These Highlights Do Not Include All The Information Needed To Use Decitabine For Injection Safely And Effectively.

Pre-Medications and Baseline Testing

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

Storage

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

Principal Display Panel – Vial Label

NDC 63323-825-20



Decitabine for Injection



50 mg/vial



FOR INTRAVENOUS INFUSION ONLY



WARNING: Cytotoxic Agent



Single-Dose Vial



Discard unused portion

Rx only



STERILE

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

• OSHA Hazardous Drugs. OSHA. https://www.osha.gov/SLTC/hazardousdrugs/index.html

Decitabine for Injection contains decitabine (5-aza-2'-deoxycitidine), an analogue of the natural nucleoside 2'-deoxycytidine. Decitabine is white to off-white solid with the molecular formula of C ₈H ₁₂N ₄O ₄ and a molecular weight of 228.21. Its chemical name is 4-amino-1-(2-deoxy- _β-D- erythro-pentofuranosyl)-s-triazin-2(1 H)-one and it has the following structural formula:

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

Decitabine for Injection is a white to almost white sterile lyophilized solid friable lumps or powder supplied in a clear glass vial. Each 20 mL, single dose, glass vial contains 50 mg decitabine, 68 mg monobasic potassium phosphate (potassium dihydrogen phosphate) and 11.6 mg sodium hydroxide.

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

Of the total number of patients exposed to decitabine for injection in the controlled clinical trial, 61 of 83 patients were age 65 and over, while 21 of 83 patients were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

None

Most common adverse reactions (> 50%) are neutropenia, thrombocytopenia, anemia, and pyrexia. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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

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

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

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

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

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

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

Decitabine for injection can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, decitabine for injection alters DNA synthesis and is expected to result in adverse reproductive effects [see Clinical Pharmacology ( 12.1)] . In preclinical studies in mice and rats, decitabine was teratogenic, fetotoxic, and embryotoxic. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Advise women of childbearing potential to avoid becoming pregnant while taking decitabine for injection and for 6 months following the last dose. Advise men with female partners of childbearing potential to avoid fathering a child while receiving treatment with decitabine for injection, and for 3 months following the last dose. Counsel patients of childbearing potential to use effective contraception during this time [see Use in Specific Populations ( 8.1, 8.3)].

• Neutropenia and thrombocytopenia: Perform complete blood counts and platelet counts. ( 5.1)
• Embryo-fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception ( 5.2, 8.1, 8.3)

• Three Day Regimen
  
  Administer decitabine for injection at a dose of 15 mg/m ² by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days. Repeat cycle every 6 weeks. ( 2.1)
• Five Day Regimen
  
  Administer decitabine for injection at a dose of 20 mg/m ² by continuous intravenous infusion over 1 hour repeated daily for 5 days. Repeat cycle every 4 weeks. ( 2.2)

For Injection: Decitabine for injection is supplied as a sterile, lyophilized white to almost white powder, in a single-dose vial, packaged in cartons of 1 vial. Each vial contains 50 mg of decitabine.

The following adverse reactions have been identified during post -approval use of decitabine for injection. 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.

Cases of Sweet's Syndrome (acute febrile neutrophilic dermatosis) have been reported.

Lactation: Advise not to breastfeed. ( 8.2)

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

The safety of decitabine for injection was studied in 3 single-arm studies (N = 66, N = 98, N = 99) and 1 controlled supportive care study (N = 83 decitabine for injection, N = 81 supportive care). The data described below reflect exposure to decitabine for injection in 83 patients in the MDS trial. In the trial, patients received 15 mg/m ² intravenously every 8 hours for 3 days every 6 weeks. The median number of decitabine for injection cycles was 3 (range 0 to 9).

Most Commonly Occurring Adverse Reactions: neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia.

Adverse Reactions Most Frequently (≥ 1 %) Resulting in Clinical Intervention and or Dose Modification in the Phase 3 Trials in the Decitabine for Injection Arm:

• Discontinuation: thrombocytopenia, neutropenia, pneumonia, Mycobacterium avium complex infection, cardiorespiratory arrest, increased blood bilirubin, intracranial hemorrhage, abnormal liver function tests.
• Dose Delayed: neutropenia, pulmonary edema, atrial fibrillation, central line infection, febrile neutropenia.
• Dose Reduced: neutropenia, thrombocytopenia, anemia, lethargy, edema, tachycardia, depression, pharyngitis.

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

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

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

Serious adverse reactions that occurred in patients receiving decitabine for injection regardless of causality, not previously reported in Tables 1 and 2 include:

• Blood and Lymphatic System Disorders: myelosuppression, splenomegaly.
• Cardiac Disorders: myocardial infarction, cardio-respiratory arrest, cardiomyopathy, atrial fibrillation, supraventricular tachycardia.
• Gastrointestinal Disorders: gingival pain, upper gastrointestinal hemorrhage.
• General Disorders and Administrative Site Conditions: chest pain, catheter site hemorrhage.
• Hepatobiliary Disorders: cholecystitis.
• Infections and Infestations: fungal infection, sepsis, bronchopulmonary aspergillosis, peridiverticular abscess, respiratory tract infection, pseudomonal lung infection, Mycobacterium avium complex infection.
• Injury, Poisoning and Procedural Complications: post procedural pain, post procedural hemorrhage.
• Nervous System Disorders: intracranial hemorrhage.
• Psychiatric Disorders: mental status changes.
• Renal and Urinary Disorders: renal failure, urethral hemorrhage.
• Respiratory, Thoracic and Mediastinal Disorders: hemoptysis, lung infiltration, pulmonary embolism, respiratory arrest, pulmonary mass.
• Allergic Reaction: Hypersensitivity (anaphylactic reaction) to decitabine for injection has been reported in a Phase 2 trial.

Advise women of childbearing potential to avoid pregnancy and to use effective contraception while receiving decitabine for injection and for 6 months after last dose [see Warnings and Precautions ( 5.2) ] .

Advise men not to father a child while receiving treatment with decitabine for injection, and for 3 months after the last dose. Advise men with female partners of childbearing potential to use effective contraception [see Warnings and Precautions ( 5.2) and Nonclinical Toxicology ( 13.1)] .

Advise patients to avoid breastfeeding while receiving decitabine for injection and for at 1 week after the last dose [see Use in Specific Populations ( 8.2)] . Advise patients of the risk of myelosuppression and to report any symptoms of infection, anemia, or bleeding to their healthcare provider as soon as possible. Advise patients for the need for laboratory monitoring [see Warnings and Precautions ( 5.1)] .

Manufactured for:

Lake Zurich, IL 60047

www.fresenius-kabi.com/us

Made in India

451632

Issued: June 2019

4500142

Decitabine for injection is a white to almost white solid friable lumps or powder forming clear colorless solution free from visible particulate matter on reconstitution as directed. It is supplied as 50 mg single-dose vial individually packaged in a carton as follows:

Decitabine is a cytotoxic drug and caution should be exercised when handling and preparing decitabine for injection ¹.

Aseptically reconstitute decitabine for injection with room temperature (20°C to 25°C) 10 mL of Sterile Water for

Injection, USP. Upon reconstitution, the final concentration of the reconstituted decitabine for injection solution is 5 mg/mL. You must dilute the reconstituted solution with 0.9% Sodium Chloride Injection or 5% Dextrose Injection prior to administration. Temperature of the diluent (0.9% Sodium Chloride Injection or 5% Dextrose Injection) depends on time of administration after preparation.

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

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

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

All patients with a CR or PR were RBC and platelet transfusion independent in the absence of growth factors.

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

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

Carcinogenicity studies with decitabine have not been conducted.

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

In male mice given IP injections of 0.15, 0.3 or 0.45 mg/m ² decitabine (approximately 0.3% to 1% the recommended clinical dose) 3 times a week for 7 weeks, decitabine did not affect survival, body weight gain or hematological measures (hemoglobin and WBC counts). Testes weights were reduced, abnormal histology was observed and significant decreases in sperm number were found at doses ≥ 0.3 mg/m ². In females mated to males dosed with≥ 0.3 mg/m ² decitabine, pregnancy rate was reduced and preimplantation loss was significantly increased.

Pre-Medications and Baseline Testing

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

Storage

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

Principal Display Panel – Vial Label

NDC 63323-825-20



Decitabine for Injection



50 mg/vial



FOR INTRAVENOUS INFUSION ONLY



WARNING: Cytotoxic Agent



Single-Dose Vial



Discard unused portion

Rx only



STERILE

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

• OSHA Hazardous Drugs. OSHA. https://www.osha.gov/SLTC/hazardousdrugs/index.html

Decitabine for Injection contains decitabine (5-aza-2'-deoxycitidine), an analogue of the natural nucleoside 2'-deoxycytidine. Decitabine is white to off-white solid with the molecular formula of C ₈H ₁₂N ₄O ₄ and a molecular weight of 228.21. Its chemical name is 4-amino-1-(2-deoxy- _β-D- erythro-pentofuranosyl)-s-triazin-2(1 H)-one and it has the following structural formula:

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

Decitabine for Injection is a white to almost white sterile lyophilized solid friable lumps or powder supplied in a clear glass vial. Each 20 mL, single dose, glass vial contains 50 mg decitabine, 68 mg monobasic potassium phosphate (potassium dihydrogen phosphate) and 11.6 mg sodium hydroxide.

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

Of the total number of patients exposed to decitabine for injection in the controlled clinical trial, 61 of 83 patients were age 65 and over, while 21 of 83 patients were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

None

Most common adverse reactions (> 50%) are neutropenia, thrombocytopenia, anemia, and pyrexia. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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

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

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

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

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

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

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

Decitabine for injection can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, decitabine for injection alters DNA synthesis and is expected to result in adverse reproductive effects [see Clinical Pharmacology ( 12.1)] . In preclinical studies in mice and rats, decitabine was teratogenic, fetotoxic, and embryotoxic. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Advise women of childbearing potential to avoid becoming pregnant while taking decitabine for injection and for 6 months following the last dose. Advise men with female partners of childbearing potential to avoid fathering a child while receiving treatment with decitabine for injection, and for 3 months following the last dose. Counsel patients of childbearing potential to use effective contraception during this time [see Use in Specific Populations ( 8.1, 8.3)].

• Neutropenia and thrombocytopenia: Perform complete blood counts and platelet counts. ( 5.1)
• Embryo-fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception ( 5.2, 8.1, 8.3)

• Three Day Regimen
  
  Administer decitabine for injection at a dose of 15 mg/m ² by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days. Repeat cycle every 6 weeks. ( 2.1)
• Five Day Regimen
  
  Administer decitabine for injection at a dose of 20 mg/m ² by continuous intravenous infusion over 1 hour repeated daily for 5 days. Repeat cycle every 4 weeks. ( 2.2)

For Injection: Decitabine for injection is supplied as a sterile, lyophilized white to almost white powder, in a single-dose vial, packaged in cartons of 1 vial. Each vial contains 50 mg of decitabine.

The following adverse reactions have been identified during post -approval use of decitabine for injection. 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.

Cases of Sweet's Syndrome (acute febrile neutrophilic dermatosis) have been reported.

Lactation: Advise not to breastfeed. ( 8.2)

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

The safety of decitabine for injection was studied in 3 single-arm studies (N = 66, N = 98, N = 99) and 1 controlled supportive care study (N = 83 decitabine for injection, N = 81 supportive care). The data described below reflect exposure to decitabine for injection in 83 patients in the MDS trial. In the trial, patients received 15 mg/m ² intravenously every 8 hours for 3 days every 6 weeks. The median number of decitabine for injection cycles was 3 (range 0 to 9).

Most Commonly Occurring Adverse Reactions: neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia.

Adverse Reactions Most Frequently (≥ 1 %) Resulting in Clinical Intervention and or Dose Modification in the Phase 3 Trials in the Decitabine for Injection Arm:

• Discontinuation: thrombocytopenia, neutropenia, pneumonia, Mycobacterium avium complex infection, cardiorespiratory arrest, increased blood bilirubin, intracranial hemorrhage, abnormal liver function tests.
• Dose Delayed: neutropenia, pulmonary edema, atrial fibrillation, central line infection, febrile neutropenia.
• Dose Reduced: neutropenia, thrombocytopenia, anemia, lethargy, edema, tachycardia, depression, pharyngitis.

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

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

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

Serious adverse reactions that occurred in patients receiving decitabine for injection regardless of causality, not previously reported in Tables 1 and 2 include:

• Blood and Lymphatic System Disorders: myelosuppression, splenomegaly.
• Cardiac Disorders: myocardial infarction, cardio-respiratory arrest, cardiomyopathy, atrial fibrillation, supraventricular tachycardia.
• Gastrointestinal Disorders: gingival pain, upper gastrointestinal hemorrhage.
• General Disorders and Administrative Site Conditions: chest pain, catheter site hemorrhage.
• Hepatobiliary Disorders: cholecystitis.
• Infections and Infestations: fungal infection, sepsis, bronchopulmonary aspergillosis, peridiverticular abscess, respiratory tract infection, pseudomonal lung infection, Mycobacterium avium complex infection.
• Injury, Poisoning and Procedural Complications: post procedural pain, post procedural hemorrhage.
• Nervous System Disorders: intracranial hemorrhage.
• Psychiatric Disorders: mental status changes.
• Renal and Urinary Disorders: renal failure, urethral hemorrhage.
• Respiratory, Thoracic and Mediastinal Disorders: hemoptysis, lung infiltration, pulmonary embolism, respiratory arrest, pulmonary mass.
• Allergic Reaction: Hypersensitivity (anaphylactic reaction) to decitabine for injection has been reported in a Phase 2 trial.

Advise women of childbearing potential to avoid pregnancy and to use effective contraception while receiving decitabine for injection and for 6 months after last dose [see Warnings and Precautions ( 5.2) ] .

Advise men not to father a child while receiving treatment with decitabine for injection, and for 3 months after the last dose. Advise men with female partners of childbearing potential to use effective contraception [see Warnings and Precautions ( 5.2) and Nonclinical Toxicology ( 13.1)] .

Advise patients to avoid breastfeeding while receiving decitabine for injection and for at 1 week after the last dose [see Use in Specific Populations ( 8.2)] . Advise patients of the risk of myelosuppression and to report any symptoms of infection, anemia, or bleeding to their healthcare provider as soon as possible. Advise patients for the need for laboratory monitoring [see Warnings and Precautions ( 5.1)] .

Manufactured for:

Lake Zurich, IL 60047

www.fresenius-kabi.com/us

Made in India

451632

Issued: June 2019

4500142

Decitabine for injection is a white to almost white solid friable lumps or powder forming clear colorless solution free from visible particulate matter on reconstitution as directed. It is supplied as 50 mg single-dose vial individually packaged in a carton as follows:

Decitabine is a cytotoxic drug and caution should be exercised when handling and preparing decitabine for injection ¹.

Aseptically reconstitute decitabine for injection with room temperature (20°C to 25°C) 10 mL of Sterile Water for

Injection, USP. Upon reconstitution, the final concentration of the reconstituted decitabine for injection solution is 5 mg/mL. You must dilute the reconstituted solution with 0.9% Sodium Chloride Injection or 5% Dextrose Injection prior to administration. Temperature of the diluent (0.9% Sodium Chloride Injection or 5% Dextrose Injection) depends on time of administration after preparation.

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

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

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

All patients with a CR or PR were RBC and platelet transfusion independent in the absence of growth factors.

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

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

Carcinogenicity studies with decitabine have not been conducted.

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

In male mice given IP injections of 0.15, 0.3 or 0.45 mg/m ² decitabine (approximately 0.3% to 1% the recommended clinical dose) 3 times a week for 7 weeks, decitabine did not affect survival, body weight gain or hematological measures (hemoglobin and WBC counts). Testes weights were reduced, abnormal histology was observed and significant decreases in sperm number were found at doses ≥ 0.3 mg/m ². In females mated to males dosed with≥ 0.3 mg/m ² decitabine, pregnancy rate was reduced and preimplantation loss was significantly increased.