Hyperqbank

azacitidine

VIDAZA

100

SUBCUTANEOUS

POWDER FOR SUSPENSION

Marketed

[ "azacitidine" ]

Product Monograph

AZACITIDINE FOR INJECTION

100

SUBCUTANEOUS

POWDER FOR SUSPENSION

Marketed

[ "azacitidine" ]

Product Monograph

AZACITIDINE FOR INJECTION

100

SUBCUTANEOUS

POWDER FOR SUSPENSION

Marketed

[ "azacitidine" ]

Product Monograph

AZACITIDINE FOR INJECTION

100

SUBCUTANEOUS

POWDER FOR SUSPENSION

Marketed

[ "azacitidine" ]

Product Monograph

AZACITIDINE FOR INJECTION

100

SUBCUTANEOUS

POWDER FOR SUSPENSION

Marketed

[ "azacitidine" ]

Product Monograph

ONUREG

200

ORAL

TABLET

Marketed

[ "azacitidine" ]

Product Monograph

ONUREG

300

ORAL

TABLET

Marketed

[ "azacitidine" ]

Product Monograph

AZACITIDINE FOR INJECTION

100

SUBCUTANEOUS

POWDER FOR SUSPENSION

Marketed

[ "azacitidine" ]

Product Monograph

[ "DNA Methylation Inhibitors", "Cytidine Analogues" ]

[ "Antineoplastics" ]

[ "Antineoplastic Agents" ]

d24f1fc5-17c6-4e0c-b852-72692e835cff

AZACITIDINE injection, powder, lyophilized, for solution

1 Indications And Usage

1.1 Myelodysplastic Syndromes (Mds)

Azacitidine for injection is indicated for treatment of adult patients with the following French-American-British (FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL).

Pediatric use information is approved for Celgene Corporation's Vidaza (azacitidine for injection). However, due to Celgene Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

2 Dosage And Administration

2.1 Important Administration Information

Do not substitute azacitidine for injection for oral azacitidine. The indications and dosing regimen for azacitidine for injection differ from that of oral azacitidine [see Warnings and Precautions (5.1)]

2.2 First Treatment Cycle For Adults

The recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology laboratory values, is 75 mg/m2 subcutaneously or intravenously, daily for 7 days. Premedicate patients for nausea and vomiting. Obtain complete blood counts, liver chemistries and serum creatinine prior to the first dose.

2.3 Subsequent Treatment Cycles For Adults

Repeat cycles every 4 weeks. The dose may be increased to 100 mg/m2 if no beneficial effect is seen after 2 treatment cycles and if no toxicity other than nausea and vomiting has occurred. It is recommended that patients be treated for a minimum of 4 to 6 cycles. However, complete or partial response may require additional treatment cycles. Treatment may be continued as long as the patient continues to benefit. Monitor patients for hematologic response and renal toxicities [see Warnings and Precautions (5.4)], and delay or reduce dosage if necessary [see Dosage and Administration (2.6)].

2.5 Dosage Adjustment Based On Hematology Laboratory Values

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <colgroup> <col width="23%"/> <col width="23%"/> <col width="23%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" rowspan="2" valign="top">WBC or Platelet Nadir % decrease in counts from baseline </td><td align="left" class="Rrule" colspan="3" valign="top">Bone Marrow Biopsy Cellularity at Time of Nadir (%) </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">30-60 </td><td align="center" class="Rrule" valign="middle">15-30 </td><td align="center" class="Rrule" valign="middle">Less than 15 </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" rowspan="3" valign="top"> 50-75 Greater than 75 </td><td class="Rrule" colspan="3" valign="top"> % Dose in the Next Course </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">100 </td><td align="center" class="Rrule" valign="top">50 </td><td align="center" class="Rrule" valign="top">33 </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="top">75 </td><td align="left" class="Rrule" valign="top">50 </td><td align="center" class="Rrule" valign="top">33 </td> </tr> </tbody> </table></div>

If a nadir as defined in the table above has occurred, give the next course 28 days after the start of the preceding course, provided that both the WBC and the platelet counts are greater than 25% above the nadir and rising. If a greater than 25% increase above the nadir is not seen by day 28, reassess counts every 7 days. If a 25% increase is not seen by day 42, reduce the scheduled dose by 50%.

2.6 Dosage Adjustment Based On Serum Electrolytes And Renal Toxicity

If unexplained reductions in serum bicarbonate levels to less than 20 mEq/L occur, reduce the dosage by 50% for the next course. Similarly, if unexplained elevations of BUN or serum creatinine occur, delay the next cycle until values return to normal or baseline and reduce the dose by 50% for the next course [see Warnings and Precautions (5.4)].

2.7 Use In Geriatric Patients

Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, select the dose carefully and monitor renal function [see Warnings and Precautions (5.4) and Use in Specific Populations (8.5)].

2.8 Preparation Of Azacitidine For Injection

Azacitidine for injection is a hazardous drug. Follow applicable special handling and disposal procedures.1 The azacitidine for injection vial is single-dose and does not contain any preservatives. Discard unused portions of each vial properly [see How Supplied/Storage and Handling (16)]. Do not save any unused portions for later administration.

2.9 Instructions For Subcutaneous Administration

Reconstitute azacitidine for injection aseptically with 4 mL Sterile Water for Injection, USP to obtain a concentration of 25 mg/mL. Inject the diluent slowly into the vial. Vigorously shake or roll the vial until a uniform suspension is achieved. The suspension will be cloudy. Do not filter the suspension after reconstitution. Doing so could remove the active substance. Preparation for Immediate Subcutaneous Administration: For doses requiring more than 1 vial, divide the dose equally between the syringes (e.g., dose 150 mg = 6 mL, 2 syringes with 3 mL in each syringe) and inject into two separate sites. Due to retention in the vial and needle, it may not be feasible to withdraw all of the suspension from the vial. The product may be held at room temperature for up to 1 hour, but must be administered within 1 hour after reconstitution. Preparation for Delayed Subcutaneous Administration: The reconstituted product may be kept in the vial or drawn into a syringe. For doses requiring more than 1 vial, divide the dose equally between the syringes (e.g., dose 150 mg = 6 mL, 2 syringes with 3 mL in each syringe) and inject into two separate sites. Due to retention in the vial and needle, it may not be feasible to withdraw all of the suspension from the vial. The product must be refrigerated immediately. See Table 2 for suspension stability storage timelines based on the temperature of the diluent for delayed subcutaneous administration. After removal from refrigerated conditions, the suspension may be allowed to equilibrate to room temperature for up to 30 minutes prior to administration. Subcutaneous Administration To provide a homogeneous suspension, the contents of the dosing syringe must be re-suspended immediately prior to administration. To re-suspend, vigorously roll the syringe between the palms until a uniform, cloudy suspension is achieved. Azacitidine for injection suspension is administered subcutaneously. Rotate sites for each injection (thigh, abdomen, or upper arm). New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, red, or hard.

Table 2 Suspension Stability: Storage timelines based on the temperature of the diluent for suspension stability storage:

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="593.845"> <colgroup> <col width="54.2441209406495%"/> <col width="45.7558790593505%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" colspan="2" valign="top"> Suspension Stability Storage timelines </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Diluent </td><td align="justify" class="Rrule" valign="top"> Storage Temperature/Duration </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Room temperature (25°C / 77°F) Sterile Water for Injection, USP </td><td class="Rrule" valign="top"> Store at room temperature at 25°C (77°F) for up to 1 hour or refrigerated at 2°C to 8°C (36°F to 46°F) for up to 8 hours. </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top"> Cold (2°C to 8°C / 36°F to 46°F) Sterile Water for Injection, USP </td><td class="Rrule" valign="top"> Store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 22 hours. </td> </tr> </tbody> </table></div>

2.10 Instructions For Intravenous Administration

Parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use the product if there is evidence of particulate matter or discoloration. Adult Patients with MDS Reconstitute the appropriate number of azacitidine for injection vials to achieve the desired dose. Reconstitute each vial with 10 mL Sterile Water for Injection, USP. Vigorously shake or roll the vial until all solids are dissolved. The resulting solution will contain azacitidine 10 mg/mL. The solution should be clear. Withdraw the required amount of azacitidine for injection solution to deliver the desired dose and inject into a 50 to 100 mL infusion bag of either 0.9% Sodium Chloride Injection, USP or Lactated Ringer’s Injection, USP. Intravenous Solution Incompatibility Azacitidine for injection is incompatible with 5% Dextrose Injection, USP solutions, Hespan, or solutions that contain bicarbonate. These solutions have the potential to increase the rate of degradation of azacitidine for injection and should therefore be avoided. Intravenous Administration Azacitidine for injection solution is administered intravenously. Administer the total dose over a period of 10-40 minutes. The administration must be completed within 1 hour of reconstitution of the azacitidine for injection vial. Solution Stability: Azacitidine for injection reconstituted and diluted for intravenous administration may be stored at 25°C (77°F), but administration must be completed within 1 hour of reconstitution.

3 Dosage Forms And Strengths

Azacitidine for injection is supplied as lyophilized cake or powder in 100 mg single-dose vials.

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4 Contraindications

4.1 Advanced Malignant Hepatic Tumors

Azacitidine is contraindicated in patients with advanced malignant hepatic tumors [see Warnings and Precautions (5.3)].

4.2 Hypersensitivity To Azacitidine Or Mannitol

Azacitidine is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol.

5 Warnings And Precautions

5.1 Risks Of Substitution With Other Azacitidine Products

Due to substantial differences in the pharmacokinetic parameters [see Clinical Pharmacology (12.3)], the recommended dose and schedule for azacitidine for injection are different from those of oral azacitidine products. Treatment of patients using azacitidine for injection at the recommended dosage of oral azacitidine may result in a fatal adverse reaction. Treatment of patients using oral azacitidine at the doses recommended for azacitidine for injection may not be effective. Do not substitute azacitidine for injection for oral azacitidine [see Dosage and Administration (2.1)].

5.2 Anemia, Neutropenia And Thrombocytopenia

Azacitidine causes anemia, neutropenia and thrombocytopenia in adult patients with MDS. Monitor complete blood counts frequently for response and/or toxicity, at a minimum, prior to each dosing cycle. In adult patients with MDS, after administration of the recommended dosage for the first cycle, adjust dosage for subsequent cycles based on nadir counts and hematologic response [see Dosage and Administration (2.5)]. Pediatric use information is approved for Celgene Corporation's Vidaza (azacitidine for injection). However, due to Celgene Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

5.3 Hepatotoxicity In Patients With Severe Pre-Existing Hepatic Impairment

Because azacitidine is potentially hepatotoxic in patients with severe pre-existing hepatic impairment, caution is needed in patients with liver disease. Patients with extensive tumor burden due to metastatic disease have been reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline albumin <30 g/L. Azacitidine is contraindicated in patients with advanced malignant hepatic tumors [see Contraindications (4.1)]. Monitor liver chemistries prior to initiation of therapy and with each cycle. Safety and effectiveness of azacitidine in patients with MDS and hepatic impairment have not been studied as these patients were excluded from the clinical trials. Pediatric use information is approved for Celgene Corporation's Vidaza (azacitidine for injection). However, due to Celgene Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

5.4 Renal Toxicity

Renal toxicity ranging from elevated serum creatinine to renal failure and death have been reported in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for non-MDS conditions. In addition, renal tubular acidosis, defined as a fall in serum bicarbonate to <20 mEq/L in association with an alkaline urine and hypokalemia (serum potassium <3 mEq/L) developed in 5 patients with CML treated with azacitidine and etoposide. Monitor serum creatinine and electrolytes prior to initiation of therapy and with each cycle. If unexplained reductions in serum bicarbonate <20 mEq/L or elevations of BUN or serum creatinine occur, reduce or hold the dose [see Dosage and Administration (2.6)]. Patients with renal impairment may be at increased risk for renal toxicity. Also, azacitidine and its metabolites are primarily excreted by the kidney. Therefore, monitor these patients closely for toxicity [see Dosage and Administration (2.6, 2.7)]. Patients with MDS and renal impairment were excluded from the clinical studies. Pediatric use information is approved for Celgene Corporation's Vidaza (azacitidine for injection). However, due to Celgene Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

5.5 Tumor Lysis Syndrome

Azacitidine may cause fatal or serious tumor lysis syndrome, including in patients with MDS. Tumor lysis syndrome may occur despite concomitant use of allopurinol. Assess baseline risk and monitor and treat as appropriate.

5.6 Embryo-Fetal Toxicity

Based on the mechanism of action and findings in animals, azacitidine can cause fetal harm when administered to a pregnant woman. Azacitidine administered to pregnant rats via a single intraperitoneal (IP) dose approximating 8% of the recommended human daily dose caused fetal death and anomalies. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with azacitidine and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with azacitidine and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

6 Adverse Reactions

6.1 Clinical Trials Experience

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

MDS

The data described below reflect exposure to azacitidine in 443 patients with MDS from 4 clinical studies. Study 1 was a supportive-care controlled trial (subcutaneous administration), Studies 2 and 3 were single arm studies (one with subcutaneous administration and one with intravenous administration), and Study 4 was an international randomized trial (subcutaneous administration) [see Clinical Studies (14.1)]. In Studies 1, 2 and 3, a total of 268 patients were exposed to azacitidine, including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately one year). Azacitidine was studied primarily in supportive-care controlled and uncontrolled trials (n=150 and n=118, respectively). The population in the subcutaneous studies (n=220) was 23 to 92 years old (mean 66.4 years), 68% male, and 94% white, and had MDS or AML. The population in the intravenous study (n=48) was 35 to 81 years old (mean 63.1 years), 65% male, and 100% white. Most patients received average daily doses between 50 and 100 mg/m2. In Study 4, a total of 175 patients with higher-risk MDS (primarily RAEB and RAEB-T subtypes) were exposed to azacitidine. Of these patients, 119 were exposed for 6 or more cycles, and 63 for at least 12 cycles. The mean age of this population was 68.1 years (ranging from 42 to 83 years), 74% were male, and 99% were white. Most patients received daily azacitidine doses of 75 mg/m2. Most Commonly Occurring Adverse Reactions (Subcutaneous or Intravenous Route) in Adult Patients with MDS: nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia, ecchymosis. The most common adverse reactions by intravenous route also included petechiae, rigors, weakness and hypokalemia. Adverse Reactions Most Frequently (>2%) Resulting in Clinical Intervention (Subcutaneous or Intravenous Route) in Adult Patients with MDS: Discontinuation: leukopenia, thrombocytopenia, neutropenia. Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia. Dose Reduced: leukopenia, neutropenia, thrombocytopenia. Table 3 presents adverse reactions occurring in at least 5% of patients treated with azacitidine (subcutaneous) in Studies 1 and 2. It is important to note that duration of exposure was longer for the azacitidine-treated group than for the observation group: patients received azacitidine for a mean of 11.4 months while mean time in the observation arm was 6.1 months.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <colgroup> <col width="40%"/> <col width="25%"/> <col width="33%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" colspan="3" valign="top">Table 3: Most Frequently Observed Adverse Reactions (≥5% in All Subcutaneous Azacitidine Treated Patients; Studies 1 and 2)</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> </td><td align="left" class="Rrule" colspan="2" valign="top">Number (%) of Patients </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">System Organ Class Preferred Terma </td><td align="center" class="Rrule" valign="top">All Azacitidineb (N=220) </td><td align="center" class="Rrule" valign="top">Observationc (N=92) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Blood and lymphatic system disorders </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Anemia </td><td class="Rrule" valign="top">153 (70) </td><td class="Rrule" valign="top">59 (64) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Anemia aggravated </td><td class="Rrule" valign="top">12 (6) </td><td class="Rrule" valign="top">5 (5) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Febrile neutropenia </td><td class="Rrule" valign="top">36 (16) </td><td class="Rrule" valign="top">4 (4) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Leukopenia </td><td class="Rrule" valign="top">106 (48) </td><td class="Rrule" valign="top">27 (29) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Neutropenia </td><td class="Rrule" valign="top">71 (32) </td><td class="Rrule" valign="top">10 (11) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Thrombocytopenia </td><td class="Rrule" valign="top">144 (66) </td><td class="Rrule" valign="top">42 (46) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Gastrointestinal disorders </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Abdominal tenderness </td><td class="Rrule" valign="top">26 (12) </td><td class="Rrule" valign="top">1 (1) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Constipation </td><td class="Rrule" valign="top">74 (34) </td><td class="Rrule" valign="top">6 (7) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Diarrhea </td><td class="Rrule" valign="top">80 (36) </td><td class="Rrule" valign="top">13 (14) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Gingival bleeding </td><td class="Rrule" valign="top">21 (10) </td><td class="Rrule" valign="top">4 (4) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Loose stools </td><td class="Rrule" valign="top">12 (6) </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Mouth hemorrhage </td><td class="Rrule" valign="top">11 (5) </td><td class="Rrule" valign="top">1 (1) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Nausea </td><td class="Rrule" valign="top">155 (71) </td><td class="Rrule" valign="top">16 (17) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Stomatitis </td><td class="Rrule" valign="top">17 (8) </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Vomiting </td><td class="Rrule" valign="top">119 (54) </td><td class="Rrule" valign="top">5 (5) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top">General disorders and administration site conditions </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Chest pain </td><td class="Rrule" valign="top">36 (16) </td><td class="Rrule" valign="top">5 (5) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Injection site bruising </td><td class="Rrule" valign="top">31 (14) </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Injection site erythema </td><td class="Rrule" valign="top">77 (35) </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Injection site granuloma </td><td class="Rrule" valign="top">11 (5) </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Injection site pain </td><td class="Rrule" valign="top">50 (23) </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Injection site pigmentation changes </td><td class="Rrule" valign="top">11 (5) </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Injection site pruritus </td><td class="Rrule" valign="top">15 (7) </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Injection site reaction </td><td class="Rrule" valign="top">30 (14) </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Injection site swelling </td><td class="Rrule" valign="top">11 (5) </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Lethargy </td><td class="Rrule" valign="top">17 (8) </td><td class="Rrule" valign="top">2 (2) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Malaise </td><td class="Rrule" valign="top">24 (11) </td><td class="Rrule" valign="top">1 (1) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Pyrexia </td><td class="Rrule" valign="top">114 (52) </td><td class="Rrule" valign="top">28 (30) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Infections and infestations </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Nasopharyngitis </td><td class="Rrule" valign="top">32 (15) </td><td class="Rrule" valign="top">3 (3) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Pneumonia </td><td class="Rrule" valign="top">24 (11) </td><td class="Rrule" valign="top">5 (5) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Upper respiratory tract infection </td><td class="Rrule" valign="top">28 (13) </td><td class="Rrule" valign="top">4 (4) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top">Injury, poisoning, and procedural complications </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Post procedural hemorrhage </td><td class="Rrule" valign="top">13 (6) </td><td class="Rrule" valign="top">1 (1) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Metabolism and nutrition disorders </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Anorexia </td><td class="Rrule" valign="top">45 (21) </td><td class="Rrule" valign="top">6 (7) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top">Musculoskeletal and connective tissue disorders </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Arthralgia </td><td class="Rrule" valign="top">49 (22) </td><td class="Rrule" valign="top">3 (3) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Chest wall pain </td><td class="Rrule" valign="top">11 (5) </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Myalgia </td><td class="Rrule" valign="top">35 (16) </td><td class="Rrule" valign="top">2 (2) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Nervous system disorders </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Dizziness </td><td class="Rrule" valign="top">41 (19) </td><td class="Rrule" valign="top">5 (5) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Headache </td><td class="Rrule" valign="top">48 (22) </td><td class="Rrule" valign="top">10 (11) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Psychiatric disorders </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Anxiety </td><td class="Rrule" valign="top">29 (13) </td><td class="Rrule" valign="top">3 (3) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Insomnia </td><td class="Rrule" valign="top">24 (11) </td><td class="Rrule" valign="top">4 (4) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top">Respiratory, thoracic and mediastinal disorders </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Dyspnea </td><td class="Rrule" valign="top">64 (29) </td><td class="Rrule" valign="top">11 (12) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top">Skin and subcutaneous tissue disorders </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Dry skin </td><td class="Rrule" valign="top">11 (5) </td><td class="Rrule" valign="top">1 (1) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Ecchymosis </td><td class="Rrule" valign="top">67 (31) </td><td class="Rrule" valign="top">14 (15) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Erythema </td><td class="Rrule" valign="top">37 (17) </td><td class="Rrule" valign="top">4 (4) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Rash </td><td class="Rrule" valign="top">31 (14) </td><td class="Rrule" valign="top">9 (10) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Skin nodule </td><td class="Rrule" valign="top">11 (5) </td><td class="Rrule" valign="top">1 (1) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Urticaria </td><td class="Rrule" valign="top">13 (6) </td><td class="Rrule" valign="top">1 (1) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Vascular disorders </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Hematoma </td><td class="Rrule" valign="top">19 (9) </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Hypotension </td><td class="Rrule" valign="top">15 (7) </td><td class="Rrule" valign="top">2 (2) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Petechiae </td><td class="Rrule" valign="top">52 (24) </td><td class="Rrule" valign="top">8 (9) </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top">a Multiple terms of the same preferred terms for a patient are only counted once within each treatment group. b Includes adverse reactions from all patients exposed to azacitidine, including patients after crossing over from observations. c Includes adverse reactions from observation period only; excludes any adverse events after crossover to azacitidine. </td> </tr> </tbody> </table></div>

Table 4 presents adverse reactions occurring in at least 5% of patients treated with azacitidine in Study 4. Similar to Studies 1 and 2 described above, duration of exposure to treatment with azacitidine was longer (mean 12.2 months) compared with best supportive care (mean 7.5 months).

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <colgroup> <col width="39%"/> <col width="12%"/> <col width="12%"/> <col width="12%"/> <col width="21%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" colspan="5" valign="top">Table 4: Most Frequently Observed Adverse Reactions (≥5% in the Azacitidine Treated Patients and the Percentage with NCI CTC Grade 3/4 Reactions; Study 4)</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> </td><td align="left" class="Rrule" colspan="4" valign="top">Number (%) of Patients </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> </td><td align="left" class="Rrule" colspan="2" valign="top">Any Grade </td><td align="left" class="Rrule" colspan="2" valign="top">Grade 3/4 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> System Organ Class Preferred Terma </td><td align="center" class="Rrule" valign="top"> Azacitidine (N=175) </td><td align="left" class="Rrule" valign="top">Best Supportive Care Only (N=102) </td><td class="Rrule" valign="top"> Azacitidine (N=175) </td><td align="left" class="Rrule" valign="top">Best Supportive Care Only (N=102) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Blood and lymphatic system disorders </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Anemia </td><td class="Rrule" valign="top">90 (51) </td><td class="Rrule" valign="top">45 (44) </td><td class="Rrule" valign="top">24 (14) </td><td class="Rrule" valign="top">9 (9) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Febrile neutropenia </td><td class="Rrule" valign="top">24 (14) </td><td class="Rrule" valign="top">10 (10) </td><td class="Rrule" valign="top">22 (13) </td><td class="Rrule" valign="top">7 (7) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Leukopenia </td><td class="Rrule" valign="top">32 (18) </td><td class="Rrule" valign="top">2 (2) </td><td class="Rrule" valign="top">26 (15) </td><td class="Rrule" valign="top">1 (1) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Neutropenia </td><td class="Rrule" valign="top">115 (66) </td><td class="Rrule" valign="top">29 (28) </td><td class="Rrule" valign="top">107 (61) </td><td class="Rrule" valign="top">22 (22) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Thrombocytopenia </td><td class="Rrule" valign="top">122 (70) </td><td class="Rrule" valign="top">35 (34) </td><td class="Rrule" valign="top">102 (58) </td><td class="Rrule" valign="top">29 (28) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Gastrointestinal disorders </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Abdominal pain </td><td class="Rrule" valign="top">22 (13) </td><td class="Rrule" valign="top">7 (7) </td><td class="Rrule" valign="top">7 (4) </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Constipation </td><td class="Rrule" valign="top">88 (50) </td><td class="Rrule" valign="top">8 (8) </td><td class="Rrule" valign="top">2 (1) </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Dyspepsia </td><td class="Rrule" valign="top">10 (6) </td><td class="Rrule" valign="top">2 (2) </td><td class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Nausea </td><td class="Rrule" valign="top">84 (48) </td><td class="Rrule" valign="top">12 (12) </td><td class="Rrule" valign="top">3 (2) </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Vomiting </td><td class="Rrule" valign="top">47 (27) </td><td class="Rrule" valign="top">7 (7) </td><td class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">General disorders and administration site conditions </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Fatigue </td><td class="Rrule" valign="top">42 (24) </td><td class="Rrule" valign="top">12 (12) </td><td class="Rrule" valign="top">6 (3) </td><td class="Rrule" valign="top">2 (2) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Injection site bruising </td><td class="Rrule" valign="top">9 (5) </td><td align="left" class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Injection site erythema </td><td class="Rrule" valign="top">75 (43) </td><td align="left" class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Injection site hematoma </td><td class="Rrule" valign="top">11 (6) </td><td align="left" class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Injection site induration </td><td class="Rrule" valign="top">9 (5) </td><td align="left" class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Injection site pain </td><td class="Rrule" valign="top">33 (19) </td><td align="left" class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Injection site rash </td><td class="Rrule" valign="top">10 (6) </td><td align="left" class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Injection site reaction </td><td class="Rrule" valign="top">51 (29) </td><td align="left" class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">1 (1) </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Pyrexia </td><td class="Rrule" valign="top">53 (30) </td><td class="Rrule" valign="top">18 (18) </td><td class="Rrule" valign="top">8 (5) </td><td class="Rrule" valign="top">1 (1) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Infections and infestations </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Rhinitis </td><td class="Rrule" valign="top">10 (6) </td><td class="Rrule" valign="top">1 (1) </td><td class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Upper respiratory tract infection </td><td class="Rrule" valign="top">16 (9) </td><td class="Rrule" valign="top">4 (4) </td><td class="Rrule" valign="top">3 (2) </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Urinary tract infection </td><td class="Rrule" valign="top">15 (9) </td><td class="Rrule" valign="top">3 (3) </td><td class="Rrule" valign="top">3 (2) </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Investigations </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Weight decreased </td><td class="Rrule" valign="top">14 (8) </td><td align="left" class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">1 (1) </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Metabolism and nutrition disorders </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Hypokalemia </td><td class="Rrule" valign="top">11 (6) </td><td class="Rrule" valign="top">3 (3) </td><td class="Rrule" valign="top">3 (2) </td><td class="Rrule" valign="top">3 (3) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Nervous system disorders </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Lethargy </td><td class="Rrule" valign="top">13 (7) </td><td class="Rrule" valign="top">2 (2) </td><td class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">1 (1) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Psychiatric disorders </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Anxiety </td><td class="Rrule" valign="top">9 (5) </td><td class="Rrule" valign="top">1 (1) </td><td class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Insomnia </td><td class="Rrule" valign="top">15 (9) </td><td class="Rrule" valign="top">3 (3) </td><td class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Renal and urinary disorders </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Hematuria </td><td class="Rrule" valign="top">11 (6) </td><td class="Rrule" valign="top">2 (2) </td><td class="Rrule" valign="top">4 (2) </td><td class="Rrule" valign="top">1 (1) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Respiratory, thoracic and mediastinal disorders </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Dyspnea </td><td class="Rrule" valign="top">26 (15) </td><td class="Rrule" valign="top">5 (5) </td><td class="Rrule" valign="top">6 (3) </td><td class="Rrule" valign="top">2 (2) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Dyspnea exertional </td><td class="Rrule" valign="top">9 (5) </td><td class="Rrule" valign="top">1 (1) </td><td class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Pharyngolaryngeal pain </td><td class="Rrule" valign="top">11 (6) </td><td class="Rrule" valign="top">3 (3) </td><td class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Skin and subcutaneous tissue disorders </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Erythema </td><td class="Rrule" valign="top">13 (7) </td><td class="Rrule" valign="top">3 (3) </td><td class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Petechiae </td><td class="Rrule" valign="top">20 (11) </td><td class="Rrule" valign="top">4 (4) </td><td class="Rrule" valign="top">2 (1) </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Pruritus </td><td class="Rrule" valign="top">21 (12) </td><td class="Rrule" valign="top">2 (2) </td><td class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Rash </td><td class="Rrule" valign="top">18 (10) </td><td class="Rrule" valign="top">1 (1) </td><td class="Rrule" valign="top">0 </td><td class="Rrule" valign="top">0 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Vascular disorders </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Hypertension </td><td class="Rrule" valign="top">15 (9) </td><td class="Rrule" valign="top">4 (4) </td><td class="Rrule" valign="top">2 (1) </td><td class="Rrule" valign="top">2 (2) </td> </tr> <tr class="Last"> <td class="Lrule Rrule" colspan="5" valign="top">a Multiple reports of the same preferred term from a patient were only counted once within each treatment. </td> </tr> </tbody> </table></div>

In Studies 1, 2 and 4 with subcutaneous administration of azacitidine, adverse reactions of neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and injection site erythema/reaction tended to increase in incidence with higher doses of azacitidine. Adverse reactions that tended to be more pronounced during the first 1 to 2 cycles of subcutaneous treatment compared with later cycles included thrombocytopenia, neutropenia, anemia, nausea, vomiting, injection site erythema/pain/bruising/reaction, constipation, petechiae, dizziness, anxiety, hypokalemia, and insomnia. There did not appear to be any adverse reactions that increased in frequency over the course of treatment. Overall, adverse reactions were qualitatively similar between the intravenous and subcutaneous studies. Adverse reactions that appeared to be specifically associated with the intravenous route of administration included infusion site reactions (e.g. erythema or pain) and catheter site reactions (e.g. infection, erythema, or hemorrhage). In clinical studies of either subcutaneous or intravenous azacitidine, the following serious adverse reactions occurring at a rate of <5% (and not described in Tables 2 or 3) were reported: Blood and lymphatic system disorders: agranulocytosis, bone marrow failure, pancytopenia splenomegaly. Cardiac disorders: atrial fibrillation, cardiac failure, cardiac failure congestive, cardio respiratory arrest, congestive cardiomyopathy. Eye disorders: eye hemorrhage Gastrointestinal disorders: diverticulitis, gastrointestinal hemorrhage, melena, perirectal abscess. General disorders and administration site conditions: catheter site hemorrhage, general physical health deterioration, systemic inflammatory response syndrome. Hepatobiliary disorders: cholecystitis. Immune system disorders: anaphylactic shock, hypersensitivity. Infections and infestations: abscess limb, bacterial infection, cellulitis, blastomycosis, injection site infection, Klebsiella sepsis, neutropenic sepsis, pharyngitis streptococcal, pneumonia Klebsiella, sepsis, septic shock, Staphylococcal bacteremia, Staphylococcal infection, toxoplasmosis. Metabolism and nutrition disorders: dehydration. Musculoskeletal and connective tissue disorders: bone pain aggravated, muscle weakness, neck pain. Neoplasms benign, malignant and unspecified: leukemia cutis. Nervous system disorders: cerebral hemorrhage, convulsions, intracranial hemorrhage. Renal and urinary disorders: loin pain, renal failure. Respiratory, thoracic and mediastinal disorders: hemoptysis, lung infiltration, pneumonitis, respiratory distress. Skin and subcutaneous tissue disorders: pyoderma gangrenosum, rash pruritic, skin induration. Surgical and medical procedures: cholecystectomy. Vascular disorders: orthostatic hypotension.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of azacitidine. 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. - Interstitial lung disease - Tumor lysis syndrome - Injection site necrosis - Sweet’s syndrome (acute febrile neutrophilic dermatosis) - Necrotizing fasciitis (including fatal cases) - Differentiation syndrome - Pericardial effusion - Pericarditis - Cutaneous vasculitis

8 Use In Specific Populations

8.1 Pregnancy

Risk Summary Based on its mechanism of action and findings in animals, azacitidine can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)].There are no data on the use of azacitidine in pregnant women. Azacitidine was teratogenic and caused embryo-fetal lethality in animals at doses lower than the recommended human daily dose (see Data). Advise pregnant women of the potential risk to the fetus. The background rate of major birth defects and miscarriage is unknown for the indicated population. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% - 4% and 15% - 20%, respectively. Data Animal Data Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single IP (intraperitoneal) injection of 6 mg/m2 (approximately 8% of the recommended human daily dose on a mg/m2 basis) azacitidine on gestation day 10. Developmental abnormalities in the brain have been detected in mice given azacitidine on or before gestation day 15 at doses of ~3 to 12 mg/m2 (approximately 4%-16% the recommended human daily dose on a mg/m2 basis). In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4 - 8 (postimplantation) at a dose of 6 mg/m2 (approximately 8% of the recommended human daily dose on a mg/m2 basis), although treatment in the preimplantation period (on gestation days 1 - 3) had no adverse effect on the embryos. Azacitidine caused multiple fetal abnormalities in rats after a single IP dose of 3 to 12 mg/m2 (approximately 8% the recommended human daily dose on a mg/m2 basis) given on gestation day 9, 10, 11 or 12. In this study azacitidine caused fetal death when administered at 3 to 12 mg/m2 on gestation days 9 and 10; average live animals per litter was reduced to 9% of control at the highest dose on gestation day 9. Fetal anomalies included: CNS anomalies (exencephaly/encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly), and others (micrognathia, gastroschisis, edema, and rib abnormalities).

8.2 Lactation

Risk Summary There is no information regarding the presence of azacitidine in human milk, the effects of azacitidine on the breastfed infant, or the effects of azacitidine on milk production. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for azacitidine in animal studies [see Nonclinical Toxicology (13.1)] and the potential for serious adverse reactions in nursing infants from azacitidine, advise patients not to breastfeed during treatment with azacitidine and for 1 week after the last dose.

8.3 Females And Males Of Reproductive Potential

Based on its mechanism of action and findings in animals, azacitidine can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating azacitidine. Contraception Females Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with azacitidine and for 6 months after the last dose. Males Advise males with female partners of reproductive potential to use effective contraception during treatment with azacitidine and for 3 months after the last dose. Infertility Based on animal data, azacitidine could have an effect on male or female fertility [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness of azacitidine in pediatric patients with MDS have not been established.

8.5 Geriatric Use

Of the total number of patients in Studies 1, 2 and 3, 62% were 65 years and older and 21% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In addition, there were no relevant differences in the frequency of adverse reactions observed in patients 65 years and older compared to younger patients. Of the 179 patients randomized to azacitidine in Study 4, 68% were 65 years and older and 21% were 75 years and older. Survival data for patients 65 years and older were consistent with overall survival results. The majority of adverse reactions occurred at similar frequencies in patients <65 years of age and patients 65 years of age and older. Elderly patients are more likely to have decreased renal function. Monitor renal function in these patients [see Dosage and Administration (2.7) and Warnings and Precautions (5.4)].

10 Overdosage

One case of overdose with azacitidine was reported during clinical trials. A patient experienced diarrhea, nausea, and vomiting after receiving a single intravenous dose of approximately 290 mg/m2, almost 4 times the recommended starting dose. The events resolved without sequelae, and the correct dose was resumed the following day. In the event of overdosage, the patient should be monitored with appropriate blood counts and should receive supportive treatment, as necessary. There is no known specific antidote for azacitidine overdosage.

{ "type": "p", "children": [], "text": "One case of overdose with azacitidine was reported during clinical trials. A patient experienced diarrhea, nausea, and vomiting after receiving a single intravenous dose of approximately 290 mg/m2, almost 4 times the recommended starting dose. The events resolved without sequelae, and the correct dose was resumed the following day. In the event of overdosage, the patient should be monitored with appropriate blood counts and should receive supportive treatment, as necessary. There is no known specific antidote for azacitidine overdosage." }

11 Description

Azacitidine for injection contains azacitidine, which is a nucleoside metabolic inhibitor. Azacitidine is 4-Amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one. The structural formula is as follows:

{ "type": "p", "children": [], "text": "Azacitidine for injection contains azacitidine, which is a nucleoside metabolic inhibitor. Azacitidine is 4-Amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one. The structural formula is as follows:" }

The molecular formula is C8H12N4O5.The molecular weight is 244.20. Azacitidine is a white to off-white solid. Azacitidine was found to be Soluble in Dimethyl sulphoxide, sparingly soluble in water and insoluble in acetone and ethanol. The finished product is supplied in a sterile form for reconstitution as a suspension for subcutaneous injection or reconstitution as a solution with further dilution for intravenous infusion. Vials of azacitidine for injection contain 100 mg of azacitidine and 100 mg mannitol as a sterile lyophilized powder.

{ "type": "p", "children": [], "text": " The molecular formula is C8H12N4O5.The molecular weight is 244.20. Azacitidine is a white to off-white solid. Azacitidine was found to be Soluble in Dimethyl sulphoxide, sparingly soluble in water and insoluble in acetone and ethanol. The finished product is supplied in a sterile form for reconstitution as a suspension for subcutaneous injection or reconstitution as a solution with further dilution for intravenous infusion. Vials of azacitidine for injection contain 100 mg of azacitidine and 100 mg mannitol as a sterile lyophilized powder." }

12 Clinical Pharmacology

12.1 Mechanism Of Action

Azacitidine is a pyrimidine nucleoside analog of cytidine. Azacitidine is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

The pharmacokinetics of azacitidine were studied in 6 adult patients with MDS following a single 75 mg/m2 subcutaneous dose and a single 75 mg/m2 intravenous dose. Absorption Azacitidine is rapidly absorbed after subcutaneous administration; the peak plasma azacitidine concentration of 750 ± 403 ng/ml occurred in 0.5 hour after subcutaneous administration. Distribution The bioavailability of subcutaneous azacitidine relative to intravenous azacitidine is approximately 89%, based on area under the curve. Mean volume of distribution following intravenous dosing is 76 ± 26 L. Mean apparent subcutaneous clearance is 167 ± 49 L/hour and mean half-life after subcutaneous administration is 41 ± 8 minutes. The AUC and Cmax of subcutaneous administration of azacitidine in 21 patients with cancer were approximately dose proportional within the 25 to 100 mg/m2 dose range. Multiple dosing at the recommended dose- regimen does not result in drug accumulation with intravenous or subcutaneous administration. Elimination Metabolism An in vitro study of azacitidine incubation in human liver fractions indicated that azacitidine is not metabolized by the cytochrome P450 (CYP) enzymes. Azacitidine undergoes spontaneous hydrolysis and deamination mediated by cytidine deaminase. Excretion

Published studies indicate that urinary excretion is the primary route of elimination of azacitidine and its metabolites. Following intravenous administration of radioactive azacitidine to 5 cancer patients, the cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for <1% of administered radioactivity over 3 days. Mean excretion of radioactivity in urine following subcutaneous administration of 14C-azacitidine was 50%. The mean elimination half-lives of total radioactivity (azacitidine and its metabolites) were similar after intravenous and subcutaneous administrations, about 4 hours. Specific Populations The effects of hepatic impairment, gender, or race/ethnicity on the pharmacokinetics of intravenous and subcutaneous azacitidine have not been studied. Pediatric Patients Pediatric use information is approved for Celgene Corporation's Vidaza (azacitidine for injection). However, due to Celgene Corporation's marketing exclusivity rights, this drug product is not labeled with that information. Patients with Renal Impairment In adult patients with cancer, the pharmacokinetics of azacitidine in 6 patients with normal renal function (CLcr>80 mL/min) and 6 patients with severe renal impairment (CLcr<30 mL/min) were compared following daily subcutaneous dosing (Days 1 through 5) at 75 mg/m2/day. Severe renal impairment increased azacitidine exposure by approximately 70% after single and 41% after multiple subcutaneous administrations. This increase in exposure was not correlated with an increase in adverse events. The exposure was similar to exposure in patients with normal renal function receiving 100 mg/m2. Drug-Drug Interactions No formal clinical drug interaction studies with azacitidine have been conducted. In vitro Studies Cytochrome P450 (CYP) Enzymes: An in vitro study at azacitidine concentrations up to 100 mcM (IV Cmax = 10.6 mcM) in human liver microsomes indicated that azacitidine does not cause any inhibition of CYP isoforms CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or CYP2E1 at clinically achievable concentrations. In vitro studies with human cultured hepatocytes indicate that azacitidine at concentrations of 1.0 mcM to 100 mcM does not induce CYP 1A2, 2C19, or 3A4/5. Transporter Systems: An in vitro study with LLC-PK1 cells expressing P-glycoprotein (P-gp) indicated that azacitidine is not a substrate or inhibitor of P-gp. Azacitidine does not inhibit, breast cancer resistance protein (BCRP), organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptides (OATP) OATP1B1 and OATP1B3, or organic cation transporter (OCT) OCT2 at clinically relevant concentrations.

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

The potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine induced tumors of the hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m2, approximately 8% the recommended human daily dose on a mg/m2 basis) administered IP three times per week for 52 weeks. An increased incidence of tumors in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine IP at 2 mg/kg (6 mg/m2, approximately 8% the recommended human daily dose on a mg/m2 basis) once a week for 50 weeks. A tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m2 (approximately 20%-80% the recommended human daily dose on a mg/m2 basis) revealed an increased incidence of testicular tumors compared with controls. The mutagenic and clastogenic potential of azacitidine was tested in in vitro bacterial systems Salmonella typhimurium strains TA100 and several strains of trpE8, Escherichia coli strains WP14 Pro, WP3103P, WP3104P, and CC103; in in vitro forward gene mutation assay in mouse lymphoma cells and human lymphoblast cells; and in an in vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian hamster embryo cells. Azacitidine was mutagenic in bacterial and mammalian cell systems. The clastogenic effect of azacitidine was shown by the induction of micronuclei in L5178Y mouse cells and Syrian hamster embryo cells. Administration of azacitidine to male mice at 9.9 mg/m2 (approximately 9% the recommended human daily dose on a mg/m2 basis) daily for 3 days prior to mating with untreated female mice resulted in decreased fertility and loss of offspring during subsequent embryonic and postnatal development. Treatment of male rats 3 times per week for 11 or 16 weeks at doses of 15 to 30 mg/m2 (approximately 20%-40%, the recommended human daily dose on a mg/m2 basis) resulted in decreased weight of the testes and epididymides, and decreased sperm counts accompanied by decreased pregnancy rates and increased loss of embryos in mated females. In a related study, male rats treated for 16 weeks at 24 mg/m2 resulted in an increase in abnormal embryos in mated females when examined on day 2 of gestation.

14 Clinical Studies

14.1 Myelodysplastic Syndromes (Mds)

Study 1 was a randomized, open-label, controlled trial carried out in 53 U.S. sites compared the safety and efficacy of subcutaneous azacitidine plus supportive care with supportive care alone (“observation”) in adult patients with any of the five FAB subtypes of myelodysplastic syndromes (MDS): refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL). RA and RARS patients were included if they met one or more of the following criteria: required packed RBC transfusions; had platelet counts ≤50 x 109/L; required platelet transfusions; or were neutropenic (ANC <1.0 x 109/L) with infections requiring treatment with antibiotics. Patients with acute myelogenous leukemia (AML) were not intended to be included. Supportive care allowed in this study included blood transfusion products, antibiotics, antiemetics, analgesics and antipyretics. The use of hematopoietic growth factors was prohibited. Baseline patient and disease characteristics are summarized in Table 6; the 2 groups were similar. Azacitidine was administered at a subcutaneous dose of 75 mg/m2 daily for 7 days every 4 weeks. The dose was increased to 100 mg/m2 if no beneficial effect was seen after 2 treatment cycles. The dose was decreased and/or delayed based on hematologic response or evidence of renal toxicity. Patients in the observation arm were allowed by protocol to cross over to azacitidine if they had increases in bone marrow blasts, decreases in hemoglobin, increases in red cell transfusion requirements, or decreases in platelets, or if they required a platelet transfusion or developed a clinical infection requiring treatment with antibiotics. For purposes of assessing efficacy, the primary endpoint was response rate (as defined in Table 7). Of the 191 patients included in the study, independent review (adjudicated diagnosis) found that 19 had the diagnosis of AML at baseline. These patients were excluded from the primary analysis of response rate, although they were included in an intent-to-treat (ITT) analysis of all patients randomized. Approximately 55% of the patients randomized to observation crossed over to receive azacitidine treatment. Table 6. Baseline Demographics and Disease Characteristics

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <colgroup> <col width="53%"/> <col width="22%"/> <col width="24%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"> </td><td align="left" class="Rrule" valign="top">Azacitidine (N=99) </td><td class="Rrule" valign="top">Observation (N=92) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Gender (n%) </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Male </td><td class="Rrule" valign="top">72 (72.7) </td><td class="Rrule" valign="top">60 (65.2) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Female </td><td class="Rrule" valign="top">27 (27.3) </td><td class="Rrule" valign="top">32 (34.8) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Race (n%) </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">White </td><td class="Rrule" valign="top">93 (93.9) </td><td class="Rrule" valign="top">85 (92.4) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Black </td><td class="Rrule" valign="top">1 (1.0) </td><td class="Rrule" valign="top">1 (1.1) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Hispanic </td><td class="Rrule" valign="top">3 (3.0) </td><td class="Rrule" valign="top">5 (5.4) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Asian/Oriental </td><td class="Rrule" valign="top">2 (2.0) </td><td class="Rrule" valign="top">1 (1.1) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Age (years) </td><td class="Rrule" valign="top"> </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">N </td><td align="center" class="Rrule" valign="top">99 </td><td align="center" class="Rrule" valign="top">91 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Mean ± SD </td><td class="Rrule" valign="top">67.3 ± 10.39 </td><td class="Rrule" valign="top">68.0 ± 10.23 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Range </td><td class="Rrule" valign="top">31 - 92 </td><td class="Rrule" valign="top">35 - 88 </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top">Adjudicated MDS diagnosis at study entry (n%) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">RA </td><td class="Rrule" valign="top">21 (21.2) </td><td class="Rrule" valign="top">18 (19.6) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">RARS </td><td class="Rrule" valign="top">6 (6.1) </td><td class="Rrule" valign="top">5 (5.4) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">RAEB </td><td class="Rrule" valign="top">38 (38.4) </td><td class="Rrule" valign="top">39 (42.4) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">RAEB-T </td><td class="Rrule" valign="top">16 (16.2) </td><td class="Rrule" valign="top">14 (15.2) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">CMMoL </td><td class="Rrule" valign="top">8 (8.1) </td><td class="Rrule" valign="top">7 (7.6) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">AML </td><td class="Rrule" valign="top">10 (10.1) </td><td class="Rrule" valign="top">9 (9.8) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top">Transfusion product used in 3 months before study entry (n%) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Any transfusion product </td><td class="Rrule" valign="top">70 (70.7) </td><td class="Rrule" valign="top">59 (64.1) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Blood cells, packed human </td><td class="Rrule" valign="top">66 (66.7) </td><td class="Rrule" valign="top">55 (59.8) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Platelets, human blood </td><td class="Rrule" valign="top">15 (15.2) </td><td class="Rrule" valign="top">12 (13.0) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Hetastarch </td><td class="Rrule" valign="top">0(0.0) </td><td class="Rrule" valign="top">1(1.1) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Plasma protein fraction </td><td class="Rrule" valign="top">1(1.0) </td><td class="Rrule" valign="top">0(0.0) </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">Other </td><td class="Rrule" valign="top">2(2.0) </td><td class="Rrule" valign="top">2(2.2) </td> </tr> </tbody> </table></div>

Table 7. Response Criteria

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <colgroup> <col width="28%"/> <col width="14%"/> <col width="14%"/> <col width="14%"/> <col width="14%"/> <col width="14%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" colspan="2" valign="top"> </td><td align="left" class="Rrule" valign="top">RA </td><td class="Rrule" valign="top">RARS </td><td class="Rrule" valign="top">RAEB </td><td class="Rrule" valign="top">RAEB-T </td><td class="Rrule" valign="top">CMMoL </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" rowspan="2" valign="top">Complete Response (CR), duration >4 weeks </td><td class="Rrule" valign="top">Marrow </td><td class="Rrule" colspan="5" valign="top"><5% blasts </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Peripheral Blood </td><td class="Rrule" colspan="5" valign="top">Normal CBC if abnormal at baseline Absence of blasts in the peripheral circulation </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" rowspan="2" valign="top">Partial Response (PR), duration>4 weeks </td><td class="Rrule" valign="top">Marrow </td><td class="Rrule" colspan="2" valign="top">No marrow requirements </td><td class="Rrule" colspan="3" valign="top">≥50% decrease in blasts Improvement of marrow dyspoiesis </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top"> Peripheral Blood </td><td class="Rrule" colspan="5" valign="top">≥50% restoration in the deficit from normal levels of baseline white cells, hemoglobin and platelets if abnormal at baseline No blasts in the peripheral circulation For CMMoL, if WBC is elevated at baseline, a ≥75% reduction in the excess count over the upper limit of normal </td> </tr> </tbody> </table></div>

The overall response rate (CR + PR) of 15.7% in azacitidine-treated patients without AML (16.2% for all azacitidine randomized patients including AML) was statistically significantly higher than the response rate of 0% in the observation group (p<0.0001) (Table 8). The majority of patients who achieved either CR or PR had either 2 or 3 cell line abnormalities at baseline (79%; 11/14) and had elevated bone marrow blasts or were transfusion dependent at baseline. Patients responding to azacitidine had a decrease in bone marrow blasts percentage, or an increase in platelets, hemoglobin or WBC. Greater than 90% of the responders initially demonstrated these changes by the 5th treatment cycle. All patients who had been transfusion dependent became transfusion independent during PR or CR. The mean and median duration of clinical response of PR or better was estimated as 512 and 330 days, respectively; 75% of the responding patients were still in PR or better at completion of treatment. Response occurred in all MDS subtypes as well as in patients with adjudicated baseline diagnosis of AML. Table 8. Response Rates

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <colgroup> <col width="24%"/> <col width="28%"/> <col width="27%"/> <col width="19%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"> </td><td align="left" class="Rrule" valign="middle">Azacitidine (N=89) </td><td align="left" class="Rrule" valign="middle">Observation Before Crossover (N=83) </td><td class="Rrule" valign="top"> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Response </td><td align="left" class="Rrule" valign="top">n (%) </td><td align="left" class="Rrule" valign="top">n (%) </td><td class="Rrule" valign="top">P value </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Overall (CR+PR) </td><td class="Rrule" valign="top">14 (15.7) </td><td align="left" class="Rrule" valign="top">0 ( 0.0) </td><td class="Rrule" valign="top">(<0.0001) </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Complete (CR) </td><td align="left" class="Rrule" valign="top">5 ( 5.6) </td><td align="left" class="Rrule" valign="top">0 ( 0.0) </td><td align="left" class="Rrule" valign="top">(0.06) </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">Partial (PR) </td><td align="left" class="Rrule" valign="top">9 (10.1) </td><td align="left" class="Rrule" valign="top">0 ( 0.0) </td><td align="left" class="Rrule" valign="top">-- </td> </tr> </tbody> </table></div>

Patients in the observation group who crossed over to receive azacitidine treatment (47 patients) had a response rate of 12.8%. Study 2, a multi-center, open-label, single-arm study of 72 patients with RAEB, RAEB-T, CMMoL, or AML was also carried out. Treatment with subcutaneous azacitidine resulted in a response rate (CR + PR) of 13.9%, using criteria similar to those described above. The mean and median duration of clinical response of PR or better was estimated as 810 and 430 days, respectively; 80% of the responding patients were still in PR or better at the time of completion of study involvement. In Study 3, another open-label, single-arm study of 48 patients with RAEB, RAEB-T, or AML, treatment with intravenous azacitidine resulted in a response rate of 18.8%, again using criteria similar to those described above. The mean and median duration of clinical response of PR or better was estimated as 389 and 281 days, respectively; 67% of the responding patients were still in PR or better at the time of completion of treatment. Response occurred in all MDS subtypes as well as in patients with adjudicated baseline diagnosis of AML in both of these studies. Azacitidine dosage regimens in these 2 studies were similar to the regimen used in the controlled study. Benefit was seen in patients who did not meet the criteria for PR or better, but were considered “improved.”About 24% of azacitidine-treated patients were considered improved, and about 2/3 of those lost transfusion dependence. In the observation group, only 5/83 patients met criteria for improvement; none lost transfusion dependence. In all 3 studies, about 19% of patients met criteria for improvement with a median duration of 195 days. Study 4 was an international, multicenter, open-label, randomized trial in patients with MDS with RAEB, RAEB-T or modified CMMoL according to FAB classification and Intermediate-2 and High risk according to IPSS classification. Of the 358 patients enrolled in the study, 179 were randomized to receive azacitidine plus best supportive care (BSC) and 179 were randomized to receive conventional care regimens (CCR) plus BSC (105 to BSC alone, 49 to low dose cytarabine and 25 to chemotherapy with cytarabine and anthracycline). The primary efficacy endpoint was overall survival. The azacitidine and CCR groups were comparable for baseline parameters. The median age of patients was 69 years (range was 38 - 88 years), 98% were Caucasian, and 70% were male. At baseline, 95% of the patients were higher risk by FAB classification: RAEB (58%), RAEB-T (34%), and CMMoL (3%). By IPSS classification, 87% were higher risk: Int-2 (41%), High (47%). At baseline, 32% of patients met WHO criteria for AML. Azacitidine was administered subcutaneously at a dose of 75 mg/m2 daily for 7 consecutive days every 28 days (which constituted one cycle of therapy). Patients continued treatment until disease progression, relapse after response, or unacceptable toxicity. Azacitidine patients were treated for a median of 9 cycles (range 1 to 39), BSC only patients for a median of 7 cycles (range 1 to 26), low dose cytarabine patients for a median of 4.5 cycles (range 1 to 15), and chemotherapy with cytarabine and anthracycline patients for a median of 1 cycle (range 1 to 3, i.e. induction plus 1 or 2 consolidation cycles). In the Intent-to-Treat analysis, patients treated with azacitidine demonstrated a statistically significant difference in overall survival as compared to patients treated with CCR (median survival of 24.5 months vs. 15.0 months; stratified log-rank p=0.0001). The hazard ratio describing this treatment effect was 0.58 (95% CI: 0.43, 0.77). Kaplan-Meier Curve of Time to Death from Any Cause: (Intent-to-Treat Population)

Key: AZA = azacitidine; CCR = conventional care regimens; CI = confidence interval; HR = Hazard Ratio Azacitidine treatment led to a reduced need for red blood cell transfusions (see Table 8). In patients treated with azacitidine who were RBC transfusion dependent at baseline and became transfusion independent, the median duration of RBC transfusion independence was 13.0 months. Table 9. Effect of Azacitidine on RBC Transfusions in Patients with MDS

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <colgroup> <col width="39%"/> <col width="29%"/> <col width="30%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top">Efficacy Parameter </td><td align="left" class="Rrule" valign="top">Azacitidine plus BSC (n= 179) </td><td align="left" class="Rrule" valign="top">Conventional Care Regimens (n= 179) </td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" valign="top">Number and percent of patients who were transfusion dependent at baseline who became transfusion independent on treatment1 Number and percent of patients who were transfusion-independent at baseline who became transfusion-dependent on treatment </td><td align="left" class="Rrule" valign="top">50/111 (45.0%) (95% CI: 35.6%, 54.8%) 10/68 (14.7%) (95% CI: 7.3%, 25.4%) </td><td align="left" class="Rrule" valign="top">13/114 (11.4%) (95% CI: 6.2%, 18.7%) 28/65 (43.1%) (95% CI: 30.9%, 56.0%) </td> </tr> </tbody> </table></div>

1A patient was considered RBC transfusion independent during the treatment period if the patient had no RBC transfusions during any 56 consecutive days or more during the treatment period. Otherwise, the patient was considered transfusion dependent.

15 References

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

16 How Supplied/Storage And Handling

How Supplied Azacitidine for injection is supplied as a lyophilized cake or powder in 100 mg single-dose vials packaged in cartons of 1 vial (NDC 69539-112-01). Storage Store unreconstituted vials at 25º C (77º F); excursions permitted to 15º - 30º C (59º - 86º F) (See USP Controlled Room Temperature). Handling and Disposal Azacitidine for injection is a hazardous drug. Follow applicable special handling and disposal procedures.1

{ "type": "p", "children": [], "text": "\nHow Supplied\n Azacitidine for injection is supplied as a lyophilized cake or powder in 100 mg single-dose vials packaged in cartons of 1 vial (NDC 69539-112-01).\nStorage\n Store unreconstituted vials at 25º C (77º F); excursions permitted to 15º - 30º C (59º - 86º F) (See USP Controlled Room Temperature).\nHandling and Disposal\n Azacitidine for injection is a hazardous drug. Follow applicable special handling and disposal procedures.1\n" }

17 Patient Counseling Information

Hepatotoxicity in Patients with Severe Pre-Existing Hepatic Impairment Instruct patients to inform their physician about any underlying liver disease [see Warnings and Precautions (5.3)]. Renal Toxicity Instruct patients to inform their physician about any underlying renal disease [see Warnings and Precautions (5.4)] Embryo-Fetal Toxicity Advise pregnant women of the potential risk to a fetus [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with azacitidine and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with azacitidine and for 3 months after the last dose. Advise patients to report known or suspected pregnancy to their physicians immediately [see Warnings and Precautions (5.6) and Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "\nHepatotoxicity in Patients with Severe Pre-Existing Hepatic Impairment\n Instruct patients to inform their physician about any underlying liver disease [see Warnings and Precautions (5.3)].\nRenal Toxicity\n Instruct patients to inform their physician about any underlying renal disease [see Warnings and Precautions (5.4)]\nEmbryo-Fetal Toxicity\n Advise pregnant women of the potential risk to a fetus [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)].\n Advise females of reproductive potential to use effective contraception during treatment with azacitidine and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with azacitidine and for 3 months after the last dose. Advise patients to report known or suspected pregnancy to their physicians immediately [see Warnings and Precautions (5.6) and Use in Specific Populations (8.3)]." }

Lactation Advise patients to avoid breastfeeding while receiving azacitidine and for 1 week after the last dose [see Use in Specific Populations (8.2)]. Infertility

{ "type": "p", "children": [], "text": "\nLactation\n Advise patients to avoid breastfeeding while receiving azacitidine and for 1 week after the last dose [see Use in Specific Populations (8.2)].\n\nInfertility\n" }

Advise males and females that azacitidine may impair fertility [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)]. Manufactured by: MSN Laboratories Private Limited Telangana – 509 228, INDIA

{ "type": "p", "children": [], "text": "Advise males and females that azacitidine may impair fertility [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].\n\nManufactured by: MSN Laboratories Private Limited\n Telangana – 509 228, INDIA" }

Distributed by: MSN Pharmaceuticals Inc. Piscataway, NJ 08854 -3714

{ "type": "p", "children": [], "text": "\nDistributed by: MSN Pharmaceuticals Inc.\n Piscataway, NJ 08854 -3714" }

Issued on: 07/2024

{ "type": "p", "children": [], "text": "\nIssued on: 07/2024" }

Package Label.Principal Display Panel

Azacitidine Vial Label:

{ "type": "p", "children": [], "text": "\nAzacitidine Vial Label:\n" }

Azacitidine Carton Label:

{ "type": "p", "children": [], "text": "\nAzacitidine Carton Label:\n\n\n\n" }

0e95e33f-8aba-4f19-b332-2416580d358b

ONUREG- azacitidine tablet, film coated

1 Indications And Usage

ONUREG is indicated for continued treatment of adult patients with acute myeloid leukemia who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy.

{ "type": "p", "children": [], "text": "ONUREG is indicated for continued treatment of adult patients with acute myeloid leukemia who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy." }

2 Dosage And Administration

2.1 Important Administration Information

Do not substitute ONUREG for intravenous or subcutaneous azacitidine. The indications and dosing regimen for ONUREG differ from that of intravenous or subcutaneous azacitidine [see Warnings and Precautions (5.1)].

2.2 Recommended Dosage

The recommended dosage of ONUREG is 300 mg orally once daily with or without food on Days 1 through 14 of each 28-day cycle. Continue ONUREG until disease progression or unacceptable toxicity.

Administer an antiemetic 30 minutes prior to each dose of ONUREG for the first 2 cycles. Antiemetic prophylaxis may be omitted after 2 cycles if there has been no nausea and vomiting.

If the absolute neutrophil count (ANC) is less than 0.5 Gi/L on Day 1 of a cycle, do not administer ONUREG. Delay the start of the cycle until the ANC is 0.5 Gi/L or more.

Instruct patients on the following:

ONUREG is a hazardous drug. Follow applicable special handling and disposal procedures.1

2.3 Monitoring And Dosage Modifications For Adverse Reactions

Monitor complete blood count every other week for the first 2 cycles and prior to the start of each cycle thereafter. Increase monitoring to every other week for the 2 cycles after any dose reduction for myelosuppression.

The recommended dosage modifications for adverse reactions are provided in Table 1.

<div class="scrollingtable"><table width="80%"> <caption> Table 1: Recommended Dosage Modifications for Adverse Reactions </caption> <col width="20%"/> <col width="27%"/> <col width="45%"/> <thead> <tr class="First Last"> <th align="center" class="Botrule Lrule Rrule Toprule" valign="top">Adverse Reaction</th><th align="center" class="Botrule Rrule Toprule" valign="top">Severity</th><th align="center" class="Botrule Rrule Toprule" valign="top">Recommended Dosage Modification</th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="3" valign="top"> Myelosuppression [see <a href="#S5.2">Warnings and Precautions (5.2)</a>] </td><td class="Botrule Rrule Toprule" valign="top"> Neutrophils less than 0.5 Gi/L on Cycle Day 1 </td><td class="Botrule Rrule Toprule" valign="top"> <dl> <dt>•</dt> <dd>Interrupt treatment. Resume at the same dose once neutrophils return to 0.5 Gi/L or higher.</dd> </dl> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Neutrophils less than 1 Gi/L with fever at anytime </td><td class="Botrule Rrule" valign="top"> First Occurrence <dl> <dt>•</dt> <dd>Interrupt treatment. Resume at the same dose once neutrophils return to 1 Gi/L or higher.</dd> </dl> Occurrence in 2 Consecutive Cycles <dl> <dt>•</dt> <dd>Interrupt treatment. After neutrophils return to 1 Gi/L or higher, resume at reduced dose of 200 mg.</dd> <dt>•</dt> <dd>If a patient continues to experience febrile neutropenia after dose reduction, reduce the treatment duration by 7 days.</dd> <dt>•</dt> <dd>If febrile neutropenia reoccurs after dose and schedule reduction, discontinue ONUREG.</dd> </dl> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Platelets less than 50 Gi/L with bleeding </td><td class="Botrule Rrule" valign="top"> First Occurrence <dl> <dt>•</dt> <dd>Interrupt dose. Resume at the same dose once platelets return to 50 Gi/L or higher.</dd> </dl> Occurrence in 2 Consecutive Cycles <dl> <dt>•</dt> <dd>Interrupt dose. After platelets return to 50 Gi/L or higher, resume at reduced dose of 200 mg.</dd> <dt>•</dt> <dd>If a patient continues to experience thrombocytopenia with bleeding after dose reduction, reduce the treatment duration by 7 days.</dd> <dt>•</dt> <dd>If thrombocytopenia with bleeding reoccurs after dose and schedule reduction, discontinue ONUREG.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> Gastrointestinal Toxicity [see <a href="#S6.1">Adverse Reactions (6.1)</a>] </td><td class="Botrule Rrule" valign="top"> Grade 3 or 4 Nausea or Vomiting </td><td class="Botrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>Interrupt dose. Resume at the same dose once toxicity has resolved to Grade 1 or lower.</dd> <dt>•</dt> <dd>If toxicity reoccurs, interrupt dose until resolved to Grade 1 or lower. Resume at reduced dose of 200 mg.</dd> <dt>•</dt> <dd>If a patient continues to experience the toxicity after dose reduction, reduce the treatment duration by 7 days.</dd> <dt>•</dt> <dd>If the toxicity continues or reoccurs after dose and schedule reduction, discontinue ONUREG.</dd> </dl> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Grade 3 or 4 Diarrhea </td><td class="Botrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>Interrupt dose. Resume at the same dose once toxicity has resolved to Grade 1 or lower.</dd> <dt>•</dt> <dd>If toxicity reoccurs, interrupt dose until resolved to Grade 1 or lower. Resume at reduced dose of 200 mg.</dd> <dt>•</dt> <dd>If a patient continues to experience the toxicity after dose reduction, reduce the treatment duration by 7 days.</dd> <dt>•</dt> <dd>If the toxicity continues or reoccurs after dose and schedule reduction, discontinue ONUREG.</dd> </dl> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> Other Adverse Reactions [see <a href="#S6.1">Adverse Reactions (6.1)</a>] </td><td class="Botrule Rrule" valign="top"> Grade 3 or 4 </td><td class="Botrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>Interrupt dose and provide medical support. Resume at the same dose once toxicity has resolved to Grade 1 or lower.</dd> <dt>•</dt> <dd>If toxicity re-occurs, interrupt dose until resolved to Grade 1 or lower. Resume at reduced dose of 200 mg.</dd> <dt>•</dt> <dd>If a patient continues to experience the toxicity after dose reduction, reduce the treatment duration by 7 days.</dd> <dt>•</dt> <dd>If the toxicity continues or reoccurs after dose and schedule reduction, discontinue ONUREG.</dd> </dl> </td> </tr> </tbody> </table></div>

3 Dosage Forms And Strengths

Tablets:

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

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

4 Contraindications

ONUREG is contraindicated in patients with known severe hypersensitivity to azacitidine or its components [see Adverse Reactions (6.2), Description (11)].

{ "type": "p", "children": [], "text": "ONUREG is contraindicated in patients with known severe hypersensitivity to azacitidine or its components [see Adverse Reactions (6.2), Description (11)]." }

5 Warnings And Precautions

5.1 Risks Of Substitution With Other Azacitidine Products

Due to substantial differences in the pharmacokinetic parameters [see Clinical Pharmacology (12.3)], the recommended dose and schedule for ONUREG are different from those for the intravenous or subcutaneous azacitidine products. Treatment of patients using intravenous or subcutaneous azacitidine at the recommended dosage of ONUREG may result in a fatal adverse reaction. Treatment of patients using ONUREG at the doses recommended for intravenous or subcutaneous azacitidine may not be effective.

Do not substitute ONUREG for intravenous or subcutaneous azacitidine [see Dosage and Administration (2.1)].

5.2 Myelosuppression

New or worsening Grade 3 or 4 neutropenia and thrombocytopenia occurred in 49% and 22% of patients who received ONUREG, respectively. Febrile neutropenia occurred in 12%. A dose reduction was required for 7% and 2% of patients due to neutropenia and thrombocytopenia, respectively. Less than 1% of patients discontinued ONUREG due to either neutropenia or thrombocytopenia.

Monitor complete blood counts and modify the dosage as recommended [see Dosage and Administration (2.2, 2.3)]. Provide standard supportive care, including hematopoietic growth factors, if myelosuppression occurs.

5.3 Increased Early Mortality In Patients With Myelodysplastic Syndromes

In AZA-MDS-003 (NCT01566695), 216 patients with red blood cell transfusion-dependent anemia and thrombocytopenia due to myelodysplastic syndromes were randomized to ONUREG or placebo. One-hundred and seven patients received a median of 5 cycles of ONUREG 300 mg daily for 21 days of a 28-day cycle. Enrollment was discontinued early due to a higher incidence of early fatal and/or serious adverse reactions in patients who received ONUREG compared with placebo. The most frequent fatal adverse reaction was sepsis. The safety and effectiveness of ONUREG for treatment of myelodysplastic syndromes have not been established. Treatment of patients with myelodysplastic syndromes with ONUREG is not recommended outside of controlled trials.

5.4 Embryo-Fetal Toxicity

Based on the mechanism of action and findings in animals, ONUREG can cause fetal harm when administered to a pregnant woman. Azacitidine administered to pregnant rats via a single intraperitoneal dose less than the recommended human daily dose of oral azacitidine on a mg/m2 basis caused fetal death and anomalies.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ONUREG and for at least 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ONUREG and for at least 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Acute Myeloid Leukemia

The safety of ONUREG was evaluated in QUAZAR [see Clinical Studies (14)]. Patients received ONUREG 300 mg (N=236) or placebo (N=233) orally once daily on Days 1 through 14 of each 28-day cycle. Among patients who received ONUREG, 71% were exposed for 6 months or longer, and 49% were exposed for greater than one year. The median duration of exposure to ONUREG was 11.6 months (range: 0.5 to 74.3 months) and the median number of cycles was 12 (range: 1 to 82 cycles).

Serious adverse reactions occurred in 15% of patients who received ONUREG. Serious adverse reactions in ≥ 2% of patients who received ONUREG were pneumonia (8%) and febrile neutropenia (7%). One fatal adverse reaction (sepsis) occurred in a patient who received ONUREG.

Permanent discontinuation of ONUREG due to an adverse reaction occurred in 8% of patients. Adverse reactions which resulted in permanent discontinuation of ONUREG in > 1% of patients included nausea (2.1%), diarrhea (1.7%), and vomiting (1.3%). Interruptions of ONUREG due to an adverse reaction occurred in 35% of patients. Adverse reactions which required an interruption of ONUREG in > 5% of patients included neutropenia (20%), thrombocytopenia (8%), and nausea (6%).

Dose reductions of ONUREG due to an adverse reaction occurred in 14% of patients. Adverse reactions which required a dose reduction in > 1% of patients included neutropenia (6%), diarrhea (3.4%), thrombocytopenia (1.7%), and nausea (1.7%).

The most common (≥ 10%) adverse reactions were nausea, vomiting, diarrhea, fatigue/asthenia, constipation, pneumonia, abdominal pain, arthralgia, decreased appetite, febrile neutropenia, dizziness, and pain in extremity.

Table 2 summarizes the adverse reactions in QUAZAR.

<div class="scrollingtable"><table width="80%"> <caption> Table 2: Adverse Reactions (≥ 5%) in Patients with AML Who Received ONUREG with a Difference Between Arms of > 2% Compared to Placebo in QUAZAR </caption> <col width="27%"/> <col width="25%"/> <col width="13%"/> <col width="13%"/> <col width="13%"/> <thead> <tr class="First"> <th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle">Adverse Reaction</th><th align="center" class="Botrule Rrule Toprule" colspan="2" valign="top">ONUREG (N=236)</th><th align="center" class="Botrule Rrule Toprule" colspan="2" valign="top">Placebo (N=233)</th> </tr> <tr class="Last"> <th align="center" class="Botrule Rrule" valign="top">All Grades (%)</th><th align="center" class="Botrule Rrule" valign="top">Grade 3 or 4 (%)</th><th align="center" class="Botrule Rrule" valign="top">All Grades (%)</th><th align="center" class="Botrule Rrule" valign="top">Grade 3 or 4 (%)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" class="Botrule" colspan="5" valign="top">a Grouped term includes abdominal pain, abdominal pain upper, abdominal discomfort, and gastrointestinal pain. b Grouped term includes fatigue and asthenia. c Broad scope term includes influenza, pneumonia, respiratory tract infection, respiratory tract infection viral, bronchopulmonary aspergillosis, lung infection, Staphylococcal infection, atypical pneumonia, lower respiratory tract infection, lung abscess, Pneumocystis jirovecii pneumonia, pneumonia bacterial, pneumonia fungal, Pseudomonas infection, hemoptysis, productive cough, pleural effusion, atelectasis, pleuritic pain, rales, Enterobacter test positive, and Hemophilus test positive.</td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="5" valign="top"> Gastrointestinal disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Nausea </td><td align="center" class="Botrule Rrule" valign="top"> 65 </td><td align="center" class="Botrule Rrule" valign="top"> 3 </td><td align="center" class="Botrule Rrule" valign="top"> 24 </td><td align="center" class="Botrule Rrule" valign="top"> < 1 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Vomiting </td><td align="center" class="Botrule Rrule" valign="top"> 60 </td><td align="center" class="Botrule Rrule" valign="top"> 3 </td><td align="center" class="Botrule Rrule" valign="top"> 10 </td><td align="center" class="Botrule Rrule" valign="top"> 0 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Diarrhea </td><td align="center" class="Botrule Rrule" valign="top"> 50 </td><td align="center" class="Botrule Rrule" valign="top"> 5 </td><td align="center" class="Botrule Rrule" valign="top"> 21 </td><td align="center" class="Botrule Rrule" valign="top"> 1 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Constipation </td><td align="center" class="Botrule Rrule" valign="top"> 39 </td><td align="center" class="Botrule Rrule" valign="top"> 1 </td><td align="center" class="Botrule Rrule" valign="top"> 24 </td><td align="center" class="Botrule Rrule" valign="top"> 0 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Abdominal paina </td><td align="center" class="Botrule Rrule" valign="top"> 22 </td><td align="center" class="Botrule Rrule" valign="top"> 2 </td><td align="center" class="Botrule Rrule" valign="top"> 13 </td><td align="center" class="Botrule Rrule" valign="top"> < 1 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> General disorders and administration site conditions </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Fatigue / astheniab </td><td align="center" class="Botrule Rrule" valign="top"> 44 </td><td align="center" class="Botrule Rrule" valign="top"> 4 </td><td align="center" class="Botrule Rrule" valign="top"> 25 </td><td align="center" class="Botrule Rrule" valign="top"> 1 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Infections </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Pneumoniac </td><td align="center" class="Botrule Rrule" valign="top"> 27 </td><td align="center" class="Botrule Rrule" valign="top"> 9 </td><td align="center" class="Botrule Rrule" valign="top"> 17 </td><td align="center" class="Botrule Rrule" valign="top"> 5 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Musculoskeletal and connective tissue disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Arthralgia </td><td align="center" class="Botrule Rrule" valign="top"> 14 </td><td align="center" class="Botrule Rrule" valign="top"> 1 </td><td align="center" class="Botrule Rrule" valign="top"> 10 </td><td align="center" class="Botrule Rrule" valign="top"> < 1 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Pain in extremity </td><td align="center" class="Botrule Rrule" valign="top"> 11 </td><td align="center" class="Botrule Rrule" valign="top"> < 1 </td><td align="center" class="Botrule Rrule" valign="top"> 5 </td><td align="center" class="Botrule Rrule" valign="top"> 0 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Metabolism and nutrition disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Decreased appetite </td><td align="center" class="Botrule Rrule" valign="top"> 13 </td><td align="center" class="Botrule Rrule" valign="top"> 1 </td><td align="center" class="Botrule Rrule" valign="top"> 6 </td><td align="center" class="Botrule Rrule" valign="top"> 1 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Blood and lymphatic disorders </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Febrile neutropenia </td><td align="center" class="Botrule Rrule" valign="top"> 12 </td><td align="center" class="Botrule Rrule" valign="top"> 11 </td><td align="center" class="Botrule Rrule" valign="top"> 8 </td><td align="center" class="Botrule Rrule" valign="top"> 8 </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> Nervous system disorders </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> Dizziness </td><td align="center" class="Botrule Rrule" valign="top"> 11 </td><td align="center" class="Botrule Rrule" valign="top"> 0 </td><td align="center" class="Botrule Rrule" valign="top"> 9 </td><td align="center" class="Botrule Rrule" valign="top"> 0 </td> </tr> </tbody> </table></div>

Clinically relevant adverse reactions that did not meet criteria for inclusion in Table 2 were weight decreased (4%) in patients who received ONUREG.

Neutropenia, thrombocytopenia, and anemia of any grade occurred in 74%, 65%, and 25% of patients who received ONUREG. Table 3 summarizes select Grades 3 or 4 hematological laboratory abnormalities in QUAZAR.

<div class="scrollingtable"><table width="80%"> <caption> Table 3: Selected Hematological Laboratory Abnormalities That Worsened from Baseline in Patients Who Received ONUREG in QUAZAR </caption> <col width="33%"/> <col width="15%"/> <col width="15%"/> <col width="15%"/> <col width="15%"/> <thead> <tr class="First"> <th align="left" class="Lrule Rrule Toprule" valign="top"></th><th align="center" class="Botrule Rrule Toprule" colspan="2" valign="top">ONUREG</th><th align="center" class="Botrule Rrule Toprule" colspan="2" valign="top">Placebo</th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" valign="top">Laboratory Abnormality</th><th align="center" class="Botrule Rrule" valign="top">Baseline Grade 0-2 N</th><th align="center" class="Botrule Rrule" valign="top">Post-Baseline Grade 3 or 4 n (%)</th><th align="center" class="Botrule Rrule" valign="top">Baseline Grade 0-2 N</th><th align="center" class="Botrule Rrule" valign="top">Post-Baseline Grade 3 or 4 n (%)</th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> Neutropenia </td><td align="center" class="Botrule Rrule Toprule" valign="top"> 223 </td><td align="center" class="Botrule Rrule Toprule" valign="top"> 109 (49) </td><td align="center" class="Botrule Rrule Toprule" valign="top"> 217 </td><td align="center" class="Botrule Rrule Toprule" valign="top"> 50 (23) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Thrombocytopenia </td><td align="center" class="Botrule Rrule" valign="top"> 222 </td><td align="center" class="Botrule Rrule" valign="top"> 46 (21) </td><td align="center" class="Botrule Rrule" valign="top"> 212 </td><td align="center" class="Botrule Rrule" valign="top"> 22 (10) </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> Anemia </td><td align="center" class="Botrule Rrule" valign="top"> 229 </td><td align="center" class="Botrule Rrule" valign="top"> 10 (4) </td><td align="center" class="Botrule Rrule" valign="top"> 223 </td><td align="center" class="Botrule Rrule" valign="top"> 7 (3) </td> </tr> </tbody> </table></div>

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of intravenous or subcutaneous azacitidine. 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.

8 Use In Specific Populations

8.1 Pregnancy

Risk Summary

Based on its mechanism of action [see Clinical Pharmacology (12.1)] and findings in animals, ONUREG can cause fetal harm when administered to a pregnant woman. There are no available data on ONUREG use in pregnant women to evaluate for a drug-associated risk. Azacitidine was teratogenic and caused embryo-fetal lethality in animals at doses less than the recommended human daily dose of oral azacitidine on a mg/m2 basis (see Data). Advise pregnant women of the potential risk to the fetus.

The estimated background 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

No reproductive or developmental toxicity studies have been conducted with oral azacitidine.

Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single intraperitoneal injection of 6 mg/m2 azacitidine (at doses less than the recommended human daily dose of oral azacitidine on a mg/m2 basis) on gestation Day 10. Developmental abnormalities in the brain have been detected in mice given azacitidine on or before gestation Day 15 at doses of approximately 3 to 12 mg/m2 (at doses less than the recommended human daily dose on a mg/m2 basis).

In rats, azacitidine was clearly embryotoxic when given an intraperitoneal injection on gestation Days 4 to 8 (postimplantation) at a dose of 6 mg/m2 (at doses less than the recommended human daily dose on a mg/m2 basis), although treatment in the preimplantation period (on gestation Days 1 to 3) had no adverse effect on the embryos. Azacitidine caused multiple fetal abnormalities in rats after a single intraperitoneal dose of 3 to 12 mg/m2 (at doses less than the recommended human daily dose on a mg/m2 basis) given on gestation Days 9, 10, 11, or 12. In this study, azacitidine caused fetal death when administered at 3 to 12 mg/m2 on gestation Days 9 and 10; average live animals per litter was reduced to 9% of control at the highest dose on gestation Day 9. Fetal anomalies included: CNS anomalies (exencephaly/encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly), and others (micrognathia, gastroschisis, edema, and rib abnormalities).

8.2 Lactation

Risk Summary

There are no data regarding the presence of azacitidine in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with ONUREG and for 1 week after the last dose.

8.3 Females And Males Of Reproductive Potential

ONUREG can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential before starting ONUREG.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with ONUREG and for at least 6 months after the last dose.

Males

Advise males with female partners of reproductive potential to use effective contraception during treatment with ONUREG and for at least 3 months after the last dose.

Infertility

Based on animal data, ONUREG may impair male or female fertility [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

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

8.5 Geriatric Use

Of the 238 patients in QUAZAR who received ONUREG, 72% were 65 years of age or older, while 12% were 75 years of age or older. No overall differences in safety or effectiveness of ONUREG were observed between these patients and younger patients.

8.6 Renal Impairment

Monitor patients with severe renal impairment (creatinine clearance [CLcr] 15 to 29 mL/min calculated by Cockcroft-Gault formula) more frequently for adverse reactions and modify the ONUREG dosage for adverse reactions [see Dosage and Administration (2.3)].

No dose adjustment of ONUREG is recommended for patients with mild to severe renal impairment (CLcr 15 to 89 mL/min) [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

ONUREG has not been studied in patients with pre-existing severe hepatic impairment (total bilirubin > 3 × ULN).

A recommended dosage of ONUREG has not been established for patients with moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN).

No dose adjustment of ONUREG is recommended for patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 × ULN and any AST) [see Clinical Pharmacology (12.3)].

11 Description

Azacitidine is a nucleoside metabolic inhibitor with a molecular formula of C8H12N4O5 and a molecular weight of 244 g/mol. The chemical name is: 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one and the chemical structural is:

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Azacitidine is a white to off-white solid. Azacitidine was found to be soluble in aqueous media across a pH range from 1.0 to 7.0.

{ "type": "p", "children": [], "text": "Azacitidine is a white to off-white solid. Azacitidine was found to be soluble in aqueous media across a pH range from 1.0 to 7.0." }

ONUREG (azacitidine) is supplied as film-coated tablets containing 200 mg or 300 mg of azacitidine for oral use. Each core tablet contains the following inactive ingredients: croscarmellose sodium, magnesium stearate, mannitol, and silicified microcrystalline cellulose. The 200 and 300 mg tablet coating contains hypromellose, lactose monohydrate, polyethylene glycol, titanium dioxide, and triacetin. In addition, the 200 mg tablet coating contains iron oxide red and the 300 mg tablet coating contains black iron oxide, iron oxide red, and iron oxide yellow.

{ "type": "p", "children": [], "text": "ONUREG (azacitidine) is supplied as film-coated tablets containing 200 mg or 300 mg of azacitidine for oral use. Each core tablet contains the following inactive ingredients: croscarmellose sodium, magnesium stearate, mannitol, and silicified microcrystalline cellulose. The 200 and 300 mg tablet coating contains hypromellose, lactose monohydrate, polyethylene glycol, titanium dioxide, and triacetin. In addition, the 200 mg tablet coating contains iron oxide red and the 300 mg tablet coating contains black iron oxide, iron oxide red, and iron oxide yellow." }

12 Clinical Pharmacology

12.1 Mechanism Of Action

Azacitidine is a pyrimidine nucleoside analog of cytidine that inhibits DNA/RNA methyltransferases. Azacitidine is incorporated into DNA and RNA following cellular uptake and enzymatic biotransformation to nucleotide triphosphates.

Incorporation of azacitidine into the DNA of cancer cells in vitro, including acute myeloid leukemia cells, inhibited DNA methyltransferases, reduced DNA methylation and altered gene expression, including re-expression of genes regulating tumor suppression and cell differentiation. Incorporation of azacitidine into the RNA of cancer cells, including leukemic cells, inhibited RNA methyltransferases, reduced RNA methylation, decreased RNA stability and decreased protein synthesis.

Antileukemic activity of azacitidine was demonstrated by reduction of cell viability and induction of apoptosis in AML cell lines in vitro. Azacitidine decreased tumor burden and increased survival in leukemic tumor models in vivo.

12.2 Pharmacodynamics

Greater reduction in global DNA methylation was observed with higher azacitidine plasma exposure in patients with AML administered ONUREG for 14 days of a 28-day cycle.

12.3 Pharmacokinetics

The systemic exposure of azacitidine is approximately dose proportional over the dose range of 120 mg to 600 mg once daily of ONUREG (0.4 to 2 times the recommended dosage). Following a single 300 mg dose of ONUREG, the mean (coefficient of variation [CV%]) Cmax of azacitidine was 145 ng/mL (64%) and the mean AUC of azacitidine was 242 ng h/mL (65%). No accumulation was observed following ONUREG 300 mg once daily.

Absorption

The mean oral bioavailability is approximately 11% relative to subcutaneous administration. The median time to peak plasma concentration of azacitidine is 1 hour.

Effect of Food

A high-fat, high-calorie meal (approximately 800 to 1000 calories, 50% fat) did not affect AUC0-INF and decreased Cmax by 21%.

Distribution

The mean (CV%) apparent volume of distribution (Vz/F) of azacitidine is 881 L (67%). The in vitro serum protein binding of azacitidine is approximately 6% to 12%. The blood-to-plasma ratio is approximately 0.3.

Elimination

The mean (CV%) terminal half-life is approximately 0.5 hours (27%) and the apparent clearance (CL/F) is 1240 L/hour (64%).

Metabolism

Azacitidine undergoes spontaneous hydrolysis and deamination mediated by cytidine deaminase.

Excretion

Following the administration of ONUREG 300 mg orally once daily, < 2% of the dose was recovered unchanged in the urine.

Specific Populations

Age (46 years to 93 years), sex, body weight (39.3 kg to 129 kg), mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 × ULN and any AST), and mild to moderate renal impairment (CLcr 30 to 89 mL/min) have no clinically meaningful effect on the pharmacokinetics of oral azacitidine. The effects of race/ethnicity, moderate to severe hepatic impairment (total bilirubin > 1.5 × ULN and any AST), and severe renal impairment (CLcr 15 to 29 mL/min) on the pharmacokinetics of oral azacitidine is unknown.

Severe renal impairment increased azacitidine exposure by approximately 70% after a single or 41% after multiple subcutaneous daily administration.

Drug Interaction Studies

Effect of Gastric Acid Reducing Agents on Azacitidine:

Coadministration of omeprazole (a proton pump inhibitor) with ONUREG increased azacitidine AUC0-INF by 19% and had no effect on Cmax.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Azacitidine does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or CYP2E1 at clinically relevant concentrations. Azacitidine is not an inducer of CYP1A2, CYP2C19, or CYP3A.

Transporter Systems: Azacitidine is not a substrate of P-glycoprotein (P-gp). Azacitidine does not inhibit P-gp, breast cancer resistance protein (BCRP), organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptides (OATP) OATP1B1 and OATP1B3, or organic cation transporter (OCT) OCT2 at clinically relevant concentrations.

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

The mutagenic and clastogenic potential of azacitidine was tested in in vitro bacterial systems Salmonella typhimurium strains TA100 and several strains of trpE8, Escherichia coli strains WP14 Pro, WP3103P, WP3104P, and CC103; in an in vitro forward gene mutation assay in mouse lymphoma cells and human lymphoblast cells; and in an in vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian hamster embryo cells. Azacitidine was mutagenic in bacterial and mammalian cell systems. The clastogenic effect of azacitidine was shown by the induction of micronuclei in L5178Y mouse cells and Syrian hamster embryo cells.

Administration of azacitidine by intraperitoneal injection to male mice at 9.9 mg/m2 (at doses less than the recommended human daily dose on a mg/m2 basis) daily for 3 days prior to mating with untreated female mice resulted in decreased fertility and loss of offspring during subsequent embryonic and postnatal development. Treatment of male rats 3 times per week for 11 or 16 weeks at doses of 15 to 30 mg/m2 (at doses less than the recommended human daily dose on a mg/m2 basis) resulted in decreased weight of the testes and epididymides, decreased sperm counts accompanied by decreased pregnancy rates, and increased loss of embryos in mated females. In a related study, male rats treated for 16 weeks at 24 mg/m2 resulted in an increase in abnormal embryos in mated females when examined on Day 2 of gestation.

14 Clinical Studies

The efficacy of ONUREG was evaluated in QUAZAR (NCT01757535), a multicenter, randomized, double-blind, placebo-controlled study. Eligible patients were ages 55 years or older, had AML, and were within 4 months of achieving first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) with intensive induction chemotherapy. Patients may have received consolidation (see Table 4). Patients were excluded if they were candidates for hematopoietic stem cell transplantation at the time of screening.

{ "type": "p", "children": [], "text": "The efficacy of ONUREG was evaluated in QUAZAR (NCT01757535), a multicenter, randomized, double-blind, placebo-controlled study. Eligible patients were ages 55 years or older, had AML, and were within 4 months of achieving first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) with intensive induction chemotherapy. Patients may have received consolidation (see Table 4). Patients were excluded if they were candidates for hematopoietic stem cell transplantation at the time of screening." }

A total of 472 patients who completed induction with or without consolidation therapy were randomized 1:1 to receive ONUREG 300 mg (n=238) or placebo (n=234) orally on Days 1 through 14 of each 28-day cycle. Randomization was stratified by age at time of induction therapy (55 to 64 vs. ≥ 65 years), cytogenetic risk category at time of induction therapy (intermediate risk vs. poor risk), prior history of MDS/CMML (yes vs. no), and received consolidation therapy following induction therapy (yes vs. no). Baseline demographic and disease characteristics are shown in Table 4.

{ "type": "p", "children": [], "text": "A total of 472 patients who completed induction with or without consolidation therapy were randomized 1:1 to receive ONUREG 300 mg (n=238) or placebo (n=234) orally on Days 1 through 14 of each 28-day cycle. Randomization was stratified by age at time of induction therapy (55 to 64 vs. ≥ 65 years), cytogenetic risk category at time of induction therapy (intermediate risk vs. poor risk), prior history of MDS/CMML (yes vs. no), and received consolidation therapy following induction therapy (yes vs. no). Baseline demographic and disease characteristics are shown in Table 4." }

<div class="scrollingtable"><table width="80%"> <caption> Table 4: Baseline Demographics and Disease-Related Characteristics in QUAZAR </caption> <col width="55%"/> <col width="19%"/> <col width="19%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="bottom">Parameter</th><th align="center" class="Botrule Rrule Toprule" valign="top">ONUREG (N=238)</th><th align="center" class="Botrule Rrule Toprule" valign="top">Placebo (N=234)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" class="Botrule" colspan="3" valign="top">AML=Acute Myeloid Leukemia, MDS=Myelodysplastic Syndrome, CMML=Chronic Myelomonocytic Leukemia, ECOG=Eastern Cooperative Oncology Group, CR=Morphologic Complete Remission, CRi=Morphologic complete remission with incomplete blood count recovery. Source for Intermediate and Poor Risk: National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Acute Myeloid Leukemia. National Comprehensive Cancer Network website. Available at http://www.nccn.org/professionals/physician_gls/PDF/aml.pdf. Accessed 01 Mar 2011. 1 Intermediate risk was defined as normal cytogenetics +8, t(9;11), or Other undefined. 2 Poor risk was defined as Complex (≥ 3 abnormalities): -5; 5q-; -7; 7q-; 11q23 - non t(9;11); inv(3); t(3;3); t(6;9); or t(9;22).</td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> Age (years) </td><td class="Botrule Rrule Toprule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Median (Min, Max) </td><td align="center" class="Botrule Rrule" valign="top"> 68.0 (55, 86) </td><td align="center" class="Botrule Rrule" valign="top"> 68.0 (55, 82) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Age Category, n (%) </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> < 65 years </td><td align="center" class="Botrule Rrule" valign="top"> 66 (28) </td><td align="center" class="Botrule Rrule" valign="top"> 68 (29) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> 65 years to < 75 years </td><td align="center" class="Botrule Rrule" valign="top"> 144 (61) </td><td align="center" class="Botrule Rrule" valign="top"> 142 (61) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> ≥ 75 years </td><td align="center" class="Botrule Rrule" valign="top"> 28 (12) </td><td align="center" class="Botrule Rrule" valign="top"> 24 (10) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Sex, n (%) </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Male </td><td align="center" class="Botrule Rrule" valign="top"> 118 (50) </td><td align="center" class="Botrule Rrule" valign="top"> 127 (54) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Female </td><td align="center" class="Botrule Rrule" valign="top"> 120 (50) </td><td align="center" class="Botrule Rrule" valign="top"> 107 (46) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Race, n (%) </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> White </td><td align="center" class="Botrule Rrule" valign="top"> 216 (91) </td><td align="center" class="Botrule Rrule" valign="top"> 197 (84) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Black or African American </td><td align="center" class="Botrule Rrule" valign="top"> 2 (1) </td><td align="center" class="Botrule Rrule" valign="top"> 6 (3) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Asian </td><td align="center" class="Botrule Rrule" valign="top"> 6 (3) </td><td align="center" class="Botrule Rrule" valign="top"> 20 (9) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Other </td><td align="center" class="Botrule Rrule" valign="top"> 12 (5) </td><td align="center" class="Botrule Rrule" valign="top"> 11 (5) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Not Collected or Reported </td><td align="center" class="Botrule Rrule" valign="top"> 2 (1) </td><td align="center" class="Botrule Rrule" valign="top"> 0 (0) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> ECOG Performance Status, n (%) </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> 0 </td><td align="center" class="Botrule Rrule" valign="top"> 116 (49) </td><td align="center" class="Botrule Rrule" valign="top"> 111 (47) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> 1 </td><td align="center" class="Botrule Rrule" valign="top"> 101 (42) </td><td align="center" class="Botrule Rrule" valign="top"> 106 (45) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> 2 </td><td align="center" class="Botrule Rrule" valign="top"> 21 (9) </td><td align="center" class="Botrule Rrule" valign="top"> 15 (6) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> 3 </td><td align="center" class="Botrule Rrule" valign="top"> 0 (0) </td><td align="center" class="Botrule Rrule" valign="top"> 2 (1) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Cytogenetic Risk Status at Diagnosis, n (%) </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Intermediate Risk1 </td><td align="center" class="Botrule Rrule" valign="top"> 203 (85) </td><td align="center" class="Botrule Rrule" valign="top"> 203 (87) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Poor Risk2 </td><td align="center" class="Botrule Rrule" valign="top"> 35 (15) </td><td align="center" class="Botrule Rrule" valign="top"> 31 (13) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Initial AML Classification, n (%) </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> AML with recurrent genetic abnormalities </td><td align="center" class="Botrule Rrule" valign="top"> 39 (16) </td><td align="center" class="Botrule Rrule" valign="top"> 46 (20) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> AML with myelodysplasia-related changes </td><td align="center" class="Botrule Rrule" valign="top"> 49 (21) </td><td align="center" class="Botrule Rrule" valign="top"> 42 (18) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Therapy related myeloid neoplasms </td><td align="center" class="Botrule Rrule" valign="top"> 2 (1) </td><td align="center" class="Botrule Rrule" valign="top"> 0 (0) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> AML not otherwise specified </td><td align="center" class="Botrule Rrule" valign="top"> 148 (62) </td><td align="center" class="Botrule Rrule" valign="top"> 145 (62) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Missing </td><td align="center" class="Botrule Rrule" valign="top"> 0 (0) </td><td align="center" class="Botrule Rrule" valign="top"> 1 (< 1) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Type of AML, n (%) </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Primary (de novo) </td><td align="center" class="Botrule Rrule" valign="top"> 213 (89) </td><td align="center" class="Botrule Rrule" valign="top"> 216 (92) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Secondary </td><td align="center" class="Botrule Rrule" valign="top"> 25 (11) </td><td align="center" class="Botrule Rrule" valign="top"> 18 (8) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Induction Response </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> CR </td><td align="center" class="Botrule Rrule" valign="top"> 187 (79) </td><td align="center" class="Botrule Rrule" valign="top"> 197 (84) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> CRi </td><td align="center" class="Botrule Rrule" valign="top"> 51 (21) </td><td align="center" class="Botrule Rrule" valign="top"> 37 (16) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Consolidation following induction therapy </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> None </td><td align="center" class="Botrule Rrule" valign="top"> 52 (22) </td><td align="center" class="Botrule Rrule" valign="top"> 42 (18) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> 1 cycle </td><td align="center" class="Botrule Rrule" valign="top"> 110 (46) </td><td align="center" class="Botrule Rrule" valign="top"> 102 (44) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> 2 cycles </td><td align="center" class="Botrule Rrule" valign="top"> 70 (29) </td><td align="center" class="Botrule Rrule" valign="top"> 77 (33) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> 3 cycles </td><td align="center" class="Botrule Rrule" valign="top"> 6 (3) </td><td align="center" class="Botrule Rrule" valign="top"> 13 (6) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Disease status at study baseline </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> CR </td><td align="center" class="Botrule Rrule" valign="top"> 185 (78) </td><td align="center" class="Botrule Rrule" valign="top"> 181 (77) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> CRi </td><td align="center" class="Botrule Rrule" valign="top"> 44 (18) </td><td align="center" class="Botrule Rrule" valign="top"> 38 (16) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Not in CR or CRi </td><td align="center" class="Botrule Rrule" valign="top"> 9 (4) </td><td align="center" class="Botrule Rrule" valign="top"> 13 (6) </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> Not Reported </td><td align="center" class="Botrule Rrule" valign="top"> 0 </td><td align="center" class="Botrule Rrule" valign="top"> 2 (1) </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"80%\">\n<caption>\nTable 4: Baseline Demographics and Disease-Related Characteristics in QUAZAR\n</caption>\n<col width=\"55%\"/>\n<col width=\"19%\"/>\n<col width=\"19%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"bottom\">Parameter</th><th align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"top\">ONUREG\n \n (N=238)</th><th align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"top\">Placebo\n \n (N=234)</th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" class=\"Botrule\" colspan=\"3\" valign=\"top\">AML=Acute Myeloid Leukemia, MDS=Myelodysplastic Syndrome, CMML=Chronic Myelomonocytic Leukemia, ECOG=Eastern Cooperative Oncology Group, CR=Morphologic Complete Remission, CRi=Morphologic complete remission with incomplete blood count recovery. Source for Intermediate and Poor Risk: National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Acute Myeloid Leukemia. National Comprehensive Cancer Network website. Available at http://www.nccn.org/professionals/physician_gls/PDF/aml.pdf. Accessed 01 Mar 2011. \n1 Intermediate risk was defined as normal cytogenetics +8, t(9;11), or Other undefined. \n2 Poor risk was defined as Complex (≥ 3 abnormalities): -5; 5q-; -7; 7q-; 11q23 - non t(9;11); inv(3); t(3;3); t(6;9); or t(9;22).</td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\nAge (years)\n</td><td class=\"Botrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Rrule Toprule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n Median (Min, Max)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n68.0 (55, 86)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n68.0 (55, 82)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nAge Category, n (%)\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n < 65 years\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n66 (28)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n68 (29)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n 65 years to < 75 years\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n144 (61)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n142 (61)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n ≥ 75 years\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n28 (12)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n24 (10)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nSex, n (%)\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n Male\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n118 (50)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n127 (54)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n Female\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n120 (50)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n107 (46)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nRace, n (%)\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n White\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n216 (91)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n197 (84)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n Black or African American\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n2 (1)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n6 (3)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n Asian\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n6 (3)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n20 (9)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n Other\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n12 (5)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n11 (5)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n Not Collected or Reported\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n2 (1)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0 (0)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nECOG Performance Status, n (%)\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n 0\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n116 (49)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n111 (47)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n 1\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n101 (42)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n106 (45)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n 2\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n21 (9)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n15 (6)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n 3\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0 (0)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n2 (1)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nCytogenetic Risk Status at Diagnosis, n (%)\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n Intermediate Risk1\n\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n203 (85)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n203 (87)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n Poor Risk2\n\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n35 (15)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n31 (13)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nInitial AML Classification, n (%)\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n AML with recurrent genetic abnormalities\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n39 (16)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n46 (20)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n AML with myelodysplasia-related changes\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n49 (21)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n42 (18)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n Therapy related myeloid neoplasms\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n2 (1)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0 (0)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n AML not otherwise specified\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n148 (62)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n145 (62)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n Missing\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0 (0)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n1 (< 1)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nType of AML, n (%)\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n Primary (de novo)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n213 (89)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n216 (92)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n Secondary\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n25 (11)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n18 (8)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nInduction Response\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n CR\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n187 (79)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n197 (84)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n CRi\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n51 (21)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n37 (16)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nConsolidation following induction therapy\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n None\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n52 (22)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n42 (18)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n 1 cycle\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n110 (46)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n102 (44)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n 2 cycles\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n70 (29)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n77 (33)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n 3 cycles\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n6 (3)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n13 (6)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nDisease status at study baseline\n</td><td class=\"Botrule Rrule\" valign=\"top\"></td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n CR\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n185 (78)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n181 (77)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n CRi\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n44 (18)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n38 (16)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n Not in CR or CRi\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n9 (4)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n13 (6)\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n Not Reported\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n0\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n2 (1)\n</td>\n</tr>\n</tbody>\n</table></div>" }

The efficacy of ONUREG was established on the basis of overall survival (OS). The trial demonstrated a statistically significant improvement in OS for patients randomized to ONUREG compared to placebo. A subgroup analysis showed consistency in the OS benefit for patients in either CR or CRi. The efficacy results are summarized in Table 5 and Figure 1.

{ "type": "p", "children": [], "text": "The efficacy of ONUREG was established on the basis of overall survival (OS). The trial demonstrated a statistically significant improvement in OS for patients randomized to ONUREG compared to placebo. A subgroup analysis showed consistency in the OS benefit for patients in either CR or CRi. The efficacy results are summarized in Table 5 and Figure 1." }

<div class="scrollingtable"><table width="80%"> <caption> Table 5: Efficacy Results (ITT Population) in QUAZAR </caption> <col width="37%"/> <col width="28%"/> <col width="28%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"></th><th align="center" class="Botrule Rrule Toprule" valign="top">ONUREG (N=238)</th><th align="left" class="Botrule Rrule Toprule" valign="top">Placebo (N=234)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" class="Botrule" colspan="6" valign="top">1 The hazard ratio is from a Cox proportional hazards model stratified by age (55 to 64 vs. ≥65 years), cytogenetic risk category at time of induction therapy (intermediate risk vs. poor risk), and received consolidation therapy (yes vs. no). The p-value is two-sided from a log-rank test stratified by the same factors.</td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> Overall Survival </td><td class="Botrule Rrule Toprule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> OS Events, n (%) </td><td align="center" class="Botrule Rrule" valign="top"> 158 (66) </td><td align="center" class="Botrule Rrule" valign="top"> 171 (73) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Median OS (95% CI) Months </td><td align="center" class="Botrule Rrule" valign="top"> 24.7 (18.7, 30.5) </td><td class="Botrule Rrule" valign="top"> 14.8 (11.7, 17.6) </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> Hazard Ratio (95% CI)1 </td><td align="center" class="Rrule" colspan="2" valign="top"> 0.69 (0.55, 0.86) </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> p value1 </td><td align="center" class="Botrule Rrule" colspan="2" valign="top"> 0.0009 </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"80%\">\n<caption>\nTable 5: Efficacy Results (ITT Population) in QUAZAR\n</caption>\n<col width=\"37%\"/>\n<col width=\"28%\"/>\n<col width=\"28%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></th><th align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"top\">ONUREG\n \n (N=238)</th><th align=\"left\" class=\"Botrule Rrule Toprule\" valign=\"top\">Placebo\n \n (N=234)</th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" class=\"Botrule\" colspan=\"6\" valign=\"top\">1 The hazard ratio is from a Cox proportional hazards model stratified by age (55 to 64 vs. ≥65 years), cytogenetic risk category at time of induction therapy (intermediate risk vs. poor risk), and received consolidation therapy (yes vs. no). The p-value is two-sided from a log-rank test stratified by the same factors.</td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n\nOverall Survival\n\n</td><td class=\"Botrule Rrule Toprule\" valign=\"top\"></td><td class=\"Botrule Rrule Toprule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nOS Events, n (%)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n158 (66)\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n171 (73)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\nMedian OS (95% CI) Months\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n24.7 (18.7, 30.5)\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n14.8 (11.7, 17.6)\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" valign=\"top\">\nHazard Ratio (95% CI)1\n\n</td><td align=\"center\" class=\"Rrule\" colspan=\"2\" valign=\"top\">\n0.69 (0.55, 0.86)\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\np value1\n\n</td><td align=\"center\" class=\"Botrule Rrule\" colspan=\"2\" valign=\"top\">\n0.0009\n</td>\n</tr>\n</tbody>\n</table></div>" }

Figure 1: Kaplan-Meier Curve for Overall Survival (ITT Population) in QUAZAR

{ "type": "p", "children": [], "text": "\nFigure 1: Kaplan-Meier Curve for Overall Survival (ITT Population) in QUAZAR\n" }

15 References

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" }

16 How Supplied/Storage And Handling

How Supplied

ONUREG tablets are available as:

Table 6 lists the package configurations and strengths.

<div class="scrollingtable"><table width="80%"> <caption> Table 6: ONUREG Package Configurations and NDC Numbers </caption> <col width="32%"/> <col width="30%"/> <col width="30%"/> <thead> <tr class="First Last"> <th align="center" class="Botrule Lrule Rrule Toprule" valign="top">Package Configuration</th><th align="center" class="Botrule Rrule Toprule" valign="top">Tablet Strength</th><th align="center" class="Botrule Rrule Toprule" valign="top">NDC Number</th> </tr> </thead> <tbody> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Bottles of 14 with two desiccant cannisters </td><td align="center" class="Botrule Rrule Toprule" valign="top"> 200 mg </td><td align="center" class="Botrule Rrule Toprule" valign="top"> 59572-730-14 </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> Bottles of 14 with two desiccant cannisters </td><td align="center" class="Botrule Rrule" valign="top"> 300 mg </td><td align="center" class="Botrule Rrule" valign="top"> 59572-740-14 </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> One blister card containing 7 tablets </td><td align="center" class="Botrule Rrule" valign="top"> 200 mg </td><td align="center" class="Botrule Rrule" valign="top"> 59572-730-07 </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top"> One blister card containing 7 tablets </td><td align="center" class="Botrule Rrule" valign="top"> 300 mg </td><td align="center" class="Botrule Rrule" valign="top"> 59572-740-07 </td> </tr> </tbody> </table></div>

Storage

Handling and Disposal

ONUREG is a hazardous drug. Follow applicable special handling and disposal procedures.1

If powder comes in contact with skin, immediately and thoroughly wash with soap and water. If powder comes in contact with mucous membranes, immediately flush the area with water.

17 Patient Counseling Information

Myelosuppression

Advise patients of the risk of myelosuppression with ONUREG and of the need to monitor complete blood counts before and during treatment [see Warnings and Precautions (5.2)].

Gastrointestinal Toxicity

Advise patients of the risk of gastrointestinal toxicity with ONUREG and of the potential need to use anti-emetic or anti-diarrheal medications during treatment [see Adverse Reactions (6.1)].

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 (5.4), Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment with ONUREG and for at least 6 months after the last dose [see Use in Specific Populations (8.3)].

Advise males with female partners of reproductive potential to use effective contraception during treatment with ONUREG and for at least 3 months after the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with ONUREG and for 1 week after the last dose [see Use in Specific Populations (8.2)].

Administration

Advise patients to take ONUREG with or without food at about the same time each day and how to make up a missed or vomited dose. Advise patients to swallow tablets whole. Advise patients not to cut, crush, or chew the tablets [see Dosage and Administration (2.2)].

Storage Instructions

Advise patients to keep ONUREG in the original container (bottles or blisters). If bottles are dispensed, advise patients to keep the container tightly closed with both desiccant canisters inside and to not eat the desiccant canisters [see How Supplied/Storage and Handling (16)].

Spl Unclassified Section

Marketed by:Bristol-Myers Squibb CompanyPrinceton, NJ 08543 USA

{ "type": "p", "children": [], "text": "Marketed by:Bristol-Myers Squibb CompanyPrinceton, NJ 08543 USA" }

ONUREG® is a trademark of Celgene Corporation, a Bristol-Myers Squibb company.

{ "type": "p", "children": [], "text": "ONUREG® is a trademark of Celgene Corporation, a Bristol-Myers Squibb company." }

ONUPI.004

{ "type": "p", "children": [], "text": "ONUPI.004" }

Patient Package Insert

<div class="scrollingtable"><table width="100%"> <col width="2%"/> <col width="49%"/> <col width="49%"/> <tfoot> <tr class="First Last"> <td align="left" class="Botrule" colspan="3" valign="top">This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: October 2022 </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> Patient Information ONUREG® (on-u-reg) (azacitidine) tablets, for oral use </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> What is ONUREG? </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> ONUREG is a prescription medicine used for continued treatment of adults with acute myeloid leukemia (AML) who: </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <dl> <dt>•</dt> <dd>had a first complete remission (CR) following intensive induction chemotherapy with or without recovery of your blood cell counts, and </dd> <dt>•</dt> <dd>who are not able to complete intensive curative therapy.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> It is not known if ONUREG is safe and effective in children under 18 years of age. </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> Do not take ONUREG if you: </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <dl> <dt>•</dt> <dd>are allergic to azacitidine or any of the ingredients in ONUREG. See the end of this leaflet for a complete list of ingredients in ONUREG.</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> Before taking ONUREG, tell your healthcare provider about all of your medical conditions, including if you: </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <dl> <dt>•</dt> <dd>have kidney or liver problems.</dd> <dt>•</dt> <dd>are pregnant or plan to become pregnant. ONUREG can harm your unborn baby. Females who are able to become pregnant: <dl> <dt>o</dt> <dd>Your healthcare provider should perform a pregnancy test before you start treatment with ONUREG.</dd> <dt>o</dt> <dd>You should use effective birth control (contraception) during treatment and for at least 6 months after your last dose of ONUREG.</dd> <dt>o</dt> <dd>Tell your healthcare provider right away if you become pregnant during treatment with ONUREG.</dd> </dl> </dd> <dt> </dt> <dd> Males with a female sexual partner who can become pregnant: </dd> <dt> </dt> <dd> <dl> <dt>o</dt> <dd>You should use effective birth control (contraception) during treatment and for at least 3 months after your last dose of ONUREG.</dd> </dl> </dd> <dt>•</dt> <dd>are breastfeeding or plan to breastfeed. It is not known if ONUREG passes into your breast milk. Do not breastfeed during treatment and for 1 week after your last dose of ONUREG.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> How should I take ONUREG? </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <dl> <dt>•</dt> <dd>Take ONUREG exactly as your healthcare provider tells you to take it.</dd> <dt>•</dt> <dd>Your healthcare provider will prescribe an anti-nausea medicine for you to take to help prevent nausea and vomiting during your treatment with ONUREG.<dl> <dt>o</dt> <dd>Take the anti-nausea medicine 30 minutes before each dose of ONUREG.</dd> <dt>o</dt> <dd>Your healthcare provider may decide to stop the anti-nausea medicine after your second cycle of ONUREG, if you do not have any nausea or vomiting.</dd> </dl> </dd> <dt>•</dt> <dd>Take ONUREG by mouth 1 time each day beginning on Day 1 through Day 14 of each 28-day cycle.</dd> <dt>•</dt> <dd>Take ONUREG with or without food at about the same time each day.</dd> <dt>•</dt> <dd>Swallow ONUREG tablets whole. Do not cut, crush, or chew the tablets.</dd> <dt>•</dt> <dd>If the powder from ONUREG tablets comes in contact with your skin, wash the area well right away with soap and water.</dd> <dt>•</dt> <dd>If the powder from ONUREG tablets comes in contact with your eyes or mouth (mucous membranes), flush the area right away with water.</dd> <dt>•</dt> <dd>If you miss a dose of ONUREG, or if you do not take your dose at the usual time, take the dose as soon as possible that day. Take your next dose at the regular time the next day. Do not take 2 doses on the same day to make up for a missed dose.</dd> <dt>•</dt> <dd>If you vomit after taking a dose of ONUREG, do not take another dose on the same day. Take your next dose at the regular time the next day.</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> What are the possible side effects of ONUREG? </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> ONUREG can cause serious side effects, including: </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <dl> <dt>•</dt> <dd> New or worsening low white blood cell counts (neutropenia). New or worsening low white blood cell counts are common but can also be severe during treatment with ONUREG. If your white blood cell counts become very low, you are at increased risk for infections. Your healthcare provider will check your white blood cell counts before and during treatment with ONUREG. Your healthcare provider may prescribe a medicine to help increase your white blood cell count if needed. Tell your healthcare provider right away if you get any of the following symptoms:</dd> </dl> </td> </tr> <tr> <td class="Lrule" valign="top"></td><td valign="top"> <dl> <dt>o</dt> <dd>fever or chills</dd> <dt>o</dt> <dd>body aches</dd> </dl> </td><td class="Rrule" valign="top"> <dl> <dt>o</dt> <dd>feeling very tired or weak</dd> <dt>o</dt> <dd>unusual headaches</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <dl> <dt>•</dt> <dd> New or worsening low platelet counts (thrombocytopenia). Low platelet counts are common but can also be severe during treatment with ONUREG. Your healthcare provider will check your platelet counts before and during treatment with ONUREG. Tell your healthcare provider right away if you have any unusual bruising or bleeding. Your healthcare provider may change your dose or tell you to stop taking ONUREG if you have low blood cell counts.</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> ONUREG may cause fertility problems in males and females, which may affect your ability to have children. Talk with your healthcare provider if you have concerns about fertility. </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> The most common side effects of ONUREG include: </td> </tr> <tr> <td class="Lrule" colspan="2" valign="top"> <dl> <dt>•</dt> <dd>nausea and vomiting. See "How should I take ONUREG?" </dd> <dt>•</dt> <dd>diarrhea. You may need to be treated with anti-diarrheal medicines.</dd> <dt>•</dt> <dd>tiredness or weakness</dd> <dt>•</dt> <dd>constipation</dd> <dt>•</dt> <dd>stomach area (abdominal) pain</dd> </dl> </td><td class="Rrule" valign="top"> <dl> <dt>•</dt> <dd>pneumonia</dd> <dt>•</dt> <dd>joint pain</dd> <dt>•</dt> <dd>decreased appetite</dd> <dt>•</dt> <dd>pain in arms or legs</dd> <dt>•</dt> <dd>dizziness</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> These are not all of the possible side effects of ONUREG. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> How should I store ONUREG? </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> <dl> <dt>•</dt> <dd>Store bottles or blisters of ONUREG tablets at room temperature between 68°F to 77°F (20°C to 25°C).</dd> <dt>•</dt> <dd>Store ONUREG tablets in the original bottle or the original aluminum-aluminum blisters.</dd> <dt>•</dt> <dd>Bottles of ONUREG contain 2 drying agent (desiccant) canisters. Do not eat the desiccant canisters. </dd> <dt>•</dt> <dd>Keep the ONUREG bottle tightly closed.</dd> <dt>•</dt> <dd>Talk to your healthcare provider about how to safely throw away (dispose of) any unused or expired ONUREG.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Keep ONUREG and all medicines out of the reach of children </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> General information about the safe and effective use of ONUREG. </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ONUREG for a condition for which it was not prescribed. Do not give ONUREG to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ONUREG that is written for health professionals. </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> What are the ingredients in ONUREG? </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> Active ingredient: azacitidine </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> Inactive ingredients: </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> Each core tablet contains: croscarmellose sodium, magnesium stearate, mannitol, and silicified microcrystalline cellulose. </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> The pink 200 mg tablet coating contains: hypromellose, iron oxide red, lactose monohydrate, polyethylene glycol, titanium dioxide, and triacetin. </td> </tr> <tr> <td class="Lrule Rrule" colspan="3" valign="top"> The brown 300 mg tablet coating contains: black iron oxide, hypromellose, iron oxide red, iron oxide yellow, lactose monohydrate, polyethylene glycol, titanium dioxide, and triacetin. </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> Marketed by: Bristol-Myers Squibb Company, Princeton, NJ 08543 USA ONUREG® is a trademark of Celgene Corporation, a Bristol-Myers Squibb company. ONUPPI V4 10/2022 For more information, go to www.ONUREG.com or call 1-800-721-5072. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"2%\"/>\n<col width=\"49%\"/>\n<col width=\"49%\"/>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" class=\"Botrule\" colspan=\"3\" valign=\"top\">This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: October 2022 </td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\" valign=\"top\">\n\nPatient Information\n ONUREG® (on-u-reg) (azacitidine) tablets, for oral use\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n\nWhat is ONUREG?\n\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\nONUREG is a prescription medicine used for continued treatment of adults with acute myeloid leukemia (AML) who:\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>had a first complete remission (CR) following intensive induction chemotherapy with or without recovery of your blood cell counts, and\n</dd>\n<dt>•</dt>\n<dd>who are not able to complete intensive curative therapy.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\nIt is not known if ONUREG is safe and effective in children under 18 years of age.\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n\nDo not take ONUREG if you:\n\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>are allergic to azacitidine or any of the ingredients in ONUREG. See the end of this leaflet for a complete list of ingredients in ONUREG.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n\nBefore taking ONUREG, tell your healthcare provider about all of your medical conditions, including if you:\n\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>have kidney or liver problems.</dd>\n<dt>•</dt>\n<dd>are pregnant or plan to become pregnant. ONUREG can harm your unborn baby. \nFemales who are able to become pregnant:\n<dl>\n<dt>o</dt>\n<dd>Your healthcare provider should perform a pregnancy test before you start treatment with ONUREG.</dd>\n<dt>o</dt>\n<dd>You should use effective birth control (contraception) during treatment and for at least 6 months after your last dose of ONUREG.</dd>\n<dt>o</dt>\n<dd>Tell your healthcare provider right away if you become pregnant during treatment with ONUREG.</dd>\n</dl>\n</dd>\n<dt> </dt>\n<dd>\nMales with a female sexual partner who can become pregnant:\n</dd>\n<dt> </dt>\n<dd>\n<dl>\n<dt>o</dt>\n<dd>You should use effective birth control (contraception) during treatment and for at least 3 months after your last dose of ONUREG.</dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>are breastfeeding or plan to breastfeed. It is not known if ONUREG passes into your breast milk. Do not breastfeed during treatment and for 1 week after your last dose of ONUREG.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\nTell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n\nHow should I take ONUREG?\n\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>Take ONUREG exactly as your healthcare provider tells you to take it.</dd>\n<dt>•</dt>\n<dd>Your healthcare provider will prescribe an anti-nausea medicine for you to take to help prevent nausea and vomiting during your treatment with ONUREG.<dl>\n<dt>o</dt>\n<dd>Take the anti-nausea medicine 30 minutes before each dose of ONUREG.</dd>\n<dt>o</dt>\n<dd>Your healthcare provider may decide to stop the anti-nausea medicine after your second cycle of ONUREG, if you do not have any nausea or vomiting.</dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>Take ONUREG by mouth 1 time each day beginning on Day 1 through Day 14 of each 28-day cycle.</dd>\n<dt>•</dt>\n<dd>Take ONUREG with or without food at about the same time each day.</dd>\n<dt>•</dt>\n<dd>Swallow ONUREG tablets whole. Do not cut, crush, or chew the tablets.</dd>\n<dt>•</dt>\n<dd>If the powder from ONUREG tablets comes in contact with your skin, wash the area well right away with soap and water.</dd>\n<dt>•</dt>\n<dd>If the powder from ONUREG tablets comes in contact with your eyes or mouth (mucous membranes), flush the area right away with water.</dd>\n<dt>•</dt>\n<dd>If you miss a dose of ONUREG, or if you do not take your dose at the usual time, take the dose as soon as possible that day. Take your next dose at the regular time the next day. Do not take 2 doses on the same day to make up for a missed dose.</dd>\n<dt>•</dt>\n<dd>If you vomit after taking a dose of ONUREG, do not take another dose on the same day. Take your next dose at the regular time the next day.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n\nWhat are the possible side effects of ONUREG?\n\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n\nONUREG can cause serious side effects, including:\n\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>\nNew or worsening low white blood cell counts (neutropenia). New or worsening low white blood cell counts are common but can also be severe during treatment with ONUREG. If your white blood cell counts become very low, you are at increased risk for infections. Your healthcare provider will check your white blood cell counts before and during treatment with ONUREG. Your healthcare provider may prescribe a medicine to help increase your white blood cell count if needed. Tell your healthcare provider right away if you get any of the following symptoms:</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\"></td><td valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>fever or chills</dd>\n<dt>o</dt>\n<dd>body aches</dd>\n</dl>\n</td><td class=\"Rrule\" valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>feeling very tired or weak</dd>\n<dt>o</dt>\n<dd>unusual headaches</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>\nNew or worsening low platelet counts (thrombocytopenia). Low platelet counts are common but can also be severe during treatment with ONUREG. Your healthcare provider will check your platelet counts before and during treatment with ONUREG. Tell your healthcare provider right away if you have any unusual bruising or bleeding. Your healthcare provider may change your dose or tell you to stop taking ONUREG if you have low blood cell counts.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\nONUREG may cause fertility problems in males and females, which may affect your ability to have children. Talk with your healthcare provider if you have concerns about fertility.\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n\nThe most common side effects of ONUREG include:\n\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" colspan=\"2\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>nausea and vomiting. See \"How should I take ONUREG?\"\n</dd>\n<dt>•</dt>\n<dd>diarrhea. You may need to be treated with anti-diarrheal medicines.</dd>\n<dt>•</dt>\n<dd>tiredness or weakness</dd>\n<dt>•</dt>\n<dd>constipation</dd>\n<dt>•</dt>\n<dd>stomach area (abdominal) pain</dd>\n</dl>\n</td><td class=\"Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>pneumonia</dd>\n<dt>•</dt>\n<dd>joint pain</dd>\n<dt>•</dt>\n<dd>decreased appetite</dd>\n<dt>•</dt>\n<dd>pain in arms or legs</dd>\n<dt>•</dt>\n<dd>dizziness</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\nThese are not all of the possible side effects of ONUREG. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n\nHow should I store ONUREG?\n\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>Store bottles or blisters of ONUREG tablets at room temperature between 68°F to 77°F (20°C to 25°C).</dd>\n<dt>•</dt>\n<dd>Store ONUREG tablets in the original bottle or the original aluminum-aluminum blisters.</dd>\n<dt>•</dt>\n<dd>Bottles of ONUREG contain 2 drying agent (desiccant) canisters. Do not eat the desiccant canisters.\n</dd>\n<dt>•</dt>\n<dd>Keep the ONUREG bottle tightly closed.</dd>\n<dt>•</dt>\n<dd>Talk to your healthcare provider about how to safely throw away (dispose of) any unused or expired ONUREG.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\n\nKeep ONUREG and all medicines out of the reach of children\n\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n\nGeneral information about the safe and effective use of ONUREG.\n\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\nMedicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ONUREG for a condition for which it was not prescribed. Do not give ONUREG to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ONUREG that is written for health professionals.\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n\nWhat are the ingredients in ONUREG?\n\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n\nActive ingredient: azacitidine\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n\nInactive ingredients:\n\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n\nEach core tablet contains: croscarmellose sodium, magnesium stearate, mannitol, and silicified microcrystalline cellulose.\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n\nThe pink 200 mg tablet coating contains: hypromellose, iron oxide red, lactose monohydrate, polyethylene glycol, titanium dioxide, and triacetin.\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\" valign=\"top\">\n\nThe brown 300 mg tablet coating contains: black iron oxide, hypromellose, iron oxide red, iron oxide yellow, lactose monohydrate, polyethylene glycol, titanium dioxide, and triacetin.\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\" valign=\"top\">\nMarketed by: Bristol-Myers Squibb Company, Princeton, NJ 08543 USA ONUREG® is a trademark of Celgene Corporation, a Bristol-Myers Squibb company. ONUPPI V4 10/2022 For more information, go to www.ONUREG.com or call 1-800-721-5072.\n</td>\n</tr>\n</tbody>\n</table></div>" }

Principal Display Panel - 200 Mg Bottle Label

NDC 59572-730-14

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ONUREG™ (azacitidine) tablets

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200 mg

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Swallow tablets whole. Do not cut, crush, or chew the tablets.

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Rx only 14 Tablets

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CAUTION: Hazardous Agent

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Principal Display Panel - 200 Mg Blister Pack Carton

NDC 59572-730-07 Rx only

{ "type": "p", "children": [], "text": "NDC 59572-730-07 Rx only" }

ONUREG™ (azacitidine) tablets

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200 mg

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Each tablet contains 200 mg of azacitidine.

{ "type": "p", "children": [], "text": "Each tablet contains 200 mg of azacitidine." }

Swallow tablets whole. Do not cut, crush, or chew the tablets.

{ "type": "p", "children": [], "text": "Swallow tablets whole. Do not cut, crush, or chew the tablets." }

One Blister CardContaining 7 Tablets

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Bristol Myers Squibb

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CAUTION: Hazardous Agent

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Principal Display Panel - 300 Mg Blister Pack Carton

NDC 59572-740-07 Rx only

{ "type": "p", "children": [], "text": "NDC 59572-740-07 Rx only" }

ONUREG™ (azacitidine) tablets

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300 mg

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Each tablet contains 200 mg of azacitidine.

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Swallow tablets whole. Do not cut, crush, or chew the tablets.

{ "type": "p", "children": [], "text": "Swallow tablets whole. Do not cut, crush, or chew the tablets." }

One Blister CardContaining 7 Tablets

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Bristol Myers Squibb

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CAUTION: Hazardous Agent

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