</td> <td>6</td> <td>(8%)</td> <td>3</td> <td>(11%)</td> </tr> <tr> <td> Neck stiffness</td> <td>28</td> <td>(11%)</td> <td>1</td> <td>(1%)</td> <td>4</td> <td>(14%)</td> </tr> <tr> <td styleCode="bold toprule Botrule">General Disorders and Administration Site Conditions</td> <td styleCode="toprule Botrule"/> <td styleCode="toprule Botrule"/> <td styleCode="toprule Botrule"/> <td styleCode="toprule Botrule"/> <td styleCode="toprule Botrule"/> <td styleCode="toprule Botrule"/> </tr> <tr> <td> Pyrexia</td> <td>81</td> <td>(32%)</td> <td>15</td> <td>(19%)</td> <td>12</td> <td>(43%)</td> </tr> </tbody> </table>