Decitabine for Injection is indicated for treatment of adult patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.

{ "type": "p", "children": [], "text": "Decitabine for Injection is indicated for treatment of adult patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups. " }

Pre-Medications and Baseline Testing

Decitabine for Injection Regimen Options

Three Day Regimen

Administer Decitabine for Injection at a dose of 15 mg/m2 by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days. Repeat cycles every 6 weeks upon hematologic recovery (ANC at least 1,000/μL and platelets at least 50,000/μL) for a minimum of 4 cycles. A complete or partial response may take longer than 4 cycles. Delay and reduce dose for hematologic toxicity [see Dosage and Administration (2.2)].

Five Day Regimen

Administer Decitabine for Injection at a dose of 20 mg/m2 by continuous intravenous infusion over 1 hour daily for 5 days. Delay and reduce dose for hematologic toxicity [see Dosage and Administration (2.2)]. Repeat cycles every 4 weeks upon hematologic recovery (ANC at least 1,000/μL and platelets at least 50,000/μL) for a minimum of 4 cycles. A complete or partial response may take longer than 4 cycles.

Patients with Renal or Severe Hepatic Impairment

Treatment with decitabine has not been studied in patients with pre-existing renal or hepatic impairment. For patients with pre-existing renal or hepatic impairment, consider the potential risks and benefits before initiating treatment with Decitabine for Injection.

Hematologic Toxicity

If hematologic recovery from a previous treatment cycle requires more than 6 weeks, delay the next cycle and reduce the dose temporarily by following this algorithm:

Non-hematologic Toxicity

Delay subsequent treatment for any the following non-hematologic toxicities and do not restart until toxicities resolve:

Decitabine for Injection is a cytotoxic drug. Follow special handling and disposal procedures.1

Aseptically reconstitute Decitabine for Injection with room temperature (20°C to 25°C) 10 mL of diluent for Decitabine for Injection. Upon reconstitution, the final concentration of the reconstituted decitabine solution is 5 mg/mL. Dilute the reconstituted solution with 0.9% Sodium Chloride Injection or 5% Dextrose Injection prior to administration. Temperature of the diluent (0.9% Sodium Chloride Injection or 5% Dextrose Injection) depends on time of administration after preparation.

For Administration Within 15 Minutes of Preparation

If Decitabine for Injection is intended to be administered within 15 minutes from the time of preparation, dilute the reconstituted solution with room temperature (20°C to 25°C) 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration of 0.1 mg/mL to 1 mg/mL. Discard unused portion.

For Delayed Administration

If Decitabine for Injection is intended to be administered after 15 minutes of preparation, dilute the reconstituted solution with cold (2°C to 8°C) 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration of 0.1 mg/mL to 1 mg/mL. Store at 2°C to 8°C for up to 7 hours. Diluted stored solution must be used within 7 hours from the time of preparation. Use the diluted, refrigerated solution within 7 hours from the time of preparation or discard. Discard unused portion. 

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 evidence of particulate matter or discoloration.

For Injection: 50 mg of decitabine as a sterile, lyophilized white to off white powder in a single-dose vial for reconstitution with the supplied diluent.

{ "type": "p", "children": [], "text": "For Injection: 50 mg of decitabine as a sterile, lyophilized white to off white powder in a single-dose vial for reconstitution with the supplied diluent." }

None

{ "type": "p", "children": [], "text": "None" }

Fatal and serious myelosuppression occurs in Decitabine for Injection-treated patients. Myelosuppression (anemia, neutropenia, and thrombocytopenia) is the most frequent cause of dose reduction, delay, and discontinuation. Neutropenia of any grade occurred in 90% of decitabine-treated patients with grade 3 or 4 occurring in 87% of patients. Grade 3 or 4 febrile neutropenia occurred in 23% of patients. Thrombocytopenia of any grade occurred in 89% of patients with grade 3 or 4 occurring in 85% of patients. Anemia of any grade occurred in 82% of patients.

Perform complete blood count with platelets at baseline, prior to each cycle, and as needed to monitor response and toxicity. Manage toxicity using dose-delay, dose-reduction, growth factors, and anti-infective therapies as needed [see Dosage and Administration (2.2)]. Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and may not necessarily indicate progression of underlying MDS.

Based on findings from human data, animal studies and its mechanism of action, Decitabine for Injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)]. In preclinical studies in mice and rats, decitabine caused adverse developmental outcomes including embryo-fetal lethality and malformations. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception while receiving Decitabine for Injection and for 6 months following the last dose. Advise males with female partners of reproductive potential to use effective contraception while receiving treatment with Decitabine for Injection and for 3 months following the last dose [see Use in Specific Populations (8.1, 8.3)].

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 safety of decitabine was studied in 3 single-arm studies (N = 66, N = 98, N = 99) and 1 controlled supportive care study (N = 83 decitabine, N = 81 supportive care). The data described below reflect exposure to decitabine in 83 patients in the MDS trial. In the trial, patients received 15 mg/m2 intravenously every 8 hours for 3 days every 6 weeks. The median number of cycles was 3 (range 0 to 9). Most Common Adverse Reactions: neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia.

Adverse Reactions Most Frequently (≥ 1%) Resulting in Clinical Intervention and or Dose Modification in the Controlled Supportive Care Study in the Decitabine Arm: 

Table 1 presents all adverse reactions occurring in at least 5% of patients in the decitabine group and at a rate greater than supportive care.

Table 1Adverse Reactions Reported in ≥ 5% of Patients in the Decitabine Group and at a Rate Greater than Supportive Care in the Controlled Trial in MDS

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="583"> <colgroup> <col width="42.3868312757202%"/> <col width="26.7489711934156%"/> <col width="30.8641975308642%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Decitabine</span> <br/> <span class="Bold">N = 83 (%)</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Supportive Care </span> <br/> <span class="Bold">N = 81 (%)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Blood and lymphatic system disorders </span> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Neutropenia <br/> </td><td align="center" class="Rrule" valign="top">75 (90)<br/> </td><td align="center" class="Rrule" valign="top">58 (72)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Thrombocytopenia <br/> </td><td align="center" class="Rrule" valign="top">74 (89)<br/> </td><td align="center" class="Rrule" valign="top">64 (79)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Anemia NOS <br/> </td><td align="center" class="Rrule" valign="top">68 (82)<br/> </td><td align="center" class="Rrule" valign="top">60 (74)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Febrile neutropenia <br/> </td><td align="center" class="Rrule" valign="top">24 (29)<br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Leukopenia NOS <br/> </td><td align="center" class="Rrule" valign="top">23 (28)<br/> </td><td align="center" class="Rrule" valign="top">11 (14)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Lymphadenopathy <br/> </td><td align="center" class="Rrule" valign="top">10 (12)<br/> </td><td align="center" class="Rrule" valign="top">6 (7)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Thrombocythemia <br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Cardiac disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Pulmonary edema NOS <br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td><td align="center" class="Rrule" valign="top">0 (0)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Eye disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Vision blurred <br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td><td align="center" class="Rrule" valign="top">0 (0)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Gastrointestinal disorders </span> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Nausea <br/> </td><td align="center" class="Rrule" valign="top">35 (42)<br/> </td><td align="center" class="Rrule" valign="top">13 (16)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Constipation <br/> </td><td align="center" class="Rrule" valign="top">29 (35)<br/> </td><td align="center" class="Rrule" valign="top">11 (14)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Diarrhea NOS <br/> </td><td align="center" class="Rrule" valign="top">28 (34)<br/> </td><td align="center" class="Rrule" valign="top">13 (16)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Vomiting NOS <br/> </td><td align="center" class="Rrule" valign="top">21 (25)<br/> </td><td align="center" class="Rrule" valign="top">7 (9)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Abdominal pain NOS <br/> </td><td align="center" class="Rrule" valign="top">12 (14)<br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Oral mucosal petechiae <br/> </td><td align="center" class="Rrule" valign="top">11 (13)<br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Stomatitis <br/> </td><td align="center" class="Rrule" valign="top">10 (12)<br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Dyspepsia <br/> </td><td align="center" class="Rrule" valign="top">10 (12)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Ascites <br/> </td><td align="center" class="Rrule" valign="top">8 (10)<br/> </td><td align="center" class="Rrule" valign="top">2 (2)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Gingival bleeding <br/> </td><td align="center" class="Rrule" valign="top">7 (8)<br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Hemorrhoids <br/> </td><td align="center" class="Rrule" valign="top">7 (8)<br/> </td><td align="center" class="Rrule" valign="top">3 (4)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Loose stools <br/> </td><td align="center" class="Rrule" valign="top">6 (7)<br/> </td><td align="center" class="Rrule" valign="top">3 (4)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Tongue ulceration <br/> </td><td align="center" class="Rrule" valign="top">6 (7)<br/> </td><td align="center" class="Rrule" valign="top">2 (2)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Dysphagia <br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td><td align="center" class="Rrule" valign="top">2 (2)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Oral soft tissue disorder NOS <br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Lip ulceration <br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td><td align="center" class="Rrule" valign="top">3 (4)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Abdominal distension <br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Abdominal pain upper <br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Gastro-esophageal reflux disease <br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td><td align="center" class="Rrule" valign="top">0 (0)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Glossodynia <br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td><td align="center" class="Rrule" valign="top">0 (0)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">General disorders and administrative site disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Pyrexia<br/> </td><td align="center" class="Rrule" valign="top">44 (53)<br/> </td><td align="center" class="Rrule" valign="top">23 (28)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Edema peripheral<br/> </td><td align="center" class="Rrule" valign="top">21 (25)<br/> </td><td align="center" class="Rrule" valign="top">13 (16)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Rigors<br/> </td><td align="center" class="Rrule" valign="top">18 (22)<br/> </td><td align="center" class="Rrule" valign="top">14 (17)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Edema NOS<br/> </td><td align="center" class="Rrule" valign="top">15 (18)<br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Pain NOS<br/> </td><td align="center" class="Rrule" valign="top">11 (13)<br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Lethargy<br/> </td><td align="center" class="Rrule" valign="top">10 (12)<br/> </td><td align="center" class="Rrule" valign="top">3 (4)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Tenderness NOS<br/> </td><td align="center" class="Rrule" valign="top">9 (11)<br/> </td><td align="center" class="Rrule" valign="top">0 (0)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Fall<br/> </td><td align="center" class="Rrule" valign="top">7 (8)<br/> </td><td align="center" class="Rrule" valign="top">3 (4)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Chest discomfort<br/> </td><td align="center" class="Rrule" valign="top">6 (7)<br/> </td><td align="center" class="Rrule" valign="top">3 (4)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Intermittent pyrexia<br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td><td align="center" class="Rrule" valign="top">3 (4)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Malaise<br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Crepitations NOS<br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Catheter site erythema<br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Catheter site pain<br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td><td align="center" class="Rrule" valign="top">0 (0)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Injection site swelling<br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td><td align="center" class="Rrule" valign="top">0 (0)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Hepatobiliary disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Hyperbilirubinemia<br/> </td><td align="center" class="Rrule" valign="top">12 (14)<br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Infections and infestations </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Pneumonia NOS <br/> </td><td align="center" class="Rrule" valign="top">18 (22)<br/> </td><td align="center" class="Rrule" valign="top">11 (14)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Cellulitis <br/> </td><td align="center" class="Rrule" valign="top">10 (12)<br/> </td><td align="center" class="Rrule" valign="top">6 (7)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Candidal infection NOS <br/> </td><td align="center" class="Rrule" valign="top">8 (10)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Catheter related infection <br/> </td><td align="center" class="Rrule" valign="top">7 (8)<br/> </td><td align="center" class="Rrule" valign="top">0 (0)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Urinary tract infection NOS <br/> </td><td align="center" class="Rrule" valign="top">6 (7)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Staphylococcal infection <br/> </td><td align="center" class="Rrule" valign="top">6 (7)<br/> </td><td align="center" class="Rrule" valign="top">0 (0)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Oral candidiasis <br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td><td align="center" class="Rrule" valign="top">2 (2)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Sinusitis NOS <br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td><td align="center" class="Rrule" valign="top">2 (2)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Bacteremia <br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td><td align="center" class="Rrule" valign="top">0 (0)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Injury, poisoning and procedural complications </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Transfusion reaction <br/> </td><td align="center" class="Rrule" valign="top">6 (7)<br/> </td><td align="center" class="Rrule" valign="top">3 (4)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Abrasion NOS <br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Investigations </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Cardiac murmur NOS <br/> </td><td align="center" class="Rrule" valign="top">13 (16)<br/> </td><td align="center" class="Rrule" valign="top">9 (11)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Blood alkaline   phosphatase NOS <br/>  increased <br/> </td><td align="center" class="Rrule" valign="top">9 (11)<br/> </td><td align="center" class="Rrule" valign="top">7 (9)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Aspartate aminotransferase <br/>  increased <br/> </td><td align="center" class="Rrule" valign="top">8 (10)<br/> </td><td align="center" class="Rrule" valign="top">7 (9)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Blood urea increased <br/> </td><td align="center" class="Rrule" valign="top">8 (10)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Blood lactate dehydrogenase <br/>  increased <br/> </td><td align="center" class="Rrule" valign="top">7 (8)<br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Blood albumin decreased <br/> </td><td align="center" class="Rrule" valign="top">6 (7)<br/> </td><td align="center" class="Rrule" valign="top">0 (0)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Blood bicarbonate increased <br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Blood chloride decreased <br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Protein total decreased <br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td><td align="center" class="Rrule" valign="top">3 (4)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Blood bicarbonate decreased <br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Blood bilirubin decreased <br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Metabolism and nutrition disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Hyperglycemia NOS <br/> </td><td align="center" class="Rrule" valign="top">27 (33)<br/> </td><td align="center" class="Rrule" valign="top">16 (20)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Hypoalbuminemia <br/> </td><td align="center" class="Rrule" valign="top">20 (24)<br/> </td><td align="center" class="Rrule" valign="top">14 (17)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Hypomagnesemia <br/> </td><td align="center" class="Rrule" valign="top">20 (24)<br/> </td><td align="center" class="Rrule" valign="top">6 (7)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Hypokalemia <br/> </td><td align="center" class="Rrule" valign="top">18 (22)<br/> </td><td align="center" class="Rrule" valign="top">10 (12)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Hyponatremia <br/> </td><td align="center" class="Rrule" valign="top">16 (19)<br/> </td><td align="center" class="Rrule" valign="top">13 (16)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Appetite decreased NOS <br/> </td><td align="center" class="Rrule" valign="top">13 (16)<br/> </td><td align="center" class="Rrule" valign="top">12 (15)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Anorexia <br/> </td><td align="center" class="Rrule" valign="top">13 (16)<br/> </td><td align="center" class="Rrule" valign="top">8 (10)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Hyperkalemia <br/> </td><td align="center" class="Rrule" valign="top">11 (13)<br/> </td><td align="center" class="Rrule" valign="top">3 (4)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Dehydration <br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Musculoskeletal and connective tissue disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Arthralgia <br/> </td><td align="center" class="Rrule" valign="top">17 (20)<br/> </td><td align="center" class="Rrule" valign="top">8 (10)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Pain in limb <br/> </td><td align="center" class="Rrule" valign="top">16 (19)<br/> </td><td align="center" class="Rrule" valign="top">8 (10)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Back pain <br/> </td><td align="center" class="Rrule" valign="top">14 (17)<br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Chest wall pain <br/> </td><td align="center" class="Rrule" valign="top">6 (7)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Musculoskeletal discomfort <br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td><td align="center" class="Rrule" valign="top">0 (0)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Myalgia <br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Nervous system disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Headache <br/> </td><td align="center" class="Rrule" valign="top">23 (28)<br/> </td><td align="center" class="Rrule" valign="top">11 (14)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Dizziness <br/> </td><td align="center" class="Rrule" valign="top">15 (18)<br/> </td><td align="center" class="Rrule" valign="top">10 (12)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Hypoesthesia <br/> </td><td align="center" class="Rrule" valign="top">9 (11)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Psychiatric disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Insomnia <br/> </td><td align="center" class="Rrule" valign="top">23 (28)<br/> </td><td align="center" class="Rrule" valign="top">11 (14)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Confusional state <br/> </td><td align="center" class="Rrule" valign="top">10 (12)<br/> </td><td align="center" class="Rrule" valign="top">3 (4)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Anxiety <br/> </td><td align="center" class="Rrule" valign="top">9 (11)<br/> </td><td align="center" class="Rrule" valign="top">8 (10)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Renal and urinary disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Dysuria <br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td><td align="center" class="Rrule" valign="top">3 (4)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Urinary frequency <br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Respiratory, thoracic and Mediastinal disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Cough <br/> </td><td align="center" class="Rrule" valign="top">33 (40)<br/> </td><td align="center" class="Rrule" valign="top">25 (31)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Pharyngitis <br/> </td><td align="center" class="Rrule" valign="top">13 (16)<br/> </td><td align="center" class="Rrule" valign="top">6 (7)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Crackles lung <br/> </td><td align="center" class="Rrule" valign="top">12 (14)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Breath sounds decreased <br/> </td><td align="center" class="Rrule" valign="top">8 (10)<br/> </td><td align="center" class="Rrule" valign="top">7 (9)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Hypoxia <br/> </td><td align="center" class="Rrule" valign="top">8 (10)<br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Rales <br/> </td><td align="center" class="Rrule" valign="top">7 (8)<br/> </td><td align="center" class="Rrule" valign="top">2 (2)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Postnasal drip <br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td><td align="center" class="Rrule" valign="top">2 (2)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Skin and subcutaneous tissue disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Ecchymosis <br/> </td><td align="center" class="Rrule" valign="top">18 (22)<br/> </td><td align="center" class="Rrule" valign="top">12 (15)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Rash NOS <br/> </td><td align="center" class="Rrule" valign="top">16 (19)<br/> </td><td align="center" class="Rrule" valign="top">7 (9)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Erythema <br/> </td><td align="center" class="Rrule" valign="top">12 (14)<br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Skin lesion NOS <br/> </td><td align="center" class="Rrule" valign="top">9 (11)<br/> </td><td align="center" class="Rrule" valign="top">3 (4)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Pruritis <br/> </td><td align="center" class="Rrule" valign="top">9 (11)<br/> </td><td align="center" class="Rrule" valign="top">2 (2)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Alopecia <br/> </td><td align="center" class="Rrule" valign="top">7 (8)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Urticaria NOS <br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Swelling face <br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td><td align="center" class="Rrule" valign="top">0 (0)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"><span class="Bold">Vascular disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Petechiae <br/> </td><td align="center" class="Rrule" valign="top">32 (39)<br/> </td><td align="center" class="Rrule" valign="top">13 (16)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Pallor <br/> </td><td align="center" class="Rrule" valign="top">19 (23)<br/> </td><td align="center" class="Rrule" valign="top">10 (12)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Hypotension NOS <br/> </td><td align="center" class="Rrule" valign="top">5 (6)<br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">  Hematoma NOS <br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td><td align="center" class="Rrule" valign="top">3 (4)<br/> </td> </tr> </tbody> </table></div>

In a single-arm MDS study (N=99) decitabine was dosed at 20 mg/m2 intravenously, infused over one hour daily, for 5 consecutive days of a 4-week cycle. Table 2 presents all adverse reactions occurring in at least 5% of patients.

Table 2 Adverse Reactions Reported in ≥ 5% of Patients in a Single-arm Study1

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="565"> <colgroup> <col width="66.0297239915074%"/> <col width="33.9702760084926%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Decitabine</span> <br/> <span class="Bold">N = 99 (%)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Blood and lymphatic system disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Anemia <br/> </td><td align="center" class="Rrule" valign="top">31 (31)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Febrile neutropenia <br/> </td><td align="center" class="Rrule" valign="top">20 (20)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Leukopenia <br/> </td><td align="center" class="Rrule" valign="top">6 (6)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Neutropenia <br/> </td><td align="center" class="Rrule" valign="top">38 (38)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Pancytopenia <br/> </td><td align="center" class="Rrule" valign="top">5 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Thrombocythemia<br/> </td><td align="center" class="Rrule" valign="top">5 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Thrombocytopenia <br/> </td><td align="center" class="Rrule" valign="top">27 (27)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Cardiac disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Cardiac failure congestive <br/> </td><td align="center" class="Rrule" valign="top">5 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Tachycardia <br/> </td><td align="center" class="Rrule" valign="top">8 (8)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Ear and labyrinth disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Ear pain <br/> </td><td align="center" class="Rrule" valign="top">6 (6)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Gastrointestinal disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Abdominal pain <br/> </td><td align="center" class="Rrule" valign="top">14 (14)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Abdominal pain upper <br/> </td><td align="center" class="Rrule" valign="top">6 (6)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Constipation <br/> </td><td align="center" class="Rrule" valign="top">30 (30)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Diarrhea <br/> </td><td align="center" class="Rrule" valign="top">28 (28)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Dyspepsia <br/> </td><td align="center" class="Rrule" valign="top">10 (10)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Dysphagia <br/> </td><td align="center" class="Rrule" valign="top">5 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Gastro-esophageal reflux disease <br/> </td><td align="center" class="Rrule" valign="top">5 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Nausea <br/> </td><td align="center" class="Rrule" valign="top">40 (40)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Oral pain <br/> </td><td align="center" class="Rrule" valign="top">5 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Stomatitis <br/> </td><td align="center" class="Rrule" valign="top">11 (11)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Toothache <br/> </td><td align="center" class="Rrule" valign="top">6 (6)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Vomiting <br/> </td><td align="center" class="Rrule" valign="top">16 (16)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">General disorders and administration site conditions </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Asthenia <br/> </td><td align="center" class="Rrule" valign="top">15 (15)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Chest pain <br/> </td><td align="center" class="Rrule" valign="top">6 (6)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Chills <br/> </td><td align="center" class="Rrule" valign="top">16 (16)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Fatigue <br/> </td><td align="center" class="Rrule" valign="top">46 (46)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Mucosal inflammation <br/> </td><td align="center" class="Rrule" valign="top">9 (9)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Edema <br/> </td><td align="center" class="Rrule" valign="top">5 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Edema peripheral <br/> </td><td align="center" class="Rrule" valign="top">27 (27)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Pain<br/> </td><td align="center" class="Rrule" valign="top">5 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Pyrexia <br/> </td><td align="center" class="Rrule" valign="top">36 (36)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Infections and infestations </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Cellulitis<br/> </td><td align="center" class="Rrule" valign="top">9 (9)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Oral candidiasis <br/> </td><td align="center" class="Rrule" valign="top">6 (6)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Pneumonia <br/> </td><td align="center" class="Rrule" valign="top">20 (20)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Sinusitis <br/> </td><td align="center" class="Rrule" valign="top">6 (6)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Staphylococcal bacteremia <br/> </td><td align="center" class="Rrule" valign="top">8 (8)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Tooth abscess <br/> </td><td align="center" class="Rrule" valign="top">5 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Upper respiratory tract infection <br/> </td><td align="center" class="Rrule" valign="top">10 (10)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Urinary tract infection <br/> </td><td align="center" class="Rrule" valign="top">7 (7)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Injury, poisoning and procedural complications </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Contusion <br/> </td><td align="center" class="Rrule" valign="top">9 (9)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Investigations</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Blood bilirubin increased <br/> </td><td align="center" class="Rrule" valign="top">6 (6)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Breath sounds abnormal <br/> </td><td align="center" class="Rrule" valign="top">5 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Weight decreased <br/> </td><td align="center" class="Rrule" valign="top">9 (9)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Metabolism and nutrition disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Anorexia <br/> </td><td align="center" class="Rrule" valign="top">23 (23)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Decreased appetite <br/> </td><td align="center" class="Rrule" valign="top">8 (8)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Dehydration <br/> </td><td align="center" class="Rrule" valign="top">8 (8)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Hyperglycemia <br/> </td><td align="center" class="Rrule" valign="top">6 (6)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Hypokalemia <br/> </td><td align="center" class="Rrule" valign="top">12 (12)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Hypomagnesemia <br/> </td><td align="center" class="Rrule" valign="top">5 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Musculoskeletal and connective tissue disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Arthralgia <br/> </td><td align="center" class="Rrule" valign="top">17 (17)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Back pain <br/> </td><td align="center" class="Rrule" valign="top">18 (18)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Bone pain <br/> </td><td align="center" class="Rrule" valign="top">6 (6)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Muscle spasms <br/> </td><td align="center" class="Rrule" valign="top">7 (7)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Muscular weakness <br/> </td><td align="center" class="Rrule" valign="top">5 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Musculoskeletal pain <br/> </td><td align="center" class="Rrule" valign="top">5 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Myalgia <br/> </td><td align="center" class="Rrule" valign="top">9 (9)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Pain in extremity <br/> </td><td align="center" class="Rrule" valign="top">18 (18)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Nervous system disorders </span> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Dizziness <br/> </td><td align="center" class="Rrule" valign="top">21 (21)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Headache <br/> </td><td align="center" class="Rrule" valign="top">23 (23)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Psychiatric disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Anxiety<br/> </td><td align="center" class="Rrule" valign="top">9 (9)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Confusional state <br/> </td><td align="center" class="Rrule" valign="top">8 (8)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Depression <br/> </td><td align="center" class="Rrule" valign="top">9 (9)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Insomnia <br/> </td><td align="center" class="Rrule" valign="top">14 (14)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Respiratory, thoracic and mediastinal disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Cough <br/> </td><td align="center" class="Rrule" valign="top">27 (27)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Dyspnea <br/> </td><td align="center" class="Rrule" valign="top">29 (29)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Epistaxis <br/> </td><td align="center" class="Rrule" valign="top">13 (13)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Pharyngolaryngeal pain <br/> </td><td align="center" class="Rrule" valign="top">8 (8)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Pleural effusion <br/> </td><td align="center" class="Rrule" valign="top">5 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Sinus congestion <br/> </td><td align="center" class="Rrule" valign="top">5 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Skin and subcutaneous tissue disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Dry skin <br/> </td><td align="center" class="Rrule" valign="top">8 (8)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Ecchymosis <br/> </td><td align="center" class="Rrule" valign="top">9 (9)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Erythema <br/> </td><td align="center" class="Rrule" valign="top">5 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Night sweats <br/> </td><td align="center" class="Rrule" valign="top">5 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Petechiae <br/> </td><td align="center" class="Rrule" valign="top">12 (12)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Pruritus <br/> </td><td align="center" class="Rrule" valign="top">9 (9)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Rash <br/> </td><td align="center" class="Rrule" valign="top">11 (11)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Skin lesion <br/> </td><td align="center" class="Rrule" valign="top">5 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Vascular disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  Hypertension <br/> </td><td align="center" class="Rrule" valign="top">6 (6)<br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">  Hypotension <br/> </td><td align="center" class="Rrule" valign="top">11 (11)<br/> </td> </tr> </tbody> </table></div>

1In this single arm study, investigators reported adverse events based on clinical signs and symptoms rather than predefined laboratory abnormalities. Thus, not all laboratory abnormalities were recorded as adverse events. 

No overall difference in safety was detected between patients > 65 years of age and younger patients in these MDS trials. No significant differences in safety were detected between males and females. Patients with renal or hepatic dysfunction were not studied. Insufficient numbers of non-White patients were available to draw conclusions in these clinical trials.

Serious adverse reactions that occurred in patients receiving decitabine not previously reported in Tables 1 and 2 include: 

The following adverse reactions have been identified during postapproval use of decitabine. 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.

Drug interaction studies with decitabine have not been conducted. In vitro studies in human liver microsomes suggest that decitabine is unlikely to inhibit or induce cytochrome P450 enzymes. In vitro metabolism studies have suggested that decitabine is not a substrate for human liver cytochrome P450 enzymes. As plasma protein binding of decitabine is negligible (<1%), interactions due to displacement of more highly protein bound drugs from plasma proteins are not expected.

{ "type": "p", "children": [], "text": "Drug interaction studies with decitabine have not been conducted. In vitro studies in human liver microsomes suggest that decitabine is unlikely to inhibit or induce cytochrome P450 enzymes. In vitro metabolism studies have suggested that decitabine is not a substrate for human liver cytochrome P450 enzymes. As plasma protein binding of decitabine is negligible (<1%), interactions due to displacement of more highly protein bound drugs from plasma proteins are not expected. " }

Risk Summary

Based on findings from human data, animal studies, and the mechanism of action, Decitabine for Injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)and Nonclinical Toxicology (13.1)]. Limited published data on decitabine use throughout the first trimester during pregnancy describe adverse developmental outcomes including major birth defects (structural abnormalities). In animal reproduction studies, administration of decitabine to pregnant mice and rats during organogenesis caused adverse developmental outcomes including malformations and embryo-fetal lethality starting at doses approximately 7% of the recommended human dose on a mg/m2 basis (see Data). Advise pregnant women of the potential risk to a fetus. 

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

Data

Human Data

A single published case report of decitabine pregnancy exposure in a 39-year old woman with a hematologic malignancy described multiple structural abnormalities after 6 cycles of therapy in the 18th week of gestation. These abnormalities included holoprosencephaly, absence of nasal bone, mid-facial deformity, cleft lip and palate, polydactyly and rocker-bottom feet. The pregnancy was terminated.

Animal Data

In utero exposure to decitabine causes temporal related defects in the rat and/or mouse, which include growth suppression, exencephaly, defective skull bones, rib/sternabrae defects, phocomelia, digit defects, micrognathia, gastroschisis, micromelia. Decitabine inhibits proliferation and increases apoptosis of neural progenitor cells of the fetal CNS and induces palatal clefting in the developing murine fetus. Studies in mice have also shown that decitabine administration during osteoblastogenesis (day 10 of gestation) induces bone loss in offspring.

In mice exposed to single IP (intraperitoneal) injections (0, 0.9 and 3.0 mg/m2, approximately 2% and 7% of the recommended daily clinical dose, respectively) over gestation days 8, 9, 10 or 11, no maternal toxicity was observed but reduced fetal survival was observed after treatment at 3 mg/m2 and decreased fetal weight was observed at both dose levels. The 3 mg/m2 dose elicited characteristic fetal defects for each treatment day, including supernumerary ribs (both dose levels), fused vertebrae and ribs, cleft palate, vertebral defects, hind-limb defects and digital defects of fore- and hind-limbs.

In rats given a single IP injection of 2.4, 3.6 or 6 mg/m2 (approximately 5%, 8%, or 13% the daily recommended clinical dose, respectively) on gestation days 9 to 12, no maternal toxicity was observed. No live fetuses were seen at any dose when decitabine was injected on gestation day 9. A significant decrease in fetal survival and reduced fetal weight at doses greater than 3.6 mg/m2 was seen when decitabine was given on gestation day 10. Increased incidences of vertebral and rib anomalies were seen at all dose levels, and induction of exophthalmia, exencephaly, and cleft palate were observed at 6.0 mg/m2. Increased incidence of foredigit defects was seen in fetuses at doses greater than 3.6 mg/m2. Reduced size and ossification of long bones of the fore-limb and hind-limb were noted at 6.0 mg/m2.

The effect of decitabine on postnatal development and reproductive capacity was evaluated in mice administered a single 3 mg/m2 IP injection (approximately 7% the recommended daily clinical dose) on day 10 of gestation. Body weights of males and females exposed in utero to decitabine were significantly reduced relative to controls at all postnatal time points. No consistent effect on fertility was seen when female mice exposed in utero were mated to untreated males. Untreated females mated to males exposed in utero showed decreased fertility at 3 and 5 months of age (36% and 0% pregnancy rate, respectively). Follow up studies indicated that treatment of pregnant mice with decitabine on gestation day 10 was associated with a reduced pregnancy rate resulting from effects on sperm production in the F1-generation.

Risk Summary

There are no data on the presence of decitabine or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions from decitabine in a breastfed child, advise women not to breastfeed while receiving Decitabine for Injection and for at least 2 weeks after the last dose.

Pregnancy Testing

Conduct pregnancy testing of females of reproductive potential prior to initiating Decitabine for njection.

ContraceptionI

Females

Decitabine for Injection can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception while receiving Decitabine for Injection and for 6 months following the last dose.

Males

Advise males with female partners of reproductive potential to use effective contraception while receiving treatment with Decitabine for Injection and for 3 months following the last dose [see Nonclinical Toxicology (13.1)].

Infertility

Based on findings of decitabine in animals, male fertility may be compromised by treatment with decitabine. The reversibility of the effect on fertility is unknown [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of Decitabine for Injection in pediatric patients have not been established.

Of the total number of patients exposed to decitabine in the controlled clinical trial, 61 of 83 patients were age 65 years and over, while 21 of 83 patients were age 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and 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.

There is no known antidote for overdosage with decitabine. Higher doses are associated with increased myelosuppression including prolonged neutropenia and thrombocytopenia. Standard supportive measures should be taken in the event of an overdose.

{ "type": "p", "children": [], "text": "There is no known antidote for overdosage with decitabine. Higher doses are associated with increased myelosuppression including prolonged neutropenia and thrombocytopenia. Standard supportive measures should be taken in the event of an overdose. " }

Decitabine is a nucleoside metabolic inhibitor. Decitabine is a fine, white to almost white powder with the molecular formula of C8H12N4O4 and a molecular weight of 228.21. Its chemical name is 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1,3,5-triazin­-2(1H)-one and it has the following structural formula:

{ "type": "p", "children": [], "text": "Decitabine is a nucleoside metabolic inhibitor. Decitabine is a fine, white to almost white powder with the molecular formula of C8H12N4O4 and a molecular weight of 228.21. Its chemical name is 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1,3,5-triazin­-2(1H)-one and it has the following structural formula:" }

Decitabine is slightly soluble in ethanol/water (50/50), methanol/water (50/50) and methanol; sparingly soluble in water and soluble in dimethylsulfoxide (DMSO).

{ "type": "p", "children": [], "text": "Decitabine is slightly soluble in ethanol/water (50/50), methanol/water (50/50) and methanol; sparingly soluble in water and soluble in dimethylsulfoxide (DMSO). " }

DRUG PRODUCT

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

White to off white lyophilized powder in 20 mL colorless tubular glass single-dose vial with grey bromo butyl rubber stopper and sealed with baby blue flip top aluminum seal.

{ "type": "p", "children": [], "text": "White to off white lyophilized powder in 20 mL colorless tubular glass single-dose vial with grey bromo butyl rubber stopper and sealed with baby blue flip top aluminum seal." }

Each vial contains 50 mg decitabine.

{ "type": "p", "children": [], "text": "Each vial contains 50 mg decitabine." }

DILUENT

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

Clear colorless solution filled in 10 mL colorless tubular glass vial with grey bromo butyl stopper sealed with transparent flip top aluminum seal.

{ "type": "p", "children": [], "text": "Clear colorless solution filled in 10 mL colorless tubular glass vial with grey bromo butyl stopper sealed with transparent flip top aluminum seal." }

Each vial contains 68 mg monobasic potassium phosphate, 11.6 mg sodium hydroxide and 10 mL water for injection.

{ "type": "p", "children": [], "text": "Each vial contains 68 mg monobasic potassium phosphate, 11.6 mg sodium hydroxide and 10 mL water for injection." }

Decitabine is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation or apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. Decitabine-induced hypomethylation in neoplastic cells may restore normal function to genes that are critical for the control of cellular differentiation and proliferation. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and decitabine incorporated into DNA. Non-proliferating cells are relatively insensitive to decitabine.

Decitabine has been shown to induce hypomethylation both in vitro and in vivo. However, there have been no studies of decitabine-­induced hypomethylation and pharmacokinetic parameters.

Pharmacokinetic (PK) parameters were evaluated in patients. Eleven patients received 20 mg/m2 infused over 1 hour intravenously (treatment Option 2). Fourteen patients received 15 mg/m2 infused over 3 hours intravenously (treatment Option 1). PK parameters are shown in Table 3. Plasma concentration-time profiles after discontinuation of infusion showed a biexponential decline. The clearance (CL) of decitabine was higher following treatment Option 2. Upon repeat doses, there was no systemic accumulation of decitabine or any changes in PK parameters. Population PK analysis (N=35) showed that the cumulative AUC per cycle for treatment Option 2 was 2.3-fold lower than the cumulative AUC per cycle following treatment Option 1.

Table 3 Mean (CV% or 95% CI) Pharmacokinetic Parameters of Decitabine

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="675"> <colgroup> <col width="22.7829350187636%"/> <col width="14.8824807426427%"/> <col width="14.7936006320363%"/> <col width="10.5569820264665%"/> <col width="13.1542563697413%"/> <col width="23.8297452103496%"/> </colgroup> <tfoot> <tr> <td align="left" colspan="6"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>N=35 Cumulative AUC per cycle</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>N=14</dd> <dt> <a href="#footnote-reference-3" name="footnote-3">‡</a> </dt> <dd>N=11</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Dose </span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">C<span class="Sub">max</span>         (ng/mL)</span> <br/> </td><td class="Rrule" valign="top"> <br/> <span class="Bold"> <br/>AUC<span class="Sub">0-INF</span></span> <br/> <span class="Bold"> <br/> (ng·h/mL)</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">T<span class="Sub">½</span></span> <br/> <span class="Bold">(h)</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">CL (L/h/m<span class="Sup">2</span>)</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">AUC<span class="Sub">Cumulative</span> (ng·h/mL)<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">15 mg/m<span class="Sup">2</span> 3-hr infusion every 8 hours for 3 days (Option 1) <a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a> <br/> </td><td align="center" class="Rrule" valign="top">73.8     (66)<br/> </td><td align="center" class="Rrule" valign="top">163 <br/>(62)<br/> </td><td align="center" class="Rrule" valign="top">0.62 (49)<br/> </td><td align="center" class="Rrule" valign="top">125<br/>(53)<br/> </td><td align="center" class="Rrule" valign="top">1332<br/>(1010 to 1730)<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">20 mg/m<span class="Sup">2</span> 1-hr infusion daily for 5 days (Option 2)<a class="Sup" href="#footnote-3" name="footnote-reference-3">‡</a> <br/> </td><td align="center" class="Rrule" valign="top">147      (49)<br/> </td><td align="center" class="Rrule" valign="top">115  <br/>(43)<br/> </td><td align="center" class="Rrule" valign="top">0.54 (43)<br/> </td><td align="center" class="Rrule" valign="top">210 <br/>(47)<br/> </td><td align="center" class="Rrule" valign="top">570 <br/>(470 to 700)<br/> </td> </tr> </tbody> </table></div>

The exact route of elimination and metabolic fate of decitabine is not known in humans. One of the pathways of elimination of decitabine appears to be deamination by cytidine deaminase found principally in the liver but also in granulocytes, intestinal epithelium and whole blood.

Specific Populations

Patients with Renal Impairment

There are no data on the use of decitabine in patients with renal impairment.

Patients with Hepatic Impairment

There are no data on the use of decitabine in patients with hepatic impairment.

Carcinogenicity studies with decitabine have not been conducted.

The mutagenic potential of decitabine was tested in several in vitro and in vivo systems. Decitabine increased mutation frequency in L5178Y mouse lymphoma cells, and mutations were produced in an Escherichia coli lac-I transgene in colonic DNA of decitabine-treated mice. Decitabine caused chromosomal rearrangements in larvae of fruit flies.

In male mice given IP injections of 0.15, 0.3 or 0.45 mg/m2 decitabine (approximately 0.3% to 1% the recommended clinical dose) 3 times a week for 7 weeks, decitabine did not affect survival, body weight gain or hematological measures (hemoglobin and white blood cell counts). Testes weights were reduced, abnormal histology was observed and significant decreases in sperm number were found at doses ≥ 0.3 mg/m2. In females mated to males dosed with ≥ 0.3 mg/m2 decitabine, pregnancy rate was reduced and preimplantation loss was significantly increased.

A randomized open-label, multicenter, controlled trial evaluated 170 adult patients with myelodysplastic syndromes (MDS) meeting French-American-British (FAB) classification criteria and International Prognostic Scoring System (IPSS) High-Risk, Intermediate-2 and Intermediate-1 prognostic scores. Eighty-nine patients were randomized to decitabine plus supportive care (only 83 received decitabine), and 81 to Supportive Care (SC) alone. Patients with Acute Myeloid Leukemia (AML) were not intended to be included. Of the 170 patients included in the study, independent review (adjudicated diagnosis) found that 12 patients (9 in the decitabine group and 3 in the SC group) had the diagnosis of AML at baseline. Baseline demographics and other patient characteristics in the Intent-to-Treat (ITT) population were similar between the 2 groups, as shown in Table 4.

Table 4 Baseline Demographics and Other Patient Characteristics (ITT)

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="583"> <colgroup> <col width="53.7037037037037%"/> <col width="25.7201646090535%"/> <col width="20.5761316872428%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Demographic or Other Patient </span> <br/> <span class="Bold">Characteristic </span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Decitabine</span> <br/> <span class="Bold">N = 89</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Supportive Care</span> <br/> <span class="Bold">N= 81</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Age (years) </span> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Mean (±SD) <br/> </td><td align="center" class="Rrule" valign="top">69±10<br/> </td><td align="center" class="Rrule" valign="top">67±10<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Median (IQR) <br/> </td><td align="center" class="Rrule" valign="top">70 (65 to 76)<br/> </td><td align="center" class="Rrule" valign="top">70 (62 to 74)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">(Range: min-max) <br/> </td><td align="center" class="Rrule" valign="top">(31 to 85)<br/> </td><td align="center" class="Rrule" valign="top">(30 to 82)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Sex n (%) </span> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Male <br/> </td><td align="center" class="Rrule" valign="top">59 (66)<br/> </td><td align="center" class="Rrule" valign="top">57 (70)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Female <br/> </td><td align="center" class="Rrule" valign="top">30 (34)<br/> </td><td align="center" class="Rrule" valign="top">24 (30)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Race n (%) </span> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">White <br/> </td><td align="center" class="Rrule" valign="top">83 (93)<br/> </td><td align="center" class="Rrule" valign="top">76 (94)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Black <br/> </td><td align="center" class="Rrule" valign="top">4 (4)<br/> </td><td align="center" class="Rrule" valign="top">2 (2)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Other <br/> </td><td align="center" class="Rrule" valign="top">2 (2)<br/> </td><td align="center" class="Rrule" valign="top">3 (4)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Weeks Since MDS Diagnosis </span> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Mean (±SD) <br/> </td><td align="center" class="Rrule" valign="top">86±131<br/> </td><td align="center" class="Rrule" valign="top">77±119<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Median (IQR) <br/> </td><td align="center" class="Rrule" valign="top">29 (10 to 87)<br/> </td><td align="center" class="Rrule" valign="top">35 (7 to 98)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">(Range: min-max) <br/> </td><td align="center" class="Rrule" valign="top">(2 to 667)<br/> </td><td align="center" class="Rrule" valign="top">(2 to 865)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Previous MDS Therapy n (%) </span> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Yes <br/> </td><td align="center" class="Rrule" valign="top">27 (30)<br/> </td><td align="center" class="Rrule" valign="top">19 (23)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">No <br/> </td><td align="center" class="Rrule" valign="top">62 (70)<br/> </td><td align="center" class="Rrule" valign="top">62 (77)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">RBC Transfusion Status n (%) </span> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Independent <br/> </td><td align="center" class="Rrule" valign="top">23 (26)<br/> </td><td align="center" class="Rrule" valign="top">27 (33)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Dependent <br/> </td><td align="center" class="Rrule" valign="top">66 (74)<br/> </td><td align="center" class="Rrule" valign="top">54 (67)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Platelet Transfusion Status n (%)</span> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Independent <br/> </td><td align="center" class="Rrule" valign="top">69 (78)<br/> </td><td align="center" class="Rrule" valign="top">62 (77)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Dependent <br/> </td><td align="center" class="Rrule" valign="top">20 (22)<br/> </td><td align="center" class="Rrule" valign="top">19 (23)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">IPSS Classification n (%) </span> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Intermediate–1 <br/> </td><td align="center" class="Rrule" valign="top">28 (31)<br/> </td><td align="center" class="Rrule" valign="top">24 (30)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Intermediate–2 <br/> </td><td align="center" class="Rrule" valign="top">38 (43)<br/> </td><td align="center" class="Rrule" valign="top">36 (44)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">High Risk <br/> </td><td align="center" class="Rrule" valign="top">23 (26)<br/> </td><td align="center" class="Rrule" valign="top">21 (26)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">FAB Classification n (%) </span> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td><td align="justify" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">RA <br/> </td><td align="center" class="Rrule" valign="top">12 (13)<br/> </td><td align="center" class="Rrule" valign="top">12 (15)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">RARS <br/> </td><td align="center" class="Rrule" valign="top">7 (8)<br/> </td><td align="center" class="Rrule" valign="top">4 (5)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">RAEB <br/> </td><td align="center" class="Rrule" valign="top">47 (53)<br/> </td><td align="center" class="Rrule" valign="top">43 (53)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">RAEB-t <br/> </td><td align="center" class="Rrule" valign="top">17 (19)<br/> </td><td align="center" class="Rrule" valign="top">14 (17)<br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">CMML <br/> </td><td align="center" class="Rrule" valign="top">6 (7)<br/> </td><td align="center" class="Rrule" valign="top">8 (10)<br/> </td> </tr> </tbody> </table></div>

Patients randomized to the decitabine group received decitabine intravenously infused at a dose of 15 mg/m2 over a 3-hour period, every 8 hours, for 3 consecutive days. This cycle was repeated every 6 weeks, depending on the patient’s clinical response and toxicity. Supportive care consisted of blood and blood product transfusions, prophylactic antibiotics, and hematopoietic growth factors. The study endpoints were overall response rate (complete response + partial response) and time to AML or death. Responses were classified using the MDS International Working Group (IWG) criteria; patients were required to be RBC and platelet transfusion independent during the time of response. Response criteria are given in Table 5.

Table 5 Response Criteria for the Controlled Trial in MDS*

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="599"> <colgroup> <col width="24.2430988423865%"/> <col width="22.0391807658059%"/> <col width="53.7177203918077%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="2" valign="top"><span class="Bold">Complete Response (CR)      ≥ 8 weeks </span> <br/> </td><td align="justify" class="Rrule" valign="top"><span class="Bold">Bone Marrow </span> <br/> </td><td class="Rrule" valign="top"><span class="Bold">On repeat aspirates: </span> <br/> <ul class="Disc"> <li>&lt; 5% myeloblasts </li> <li>No dysplastic changes </li> </ul> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Peripheral Blood </span> <br/> </td><td class="Rrule" valign="top"><span class="Bold">In all samples during response: </span> <br/> <ul class="Disc"> <li>Hgb &gt; 11 g/dL (no transfusions or erythropoietin </li> <li>ANC ≥ 1500/µL (no growth factor) </li> <li>Platelets ≥ 100,000/ µL (no thrombopoietic agent) </li> <li>No blasts and no dysplasia </li> </ul> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" rowspan="2" valign="top"><span class="Bold">Partial Response (PR) ≥ 8 weeks </span> <br/> </td><td align="justify" class="Rrule" valign="top"><span class="Bold">Bone Marrow </span> <br/> </td><td align="justify" class="Rrule" valign="top"><span class="Bold">On repeat aspirates: </span> <br/> <ul class="Disc"> <li>≥ 50% decrease in blasts over pretreatment values </li> </ul>OR <br/> <ul class="Disc"> <li>Improvement to a less advanced MDS FAB classification </li> </ul> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Peripheral Blood </span> <br/> </td><td class="Rrule" valign="top">Same as for CR <br/> </td> </tr> </tbody> </table></div>

*Cheson BD, Bennett JM, et al. Report of an International Working Group to Standardize Response Criteria for MDS. Blood. 2000; 96:3671-3674.

The overall response rate (CR+PR) in the ITT population was 17% in decitabine group and 0% in the SC group (p<0.001) (see Table 6). The overall response rate was 21% (12/56) in decitabine-treated patients considered evaluable for response (i.e., those patients with pathologically confirmed MDS at baseline who received at least 2 cycles of treatment). The median duration of response (range) for patients who responded to decitabine was 288 days (116 to 388) and median time to response (range) was 93 days (55 to 272). All but one of the decitabine-treated patients who responded did so by the fourth cycle. Benefit was seen in an additional 13% of decitabine-treated patients who had hematologic improvement, defined as a response less than PR lasting at least 8 weeks, compared to 7% of SC patients. Treatment did not significantly delay the median time to AML or death versus supportive care.

Table 6 Analysis of Response (ITT)

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="543"> <colgroup> <col width="40.0417485265226%"/> <col width="33.8163064833006%"/> <col width="26.1419449901768%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"><span class="Bold"> <br/>Parameter </span></td><td class="Rrule" valign="top"><span class="Bold"> <br/>Decitabine</span><span class="Bold"> <br/>N=89</span></td><td class="Rrule" valign="top"><span class="Bold"> <br/>Supportive Care </span><span class="Bold"> <br/>N=81</span></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"><span class="Bold">Overall Response Rate </span> <br/> <span class="Bold">(CR+PR)† </span> <br/>    Complete Response (CR) <br/>    Partial Response (PR) <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold"> <br/>15 (17%)**</span> <br/>8 (9%)<br/>7 (8%)</td><td align="center" class="Rrule" valign="top"><span class="Bold"> <br/>0 (0%)</span> <br/>0 (0%)<br/>0 (0%)</td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top"><span class="Bold">Duration of Response </span> <br/>Median time to (CR+PR) <br/>    response - Days (range) <br/>Median Duration of (CR+PR)   <br/>    response - Days (range) <br/> </td><td align="center" class="Rrule" valign="top"> <br/>93 (55 to 272)<br/> <br/> <br/>288 (116 to 388)</td><td align="center" class="Rrule" valign="top"> <br/>NA<br/> <br/> <br/>NA</td> </tr> </tbody> </table></div>

**p-value <0.001 from two-sided Fisher’s Exact Test comparing Decitabine vs. Supportive Care. †In the statistical analysis plan, a p-value of ≤ 0.024 was required to achieve statistical significance. All patients with a CR or PR were RBC and platelet transfusion independent in the absence of growth factors. 

Responses occurred in patients with an adjudicated baseline diagnosis of AML.

Three open-label, single-arm, multicenter studies were conducted to evaluate the safety and efficacy of decitabine in patients with MDS with any of the FAB subtypes. In one study conducted in North America, 99 patients with IPSS Intermediate-1, Intermediate-2, or high-risk prognostic scores received decitabine 20 mg/m2 as an intravenous infusion over 1-hour daily, on days 1 to 5 of week 1 every 4 weeks (1 cycle). The results were consistent with the results of the controlled trial and are summarized in Table 8.

Table 7   Baseline Demographics and Other Patient Characteristics (ITT)

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="609"> <colgroup> <col width="60.0087556090621%"/> <col width="39.9912443909379%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Demographic or Other Patient Characteristic </span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Decitabine N = 99</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Age (years) </span> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Mean (±SD) <br/> </td><td align="center" class="Rrule" valign="top">71±9<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Median (Range:  min-max) <br/> </td><td align="center" class="Rrule" valign="top">72 (34 to 87)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Sex n (%) </span> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Male <br/> </td><td align="center" class="Rrule" valign="top">71 (72)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Female <br/> </td><td align="center" class="Rrule" valign="top">28 (28)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Race n (%) </span> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">White <br/> </td><td align="center" class="Rrule" valign="top">86 (87)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Black <br/> </td><td align="center" class="Rrule" valign="top">6 (6)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Asian <br/> </td><td align="center" class="Rrule" valign="top">4 (4)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Other <br/> </td><td align="center" class="Rrule" valign="top">3 (3)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Days From MDS Diagnosis to First Dose </span> <br/> </td><td align="center" class="Rrule" valign="top">444±626<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Mean (±SD) <br/>Median (Range:  min-max) <br/> </td><td align="center" class="Rrule" valign="top">154 <br/>(7 to 3079)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Previous MDS Therapy n (%) </span> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Yes <br/> </td><td align="center" class="Rrule" valign="top">27 (27)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">No <br/> </td><td align="center" class="Rrule" valign="top">72 (73)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">RBC Transfusion Status n (%) </span> <br/> </td><td class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Independent<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top">33 (33)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Dependent <br/> </td><td align="center" class="Rrule" valign="top">66 (67)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold"> Platelet Transfusion Status n (%) </span> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Independent <br/> </td><td align="center" class="Rrule" valign="top">84 (85)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Dependent <br/> </td><td align="center" class="Rrule" valign="top">15 (15)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">IPSS Classification n (%) </span> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Low Risk <br/> </td><td align="center" class="Rrule" valign="top">1 (1)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Intermediate–1 <br/> </td><td align="center" class="Rrule" valign="top">52 (53)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Intermediate–2<br/> </td><td align="center" class="Rrule" valign="top">23 (23)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">High Risk<br/> </td><td align="center" class="Rrule" valign="top">23 (23)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">FAB Classification n (%)</span> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">RA<br/> </td><td align="center" class="Rrule" valign="top">20 (20)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">RARS<br/> </td><td align="center" class="Rrule" valign="top">17 (17)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">RAEB<br/> </td><td align="center" class="Rrule" valign="top">45 (45)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">RAEB-t<br/> </td><td align="center" class="Rrule" valign="top">6 (6)<br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">CMML<br/> </td><td align="center" class="Rrule" valign="top">11 (11)<br/> </td> </tr> </tbody> </table></div>

Table 8 Analysis of Response (ITT)*

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="571"> <colgroup> <col width="66.3865546218487%"/> <col width="33.6134453781513%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">Parameter</span> <br/> </td><td align="center" class="Rrule" valign="bottom"><span class="Bold">Decitabine</span> <br/> <span class="Bold">N=99</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Overall Response Rate (CR+PR) </span> <br/>  Complete Response (CR) <br/>  Partial Response (PR) <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">16 (16%)</span> <br/>15 (15%)<br/>1 (1%)<br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Duration of Response </span> <br/>  Median time to (CR+PR) response - Days (range)  <br/>  Median Duration of (CR+PR) response - Days (range) <br/> </td><td align="center" class="Rrule" valign="middle"> <br/>162 (50 to 267)<br/>443 (72 to 722<span class="Sup">+</span>)<br/> </td> </tr> </tbody> </table></div>

 * Cheson BD, Bennett JM, et al. Report of an International Working Group to Standardize Response Criteria for MDS. Blood. 2000; 96:3671-3674. +indicates censored observation

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        http://www.osha.gov/SLTC/hazardousdrugs/index.html

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DRUG PRODUCT

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

White to off white lyophilized powder in 20 mL colorless tubular glass single-dose vial with grey bromo butyl rubber stopper and sealed with baby blue flip top aluminum seal.

{ "type": "p", "children": [], "text": "White to off white lyophilized powder in 20 mL colorless tubular glass single-dose vial with grey bromo butyl rubber stopper and sealed with baby blue flip top aluminum seal." }

Each vial contains 50 mg decitabine. (NDC 47335-361-40)

{ "type": "p", "children": [], "text": "Each vial contains 50 mg decitabine. (NDC 47335-361-40)" }

DILUENT

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Clear colorless solution filled in 10 mL colorless tubular glass vial with grey bromo butyl stopper sealed with transparent flip top aluminum seal.

{ "type": "p", "children": [], "text": "Clear colorless solution filled in 10 mL colorless tubular glass vial with grey bromo butyl stopper sealed with transparent flip top aluminum seal." }

Each vial contains 68 mg monobasic potassium phosphate, 11.6 mg sodium hydroxide and 10 mL water for injection. (NDC 47335-362-40)

{ "type": "p", "children": [], "text": "Each vial contains 68 mg monobasic potassium phosphate, 11.6 mg sodium hydroxide and 10 mL water for injection. (NDC 47335-362-40)" }

The carton contains 1 vial of drug product, and 1 vial of sterile diluent. (NDC 47335-361-41)

{ "type": "p", "children": [], "text": "The carton contains 1 vial of drug product, and 1 vial of sterile diluent. (NDC 47335-361-41)" }

Storage and Handling

{ "type": "p", "children": [], "text": "\nStorage and Handling\n" }

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "\nStore at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature].\n" }

Myelosuppression

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

Advise patients of the risk of myelosuppression and to report any symptoms of infection, anemia, or bleeding to their healthcare provider as soon as possible. Advise patients for the need for laboratory monitoring [see Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Advise patients of the risk of myelosuppression and to report any symptoms of infection, anemia, or bleeding to their healthcare provider as soon as possible. Advise patients for the need for laboratory monitoring [see Warnings and Precautions (5.1)].\n\n\n" }

Embryo-Fetal Toxicity

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

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1)].\n\n\n" }

Advise females of reproductive potential to use effective contraception while receiving Decitabine for Injection and for 6 months after last dose [see Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "Advise females of reproductive potential to use effective contraception while receiving Decitabine for Injection and for 6 months after last dose [see Use in Specific Populations (8.3)].\n" }

Advise males with female partners of reproductive potential to use effective contraception while receiving treatment with Decitabine for Injection and for 3 months after the last dose [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].

{ "type": "p", "children": [], "text": "Advise males with female partners of reproductive potential to use effective contraception while receiving treatment with Decitabine for Injection and for 3 months after the last dose [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].\n\n\n" }

Lactation

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

Advise women to avoid breastfeeding while receiving Decitabine for Injection and for at least 2 weeks after the last dose [see Use in Specific Populations (8.2)].

{ "type": "p", "children": [], "text": " Advise women to avoid breastfeeding while receiving Decitabine for Injection and for at least 2 weeks after the last dose [see Use in Specific Populations (8.2)]." }

Distributed by:

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

Sun Pharmaceutical Industries, Inc.

{ "type": "p", "children": [], "text": "\nSun Pharmaceutical Industries, Inc.\n" }

Cranbury, NJ 08512

{ "type": "p", "children": [], "text": "Cranbury, NJ 08512\n\n" }

Manufactured by: 

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

Sun Pharmaceutical Ind. Ltd.

{ "type": "p", "children": [], "text": "\nSun Pharmaceutical Ind. Ltd.\n" }

Halol-Baroda Highway,

{ "type": "p", "children": [], "text": "Halol-Baroda Highway," }

Halol-389 350, Gujarat, India.

{ "type": "p", "children": [], "text": "Halol-389 350, Gujarat, India. " }

ISS. 05/2020

{ "type": "p", "children": [], "text": "ISS. 05/2020" }

NDC 47335-361-41 Decitabine for Injection 50 mg per vial Further dilution is required. See package insert.  For intravenous infusion only  Sterile Cytotoxic Agent Stability: Unless used within 15 minutes of reconstitution, the diluted solution must be   prepared using cold (2˚C to 8˚C) infusion fluids and stored at 2˚C to 8˚C (36˚F to 46˚F) for up to a maximum of 7 hours until administration.This carton contains:

{ "type": "p", "children": [], "text": "\nNDC 47335-361-41\n\nDecitabine for Injection\n\n50 mg per vial\n\nFurther dilution is required. See package insert. \n\nFor intravenous infusion only \nSterile\n\nCytotoxic Agent\n\nStability: Unless used within 15 minutes of reconstitution, the diluted solution must be   prepared using cold (2˚C to 8˚C) infusion fluids and stored at 2˚C to 8˚C (36˚F to 46˚F) for up to a maximum of 7 hours until administration.This carton contains: " }

{ "type": "ul", "children": [ "1 vial of Decitabine for Injection ", "1 vial of Diluent" ], "text": "" }

Rx Only Single-dose vial SUN PHARMA

{ "type": "p", "children": [], "text": "Rx Only \nSingle-dose vial\n\nSUN PHARMA\n" }

Decitabine for injection is indicated for treatment of adult patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.

{ "type": "p", "children": [], "text": "Decitabine for injection is indicated for treatment of adult patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups." }

Pre-Medications and Baseline Testing

• Consider pre-medicating for nausea with antiemetics. • Conduct baseline laboratory testing: complete blood count (CBC) with platelets, serum hepatic panel, and serum creatinine.

Decitabine for injection Regimen Options

Three Day Regimen

Administer decitabine for injection at a dose of 15 mg/m 2by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days. Repeat cycles every 6 weeks upon hematologic recovery (ANC at least 1,000/μL and platelets at least 50,000/μL) for a minimum of 4 cycles. A complete or partial response may take longer than 4 cycles. Delay and reduce dose for hematologic toxicity [see Dosage and Administration (2.2)].

Five Day Regimen

Administer decitabine for injection at a dose of 20 mg/m 2by continuous intravenous infusion over 1 hour daily for 5 days. Delay and reduce dose for hematologic toxicity [see Dosage and Administration ( 2.2)]. Repeat cycles every 4 weeks upon hematologic recovery (ANC at least 1,000/μL and platelets at least 50,000/μL) for a minimum of 4 cycles. A complete or partial response may take longer than 4 cycles.

Patients with Renal or Severe Hepatic Impairment

Treatment with decitabine for injection has not been studied in patients with pre-existing renal or hepatic impairment. For patients with pre-existing renal or hepatic impairment, consider the potential risks and benefits before initiating treatment with decitabine for injection.

Hematologic Toxicity If hematologic recovery from a previous decitabine for injection treatment cycle requires more than 6 weeks, delay the next cycle of decitabine for injection therapy and reduce decitabine for injection dose temporarily by following this algorithm: • Recovery requiring more than 6, but less than 8 weeks: delay decitabine for injection dosing for up to 2 weeks and reduce the dose temporarily to 11 mg/m 2every 8 hours (33 mg/m 2/day, 99 mg/m 2/cycle) upon restarting therapy. • Recovery requiring more than 8, but less than 10 weeks: Perform bone marrow aspirate to assess for disease progression. In the absence of progression, delay decitabine for injection dosing for up to 2 more weeks and reduce the dose to 11 mg/m 2every 8 hours (33 mg/m 2/day, 99 mg/m 2/cycle) upon restarting therapy, then maintain or increase dose in subsequent cycles as clinically indicated. Non-hematologic Toxicity Delay subsequent decitabine for injection treatment for any the following nonhematologic toxicities and do not restart until toxicities resolve: • Serum creatinine greater than or equal to 2 mg/dL • Alanine transaminase (ALT), total bilirubin greater than or equal to 2 times upper limit of normal (ULN) • Active or uncontrolled infection

Decitabine for injection is a cytotoxic drug. Follow special handling and disposal procedures. 1 Aseptically reconstitute decitabine for injection with room temperature (20°C to 25°C) 10 mL of Sterile Water for Injection, USP. Upon reconstitution, the final concentration of the reconstituted decitabine for injection solution is 5 mg/mL. You must dilute the reconstituted solution with 0.9% Sodium Chloride Injection or 5% Dextrose Injection prior to administration. Temperature of the diluent (0.9% Sodium Chloride Injection or 5% Dextrose Injection) depends on time of administration after preparation. For Administration Within 15 Minutes of Preparation If decitabine for injection is intended to be administered within 15 minutes from the time of preparation, dilute the reconstituted solution with room temperature (20˚C to 25˚C) 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration of 0.1 mg/mL to 1 mg/mL. Discard unused portion. For Delayed Administration If decitabine for injection is intended to be administered after 15 minutes of preparation, dilute the reconstituted solution with cold (2˚C to 8˚C) 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration of 0.1 mg/mL to 1 mg/mL. Store at 2˚C to 8˚C for up to 4 hours. Diluted stored solution must be used within 4 hours from the time of preparation. Discard unused portion. Use the diluted, refrigerated solution within 4 hours from the time of preparation or discard. 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 evidence of particulate matter or discoloration.

For Injection: 50 mg of decitabine as a sterile, white to almost white lyophilized powder in a single-dose vial for reconstitution

{ "type": "p", "children": [], "text": "For Injection: 50 mg of decitabine as a sterile, white to almost white lyophilized powder in a single-dose vial for reconstitution" }

None.

{ "type": "p", "children": [], "text": "None." }

Fatal and serious myelosuppression occurs in decitabine-treated patients. Myelosuppression (anemia, neutropenia, and thrombocytopenia) is the most frequent cause of decitabine dose reduction, delay, and discontinuation. Neutropenia of any grade occurred in 90% of decitabine-treated patients with grade 3 or 4 occurring in 87% of patients. Grade 3 or 4 febrile neutropenia occurred in 23% of patients. Thrombocytopenia of any grade occurred in 89% of patients with grade 3 or 4 occurring in 85% of patients. Anemia of any grade occurred in 82% of patients. Perform complete blood count with platelets at baseline, prior to each cycle, and as needed to monitor response and toxicity. Manage toxicity using dose-delay, dose-reduction, growth factors, and anti-infective therapies as needed [see Dosage and Administration ( 2.2)]. Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and may not necessarily indicate progression of underlying MDS.

Based on findings from human data, animal studies and its mechanism of action, decitabine can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1) and Nonclinical Toxicology ( 13.1)] . In preclinical studies in mice and rats, decitabine caused adverse developmental outcomes including embryo-fetal lethality and malformations. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception while receiving decitabine and for 6 months following the last dose. Advise males with female partners of reproductive potential to use effective contraception while receiving treatment with decitabine and for 3 months following the last dose [see Use in Specific Populations ( 8.1,8.3)].

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 safety of decitabine was studied in 3 single-arm studies (N = 66, N = 98, N = 99) and 1 controlled supportive care study (N = 83 decitabine for injection, N = 81 supportive care). The data described below reflect exposure to decitabine in 83 patients in the MDS trial. In the trial, patients received 15 mg/m 2intravenously every 8 hours for 3 days every 6 weeks. The median number of decitabine cycles was 3 (range 0 to 9). Most Common Adverse Reactions:neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia. Adverse Reactions Most Frequently (≥ 1%) Resulting in Clinical Intervention and or Dose Modification in the Controlled Supportive Care Study in the decitabine Arm: • Discontinuation: thrombocytopenia, neutropenia, pneumonia, Mycobacterium avium complex infection, cardio-respiratory arrest, increased blood bilirubin, intracranial hemorrhage, abnormal liver function tests. • Dose Delayed: neutropenia, pulmonary edema, atrial fibrillation, central line infection, febrile neutropenia. • Dose Reduced: neutropenia, thrombocytopenia, anemia, lethargy, edema, tachycardia, depression, pharyngitis. Table 1 presents all adverse reactions occurring in at least 5% of patients in the decitabine group and at a rate greater than supportive care. Table 1 Adverse Reactions Reported in ≥ 5% of Patients in the Decitabine Group and at a Rate Greater than Supportive Care in the Controlled Trial in MDS

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tbody class="Headless"> <tr class="First"> <td align="justify" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Decitabine for Injection</span> <br/> <span class="Bold">N = 83 (%)</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Supportive Care</span> <br/> <span class="Bold">N = 81 (%)</span> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Blood and lymphatic system disorders</span> <br/> </p> </td><td align="justify" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Neutropenia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">75 (90) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">58 (72) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Thrombocytopenia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">74 (89) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">64 (79) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Anemia NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">68 (82) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">60 (74) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Febrile neutropenia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">24 (29) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Leukopenia NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">23 (28) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11 (14) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Lymphadenopathy <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10 (12) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (7) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Thrombocythemia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Cardiac disorders</span> <br/> </p> </td><td align="justify" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Pulmonary edema NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0 (0) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Eye disorders</span> <br/> </p> </td><td align="justify" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Vision blurred <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0 (0) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal disorders</span> <br/> </p> </td><td align="justify" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Nausea <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">35 (42) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13 (16) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Constipation <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">29 (35) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11 (14) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diarrhea NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">28 (34) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13 (16) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Vomiting NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">21 (25) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7 (9) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Abdominal pain NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12 (14) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Oral mucosal petechiae <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11 (13) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Stomatitis <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10 (12) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Dyspepsia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10 (12) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Ascites <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (10) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2 (2) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Gingival bleeding <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7 (8) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Hemorrhoids <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7 (8) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3 (4) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Loose stools <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (7) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3 (4) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Tongue ulceration <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (7) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2 (2) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Dysphagia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2 (2) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Oral soft tissue disorder NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Lip ulceration <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3 (4) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Abdominal distension <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Abdominal pain upper <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Gastro-esophageal reflux <br/> disease <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Glossodynia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0 (0) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">General disorders and administrative site disorders</span> <br/> </p> </td><td align="justify" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Pyrexia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">44 (53) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">23 (28) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Edema peripheral <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">21 (25) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13 (16) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Rigors <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">18 (22) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">14 (17) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Edema NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">15 (18) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pain NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11 (13) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Lethargy <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10 (12) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3 (4) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Tenderness NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (11) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0 (0) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Fall <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7 (8) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3 (4) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Chest discomfort <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (7) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3 (4) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Intermittent pyrexia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3 (4) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Malaise <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Crepitations NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Catheter site erythema <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Catheter site pain <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0 (0) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Injection site swelling <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0 (0) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Hepatobiliary disorders</span> <br/> </p> </td><td align="justify" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Hyperbilirubinemia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12 (14) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Infections and infestations</span> <br/> </p> </td><td align="justify" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pneumonia NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">18 (22) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11 (14) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Cellulitis <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10 (12) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (7) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Candidal infection NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (10) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Catheter related infection <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7 (8) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0 (0) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Urinary tract infection NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (7) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Staphylococcal infection <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (7) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0 (0) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Oral candidiasis <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2 (2) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Sinusitis NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2 (2) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Bacteremia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0 (0) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Injury, poisoning and procedural complications</span> <br/> </p> </td><td align="justify" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Transfusion reaction <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (7) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3 (4) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Abrasion NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Investigations</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Cardiac murmur NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13 (16) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (11) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Blood alkaline phosphatase <br/> NOS increased <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (11) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7 (9) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Aspartate aminotransferase increased <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (10) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7 (9) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Blood urea increased <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (10) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Blood lactate dehydrogenase increased <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7 (8) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Blood albumin decreased <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (7) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0 (0) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Blood bicarbonate increased <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Blood chloride decreased <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Protein total decreased <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3 (4) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Blood bicarbonate decreased <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Blood bilirubin decreased <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Metabolism and nutrition disorders</span> <br/> </p> </td><td align="justify" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hyperglycemia NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">27 (33) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">16 (20) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypoalbuminemia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">20 (24) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">14 (17) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypomagnesemia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">20 (24) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (7) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypokalemia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">18 (22) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10 (12) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Hyponatremia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">16 (19) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13 (16) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Appetite decreased NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13 (16) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12 (15) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Anorexia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13 (16) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (10) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Hyperkalemia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11 (13) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3 (4) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Dehydration <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Musculoskeletal and connective tissue disorders</span> <br/> </p> </td><td align="justify" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Arthralgia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">17 (20) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (10) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pain in limb <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">16 (19) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (10) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Back pain <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">14 (17) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Chest wall pain <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (7) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Musculoskeletal discomfort <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0 (0) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Myalgia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Nervous system disorders</span> <br/> </p> </td><td align="justify" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Headache <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">23 (28) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11 (14) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Dizziness <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">15 (18) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10 (12) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypoesthesia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (11) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Psychiatric disorders</span> <br/> </p> </td><td align="justify" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td><td align="justify" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Insomnia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">23 (28) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11 (14) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Confusional state <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10 (12) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3 (4) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Anxiety <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (11) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (10) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Renal and urinary disorders</span> <br/> </p> </td><td align="justify" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Dysuria <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3 (4) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Urinary frequency <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Respiratory, thoracic and Mediastinal disorders</span> <br/> </p> </td><td align="justify" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Cough <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">33 (40) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">25 (31) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Pharyngitis <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13 (16) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (7) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Crackles lung <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12 (14) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Breath sounds decreased <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (10) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7 (9) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypoxia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (10) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Rales <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7 (8) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2 (2) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Postnasal drip <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2 (2) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Skin and subcutaneous tissue disorders</span> <br/> </p> </td><td align="justify" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Ecchymosis <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">18 (22) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12 (15) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Rash NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">16 (19) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7 (9) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Erythema <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12 (14) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Skin lesion NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (11) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3 (4) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pruritis <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (11) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2 (2) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Alopecia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7 (8) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Urticaria NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Swelling face <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0 (0) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Vascular disorders</span> <br/> </p> </td><td align="justify" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Petechiae <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">32 (39) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13 (16) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pallor <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">19 (23) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10 (12) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypotension NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (6) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hematoma NOS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3 (4) <br/> </p> </td> </tr> </tbody> </table></div>

In a single-arm MDS study (N=99), decitabine was dosed at 20 mg/m 2intravenously, infused over one hour daily, for 5 consecutive days of a 4-week cycle. Table 2 presents all adverse reactions occurring in at least 5% of patients.

Table 2 Adverse Reactions Reported in ≥ 5% of Patients in a Single-arm Study*

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="51%"/> <col width="49%"/> <tbody class="Headless"> <tr class="First"> <td align="justify" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Decitabine for Injection</span> <br/> <span class="Bold">N = 99 (%)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Blood and lymphatic system disorders</span> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Anemia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">31 (31) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Febrile neutropenia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">20 (20) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Leukopenia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (6) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Neutropenia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">38 (38) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Pancytopenia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (5) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Thrombocythemia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (5) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Thrombocytopenia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">27 (27) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Cardiac disorders</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Cardiac failure congestive <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (5) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Tachycardia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (8) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Ear and labyrinth disorders</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Ear pain <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (6) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal disorders</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Abdominal pain <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">14 (14) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Abdominal pain upper <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (6) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Constipation <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">30 (30) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Diarrhea <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">28 (28) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Dyspepsia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10 (10) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Dysphagia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (5) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Gastro-esophageal reflux disease <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (5) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nausea <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">40 (40) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Oral pain <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (5) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Stomatitis <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11 (11) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Toothache <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (6) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Vomiting <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">16 (16) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">General disorders and administration site conditions</span> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Asthenia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">15 (15) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Chest pain</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (6) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Chills <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">16 (16) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Fatigue <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">46 (46) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Mucosal inflammation <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (9) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Edema <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (5) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Edema peripheral <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">27 (27) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Pain <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (5) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Pyrexia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">36 (36) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Infections and infestations</span> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Cellulitis <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (9) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Oral candidiasis <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (6) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pneumonia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">20 (20) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Sinusitis <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (6) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Staphylococcal bacteremia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (8) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Tooth abscess <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (5) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Upper respiratory tract infection <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10 (10) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Urinary tract infection <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7 (7) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Injury, poisoning and procedural complications</span> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Contusion <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (9) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Investigations</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Blood bilirubin increased <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (6) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Breath sounds abnormal <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (5) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Weight decreased <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (9) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Metabolism and nutrition disorders</span> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Anorexia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">23 (23) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Decreased appetite <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (8) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Dehydration <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (8) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Hyperglycemia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (6) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypokalemia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12 (12) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypomagnesemia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (5) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Musculoskeletal and connective tissue disorders</span> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Arthralgia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">17 (17) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Back pain <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">18 (18) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Bone pain <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (6) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Muscle spasms <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7 (7) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Muscular weakness <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (5) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Musculoskeletal pain <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (5) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Myalgia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (9) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pain in extremity <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">18 (18) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Nervous system disorders</span> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Dizziness <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">21 (21) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Headache <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">23 (23) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Psychiatric disorders</span> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Anxiety <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (9) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Confusional state <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (8) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Depression <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (9) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Insomnia <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">14 (14) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Respiratory, thoracic and mediastinal disorders</span> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Cough <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">27 (27) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Dyspnea <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">29 (29) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Epistaxis <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13 (13) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pharyngolaryngeal pain <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (8) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pleural effusion <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (5) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Sinus congestion <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (5) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Skin and subcutaneous tissue disorders</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dry skin <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (8) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Ecchymosis <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (9) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Erythema <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (5) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Night sweats <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (5) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Petechiae <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12 (12) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Pruritus <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (9) <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Rash <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11 (11) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Skin lesion <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (5) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Vascular disorders</span> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypertension <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (6) <br/> </p> </td> </tr> <tr class="Last"> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypotension <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11 (11) <br/> </p> </td> </tr> </tbody> </table></div>

* In this single arm study, investigators reported adverse events based on clinical signs and symptoms rather than predefined laboratory abnormalities. Thus, not all laboratory abnormalities were recorded as adverse events.

No overall difference in safety was detected between patients > 65 years of age and younger patients in these MDS trials. No significant differences in safety were detected between males and females. Patients with renal or hepatic dysfunction were not studied. Insufficient numbers of non-White patients were available to draw conclusions in these clinical trials.

Serious adverse reactions that occurred in patients receiving decitabine not previously reported in Tables 1 and 2 include:

• Allergic Reaction: hypersensitivity (anaphylactic reaction) • Blood and Lymphatic System Disorders: myelosuppression, splenomegaly • Cardiac Disorders: myocardial infarction, cardio-respiratory arrest, cardiomyopathy, atrial fibrillation, supraventricular tachycardia • Gastrointestinal Disorders: gingival pain, upper gastrointestinal hemorrhage • General Disorders and Administrative Site Conditions: chest pain, catheter site hemorrhage • Hepatobiliary Disorders: cholecystitis • Infections and Infestations: fungal infection, sepsis, bronchopulmonary aspergillosis, peridiverticular abscess, respiratory tract infection, pseudomonal lung infection, Mycobacterium avium complex infection • Injury, Poisoning and Procedural Complications: post procedural pain, post procedural hemorrhage • Nervous System Disorders: intracranial hemorrhage • Psychiatric Disorders: mental status changes • Renal and Urinary Disorders: renal failure, urethral hemorrhage • Respiratory, Thoracic and Mediastinal Disorders: hemoptysis, lung infiltration, pulmonary embolism, respiratory arrest, pulmonary mass

The following adverse reactions have been identified during postapproval use of decitabine. 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. • Sweet’s syndrome (acute febrile neutrophilic dermatosis) • Differentiation syndrome • Interstitial lung disease

Drug interaction studies with decitabine have not been conducted. In vitrostudies in human liver microsomes suggest that decitabine is unlikely to inhibit or induce cytochrome P450 enzymes. In vitrometabolism studies have suggested that decitabine is not a substrate for human liver cytochrome P450 enzymes. As plasma protein binding of decitabine is negligible (<1%), interactions due to displacement of more highly protein bound drugs from plasma proteins are not expected.

{ "type": "p", "children": [], "text": "Drug interaction studies with decitabine have not been conducted.\n \n In vitrostudies in human liver microsomes suggest that decitabine is unlikely to inhibit or induce cytochrome P450 enzymes.\n \n In vitrometabolism studies have suggested that decitabine is not a substrate for human liver cytochrome P450 enzymes. As plasma protein binding of decitabine is negligible (<1%), interactions due to displacement of more highly protein bound drugs from plasma proteins are not expected.\n\n " }

Risk Summary

Based on findings from human data, animal studies, and the mechanism of action, decitabine can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1) and Nonclinical Toxicology ( 13.1)]. Limited published data on decitabine use throughout the first trimester during pregnancy describe adverse developmental outcomes including major birth defects (structural abnormalities). In animal reproduction studies, administration of decitabine to pregnant mice and rats during organogenesis caused adverse developmental outcomes including malformations and embryo-fetal lethality starting at doses approximately 7% of the recommended human dose on a mg/m 2basis (see Data).Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage in the U.S. general population is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively.

Data

Human Data

A single published case report of decitabine pregnancy exposure in a 39-year old woman with a hematologic malignancy described multiple structural abnormalities after 6 cycles of therapy in the 18 thweek of gestation. These abnormalities included holoprosencephaly, absence of nasal bone, mid-facial deformity, cleft lip and palate, polydactyly and rocker-bottom feet. The pregnancy was terminated.

Animal Data

In utero exposure to decitabine causes temporal related defects in the rat and/or mouse, which include growth suppression, exencephaly, defective skull bones, rib/sternabrae defects, phocomelia, digit defects, micrognathia, gastroschisis, micromelia. Decitabine inhibits proliferation and increases apoptosis of neural progenitor cells of the fetal CNS and induces palatal clefting in the developing murine fetus. Studies in mice have also shown that decitabine administration during osteoblastogenesis (day 10 of gestation) induces bone loss in offspring. In mice exposed to single IP (intraperitoneal) injections (0, 0.9 and 3.0 mg/m 2, approximately 2% and 7% of the recommended daily clinical dose, respectively) over gestation days 8, 9, 10 or 11, no maternal toxicity was observed but reduced fetal survival was observed after treatment at 3 mg/m 2and decreased fetal weight was observed at both dose levels. The 3 mg/m 2dose elicited characteristic fetal defects for each treatment day, including supernumerary ribs (both dose levels), fused vertebrae and ribs, cleft palate, vertebral defects, hind-limb defects and digital defects of fore- and hind-limbs. In rats given a single IP injection of 2.4, 3.6 or 6 mg/m 2(approximately 5%, 8%, or 13% the daily recommended clinical dose, respectively) on gestation days 9 to 12, no maternal toxicity was observed. No live fetuses were seen at any dose when decitabine was injected on gestation day 9. A significant decrease in fetal survival and reduced fetal weight at doses greater than 3.6 mg/m 2was seen when decitabine was given on gestation day 10. Increased incidences of vertebral and rib anomalies were seen at all dose levels, and induction of exophthalmia, exencephaly, and cleft palate were observed at 6.0 mg/m 2. Increased incidence of foredigit defects was seen in fetuses at doses greater than 3.6 mg/m 2. Reduced size and ossification of long bones of the fore-limb and hind-limb were noted at 6.0 mg/m 2. The effect of decitabine on postnatal development and reproductive capacity was evaluated in mice administered a single 3 mg/m 2IP injection (approximately 7% the recommended daily clinical dose) on day 10 of gestation. Body weights of males and females exposed in utero to decitabine were significantly reduced relative to controls at all postnatal time points. No consistent effect on fertility was seen when female mice exposed in utero were mated to untreated males. Untreated females mated to males exposed in utero showed decreased fertility at 3 and 5 months of age (36% and 0% pregnancy rate, respectively). Follow up studies indicated that treatment of pregnant mice with decitabine on gestation day 10 was associated with a reduced pregnancy rate resulting from effects on sperm production in the F1-generation.

Risk Summary There are no data on the presence of decitabine or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions from decitabine in a breastfed child, advise women not to breastfeed while receiving decitabine and for at least 2 weeks after the last dose.

Pregnancy Testing

Conduct pregnancy testing of females of reproductive potential prior to initiating decitabine.

Contraception

Females

Decitabine can cause fetal harm when administered to pregnant women [see Use in Specific Populations ( 8.1)]. Advise females of reproductive potential to use effective contraception while receiving decitabine and for 6 months following the last dose. Males Advise males with female partners of reproductive potential to use effective contraception while receiving treatment with decitabine and for 3 months following the last dose [see Nonclinical Toxicology ( 13.1)]. Infertility Based on findings of decitabine in animals, male fertility may be compromised by treatment with decitabine. The reversibility of the effect on fertility is unknown [see Nonclinical Toxicology ( 13.1)].

The safety and effectiveness of decitabine in pediatric patients have not been established.

Of the total number of patients exposed to decitabine in the controlled clinical trial, 61 of 83 patients were age 65 years and over, while 21 of 83 patients were age 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and 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.

There is no known antidote for overdosage with decitabine. Higher doses are associated with increased myelosuppression including prolonged neutropenia and thrombocytopenia. Standard supportive measures should be taken in the event of an overdose.

{ "type": "p", "children": [], "text": "There is no known antidote for overdosage with decitabine. Higher doses are associated with increased myelosuppression including prolonged neutropenia and thrombocytopenia. Standard supportive measures should be taken in the event of an overdose." }

Decitabine is a nucleoside metabolic inhibitor. Decitabine is a fine, white to almost white powder with the molecular formula of C 8H 12N 4O 4and a molecular weight of 228.21. Its chemical name is 4-amino-1-(2-deoxy-beta-D-erythropentofuranosyl)-1,3,5-triazin-2(1H)-one and it has the following structural formula:

{ "type": "p", "children": [], "text": "Decitabine is a nucleoside metabolic inhibitor. Decitabine is a fine, white to almost white powder with the molecular formula of C\n \n 8H\n \n 12N\n \n 4O\n \n 4and a molecular weight of 228.21. Its chemical name is 4-amino-1-(2-deoxy-beta-D-erythropentofuranosyl)-1,3,5-triazin-2(1H)-one and it has the following structural formula:\n\n " }

Decitabine is soluble in dimethyl sulphoxide, sparingly soluble in water; slightly soluble in ethanol and water (50:50), in methanol and water (50:50) and in methanol. Decitabine for injection, for intravenous use, is a sterile, white to almost white lyophilized powder supplied in a clear colorless glass single-dose vial. Each 20 mL vial contains 50 mg decitabine, acetonitrile, hydrochloric acid, 68 mg monobasic potassium phosphate (potassium dihydrogen phosphate), 11.6 mg sodium hydroxide. Sodium hydroxide and/or hydrochloric acid are used for pH adjustment.

{ "type": "p", "children": [], "text": "Decitabine is soluble in dimethyl sulphoxide, sparingly soluble in water; slightly soluble in ethanol and water (50:50), in methanol and water (50:50) and in methanol. \n Decitabine for injection, for intravenous use, is a sterile, white to almost white lyophilized powder supplied in a clear colorless glass single-dose vial. Each 20 mL vial contains 50 mg decitabine, acetonitrile, hydrochloric acid, 68 mg monobasic potassium phosphate (potassium dihydrogen phosphate), 11.6 mg sodium hydroxide. Sodium hydroxide and/or hydrochloric acid are used for pH adjustment.\n " }

Decitabine is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation or apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. Decitabine-induced hypomethylation in neoplastic cells may restore normal function to genes that are critical for the control of cellular differentiation and proliferation. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and decitabine incorporated into DNA. Non-proliferating cells are relatively insensitive to decitabine.

Decitabine has been shown to induce hypomethylation both in vitroand in vivo. However, there have been no studies of decitabine-induced hypomethylation and pharmacokinetic parameters.

Pharmacokinetic (PK) parameters were evaluated in patients. Eleven patients received 20 mg/m 2infused over 1 hour intravenously (treatment Option 2). Fourteen patients received 15 mg/m 2infused over 3 hours intravenously (treatment Option 1). PK parameters are shown in Table 3. Plasma concentration-time profiles after discontinuation of infusion showed a biexponential decline. The clearance (CL) of decitabine was higher following treatment Option 2. Upon repeat doses, there was no systemic accumulation of decitabine or any changes in PK parameters. Population PK analysis (N=35) showed that the cumulative AUC per cycle for treatment Option 2 was 2.3-fold lower than the cumulative AUC per cycle following treatment Option 1.

Table 3 Mean (CV% or 95% CI) Pharmacokinetic Parameters of Decitabine

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="29%"/> <col width="12%"/> <col width="14%"/> <col width="11%"/> <col width="12%"/> <col width="22%"/> <tbody class="Headless"> <tr class="First"> <td align="justify" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Dose</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">C <span class="Sub">max</span></span> <br/> <span class="Bold">(ng/mL)</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">AUC <span class="Sub">0-INF</span></span> <br/> <span class="Bold">(ng·h/mL)</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">T <span class="Sub">1/2</span></span> <br/> <span class="Bold">(h)</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">CL</span> <br/> <span class="Bold">(L/h/m <span class="Sup">2</span>) </span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">AUC <span class="Sub">Cumulative</span><span class="Sup">‡</span></span> <br/> <span class="Bold">(ng·h/mL)</span> <br/> </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First"> 15 mg/m <span class="Sup">2</span>3-hr infusion every <br/> 8 hours for 3 days (Option 1) <span class="Sup">*</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 73.8 <br/> (66) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 163 <br/> (62) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.62 <br/> (49) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 125 <br/> (53) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 1332 <br/> (1010-1730) <br/> </p> </td> </tr> <tr class="Last"> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First"> 20 mg/m <span class="Sup">2</span>1-hr infusion daily <br/> for 5 days (Option 2) <span class="Sup">†</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 147 <br/> (49) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 115 <br/> (43) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 0.54 <br/> (43) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 210 <br/> (47) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> 570 <br/> (470-700) <br/> </p> </td> </tr> </tbody> </table></div>

*N=14, †N=11, ‡N=35 Cumulative AUC per cycle

The exact route of elimination and metabolic fate of decitabine is not known in humans. One of the pathways of elimination of decitabine appears to be deamination by cytidine deaminase found principally in the liver but also in granulocytes, intestinal epithelium and whole blood. Specific Populations Patients with Renal Impairment There are no data on the use of decitabine in patients with renal impairment. Patients with Hepatic Impairment There are no data on the use of decitabine in patients with hepatic impairment.

Carcinogenicity studies with decitabine have not been conducted. The mutagenic potential of decitabine was tested in several in vitroand in vivosystems. Decitabine increased mutation frequency in L5178Y mouse lymphoma cells, and mutations were produced in an Escherichia coli lac-Itransgene in colonic DNA of decitabine-treated mice. Decitabine caused chromosomal rearrangements in larvae of fruit flies. In male mice given IP injections of 0.15, 0.3 or 0.45 mg/m 2decitabine (approximately 0.3% to 1% the recommended clinical dose) 3 times a week for 7 weeks, decitabine did not affect survival, body weight gain or hematological measures (hemoglobin and white blood cell counts). Testes weights were reduced, abnormal histology was observed and significant decreases in sperm number were found at doses ≥ 0.3 mg/m 2. In females mated to males dosed with ≥ 0.3 mg/m 2decitabine, pregnancy rate was reduced and preimplantation loss was significantly increased.

A randomized open-label, multicenter, controlled trial evaluated 170 adult patients with myelodysplastic syndromes (MDS) meeting French-American-British (FAB) classification criteria and International Prognostic Scoring System (IPSS) High-Risk, Intermediate-2 and Intermediate-1 prognostic scores. Eighty-nine patients were randomized to decitabine therapy plus supportive care (only 83 received decitabine), and 81 to Supportive Care (SC) alone. Patients with Acute Myeloid Leukemia (AML) were not intended to be included. Of the 170 patients included in the study, independent review (adjudicated diagnosis) found that 12 patients (9 in the decitabine arm and 3 in the SC arm) had the diagnosis of AML at baseline. Baseline demographics and other patient characteristics in the Intent-to-Treat (ITT) population were similar between the 2 groups, as shown in Table 4.

Table 4 Baseline Demographics and Other Patient Characteristics (ITT)

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tbody class="Headless"> <tr class="First"> <td align="justify" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Demographic or Other Patient</span> <br/> <span class="Bold">Characteristic</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Decitabine for Injection</span> <br/> <span class="Bold">N = 89</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Supportive Care</span> <br/> <span class="Bold">N = 81</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Age (years)</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Mean (±SD) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">69±10 <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">67±10 <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Median (IQR) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">70 (65-76) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">70 (62-74) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">(Range: min-max) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">(31-85) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">(30-82) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Sex n (%)</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Male <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">59 (66) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">57 (70) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Female <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">30 (34) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">24 (30) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Race n (%)</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">White <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">83 (93) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">76 (94) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Black <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (4) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2 (2) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Other <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2 (2) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3 (4) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Weeks Since MDS Diagnosis</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Mean (±SD) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">86±131 <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">77±119 <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Median (IQR) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">29 (10-87) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">35 (7-98) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">(Range: min-max) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">(2-667) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">(2-865) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Previous MDS Therapy n (%)</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Yes <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">27 (30) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">19 (23) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">No <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">62 (70) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">62 (77) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">RBC Transfusion Status n (%)</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Independent <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">23 (26) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">27 (33) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dependent <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">66 (74) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">54 (67) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Platelet Transfusion Status n (%)</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Independent <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">69 (78) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">62 (77) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dependent <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">20 (22) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">19 (23) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">IPSS Classification n (%)</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Intermediate-1 <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">28 (31) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">24 (30) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Intermediate-2 <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">38 (43) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">36 (44) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">High Risk <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">23 (26) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">21 (26) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">FAB Classification n (%)</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">RA <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12 (13) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12 (15) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">RARS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7 (8) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (5) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">RAEB <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">47 (53) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">43 (53) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">RAEB-t <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">17 (19) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">14 (17) <br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">CMML <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (7) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (10) <br/> </p> </td> </tr> </tbody> </table></div>

Patients randomized to the decitabine arm received decitabine intravenously infused at a dose of 15 mg/m 2over a 3-hour period, every 8 hours, for 3 consecutive days. This cycle was repeated every 6 weeks, depending on the patient’s clinical response and toxicity. Supportive care consisted of blood and blood product transfusions, prophylactic antibiotics, and hematopoietic growth factors. The study endpoints were overall response rate (complete response + partial response) and time to AML or death. Responses were classified using the MDS International Working Group (IWG) criteria; patients were required to be RBC and platelet transfusion independent during the time of response. Response criteria are given in Table 5. Table 5 Response Criteria for the Controlled Trial in MDS*

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="23%"/> <col width="25%"/> <col width="52%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <br/> <span class="Bold">Complete</span> <br/> <span class="Bold">Response (CR)</span> <br/> <span class="Bold">≥8 weeks</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <br/> <span class="Bold">Bone Marrow</span> <br/> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">On repeat aspirates:</span> <br/> •&lt;5% myeloblasts <br/> •No dysplastic changes <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <br/> <span class="Bold">Peripheral Blood</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">In all samples during response:</span> <br/> • Hgb &gt; 11 g/dL (no transfusions or erythropoietin <br/> •ANC ≥ 1500/μL (no growth factor) <br/> •Platelets ≥ 100,000/μL (no thrombopoietic agent) <br/> • No blasts and no dysplasia <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First"> <br/> <br/> <span class="Bold">Partial Response</span> <br/> <span class="Bold">(PR)</span> <br/> <span class="Bold">≥8 weeks</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <br/> <span class="Bold">Bone Marrow</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">On repeat aspirates:</span> <br/> •≥50% decrease in blasts over pretreatment values <br/> OR <br/> • Improvement to a less advanced MDS FAB <br/> classification <br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Peripheral Blood</span> <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Same as for CR</span> <br/> </p> </td> </tr> </tbody> </table></div>

* Cheson BD, Bennett JM, et al. Report of an International Working Group to Standardize Response Criteria for MDS. Blood. 2000; 96:3671 to 3674. The overall response rate (CR+PR) in the ITT population was 17% in decitabine-treated patients and 0% in the SC group (p<0.001) (see Table 6). The overall response rate was 21% (12/56) in decitabine treated patients considered evaluable for response (i.e., those patients with pathologically confirmed MDS at baseline who received at least 2 cycles of treatment). The median duration of response (range) for patients who responded to decitabine was 288 days (116 to 388) and median time to response (range) was 93 days (55 to 272). All but one of the decitabine-treated patients who responded did so by the fourth cycle. Benefit was seen in an additional 13% of decitabine-treated patients who had hematologic improvement, defined as a response less than PR lasting at least 8 weeks, compared to 7% of SC patients. Decitabine treatment did not significantly delay the median time to AML or death versus supportive care. Table 6 Analysis of Response (ITT)

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="42%"/> <col width="30%"/> <col width="28%"/> <tbody class="Headless"> <tr class="First"> <td align="justify" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Parameter</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Decitabine For Injection</span> <br/> <span class="Bold">N=89</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Supportive Care</span> <br/> <span class="Bold">N=81</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Overall Response Rate (CR+PR)†</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">15 (17%)*</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">0 (0%)</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Complete Response (CR) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">8 (9%) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">0 (0%) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Partial Response (PR) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">7 (8%) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">0 (0%) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Duration of Response</span> <br/> </p> </td><td class="Botrule Rrule" valign="middle"></td><td class="Botrule Rrule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Median time to (CR+PR) response - Days (range) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">93 (55-272) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA <br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Median Duration of (CR+PR) response - Days (range) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">288 (116-388) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">NA <br/> </p> </td> </tr> </tbody> </table></div>

*p-value <0.001 from two-sided Fisher's Exact Test comparing Decitabine vs. Supportive Care. †In the statistical analysis plan, a p-value of ≤ 0.024 was required to achieve statistical significance. All patients with a CR or PR were RBC and platelet transfusion independent in the absence of growth factors. Responses occurred in patients with an adjudicated baseline diagnosis of AML.

Three open-label, single-arm, multicenter studies were conducted to evaluate the safety and efficacy of decitabine in MDS patients with any of the FAB subtypes. In one study conducted in North America, 99 patients with IPSS Intermediate-1, Intermediate-2, or high-risk prognostic scores received decitabine 20 mg/m 2as an intravenous infusion over 1-hour daily, on days 1 to 5 of week 1, every 4 weeks (1 cycle). The results were consistent with the results of the controlled trial and are summarized in Table 8.

Table 7 Baseline Demographics and Other Patient Characteristics (ITT)

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="50%"/> <col width="50%"/> <tbody class="Headless"> <tr class="First"> <td align="justify" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Demographic or Other Patient Characteristic</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Decitabine for Injection</span> <br/> <span class="Bold">N = 99</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Age (years)</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Mean (±SD) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">71±9 <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Median (Range: min-max) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">72 (34-87) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Sex n (%)</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Male <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">71 (72) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Female <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">28 (28) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Race n (%)</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">White <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">86 (87) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Black <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (6) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Asian <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (4) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Other <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3 (3) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Days From MDS Diagnosis to First Dose</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Mean (±SD) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">444±626 <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Median (Range: min-max) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">154 (7-3079) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Previous MDS Therapy n (%)</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Yes <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">27 (27) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">No <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">72 (73) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">RBC Transfusion Status n (%)</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Independent <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">33 (33) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dependent <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">66 (67) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Platelet Transfusion Status n (%)</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Independent <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">84 (85) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dependent <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">15 (15) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">IPSS Classification n (%)</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Low Risk <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1 (1) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Intermediate–1 <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">52 (53) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Intermediate–2 <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">23 (23) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">High Risk</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">23 (23)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">FAB Classification n (%)</span> <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">RA <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">20 (20) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">RARS <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">17 (17) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">RAEB <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">45 (45) <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">RAEB-t <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (6) <br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">CMML <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11 (11) <br/> </p> </td> </tr> </tbody> </table></div>

Table 8 Analysis of Response (ITT)*

<div class="scrollingtable"><table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="50%"/> <col width="50%"/> <tbody class="Headless"> <tr class="First"> <td align="justify" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Parameter</span> <br/> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Decitabine for Injection</span> <br/> <span class="Bold">N=99</span> <br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Overall Response Rate (CR+PR)</span> <br/> Complete Response (CR) <br/> Partial Response (PR) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">16 (16%)</span> <br/> 15 (15%) <br/> 1 (1%) <br/> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Duration of Response</span> <br/> Median time to (CR+PR) response - Days (range) <br/> Median Duration of (CR+PR) response - Days (range) <br/> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> 162 (50-267) <br/> 443 (72-722 <span class="Sup">†</span>) <br/> </p> </td> </tr> </tbody> </table></div>

*Cheson BD, Bennett JM, et al. Report of an International Working Group to Standardize Response Criteria for MDS. Blood. 2000; 96:3671 to 3674.

†indicates censored observation

1. OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

{ "type": "p", "children": [], "text": "1. OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html" }

Decitabine for injection is a sterile, white to almost white lyophilized powder for intravenous use supplied as:

{ "type": "p", "children": [], "text": "Decitabine for injection is a sterile, white to almost white lyophilized powder for intravenous use supplied as:" }

NDC 68001-642-41, 50 mg single-dose vial individually packaged in a carton.

{ "type": "p", "children": [], "text": "NDC 68001-642-41, 50 mg single-dose vial individually packaged in a carton." }

Store vials at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store vials at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]." }

Myelosuppression Advise patients of the risk of myelosuppression and to report any symptoms of infection, anemia, or bleeding to their healthcare provider as soon as possible. Advise patients for the need for laboratory monitoring [see Warnings and Precautions (5.1)]. Embryo-Fetal Toxicity Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions ( 5.2) and Use in Specific Populations ( 8.1)]. Advise females of reproductive potential to use effective contraception while receiving decitabine for injection and for 6 months after last dose [see Use in Specific Populations ( 8.3)]. Advise males with female partners of reproductive potential to use effective contraception while receiving treatment with decitabine for injection and for 3 months after the last dose [see Use in Specific Populations ( 8.3) and Nonclinical Toxicology (13.1)]. Lactation Advise women to avoid breastfeeding while receiving decitabine for injection and for at least 2 weeks after the last dose [see Use in Specific Populations ( 8.2)].

{ "type": "p", "children": [], "text": "\nMyelosuppression\n Advise patients of the risk of myelosuppression and to report any symptoms of infection, anemia, or bleeding to their healthcare provider as soon as possible. Advise patients for the need for laboratory monitoring\n \n [see Warnings and Precautions\n \n (5.1)].\n \n \n\nEmbryo-Fetal Toxicity\n Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy\n \n [see Warnings and Precautions (\n \n 5.2) and Use in Specific Populations (\n \n 8.1)].\n \n Advise females of reproductive potential to use effective contraception while receiving decitabine for injection and for 6 months after last dose\n \n [see Use in Specific Populations (\n \n 8.3)].\n \n \n Advise males with female partners of reproductive potential to use effective contraception while receiving treatment with decitabine for injection and for 3 months after the last dose\n \n [see Use in Specific Populations (\n \n 8.3)\n \n and\n \n Nonclinical Toxicology\n \n (13.1)].\n\nLactation\n Advise women to avoid breastfeeding while receiving decitabine for injection and for at least 2 weeks after the last dose\n \n [see Use in Specific Populations (\n \n 8.2)].\n \n \n" }

Manufactured by:

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

HETERO LABS LIMITED

{ "type": "p", "children": [], "text": "HETERO LABS LIMITED" }

Unit VI, Polepally, Jadcherla, Mahabubnagar - 509 301, India.

{ "type": "p", "children": [], "text": "Unit VI, Polepally, Jadcherla, \n Mahabubnagar - 509 301, India.\n " }

For BluePoint Laboratories

{ "type": "p", "children": [], "text": "For BluePoint Laboratories" }

Rev: 11/2024

{ "type": "p", "children": [], "text": "Rev: 11/2024" }

Decitabine for injection, (50 mg per vial)-Carton label

{ "type": "p", "children": [], "text": "Decitabine for injection, (50 mg per vial)-Carton label" }

Decitabine for injection, (50 mg per vial)-Vial label

{ "type": "p", "children": [], "text": "\n\nDecitabine for injection, (50 mg per vial)-Vial label\n " }