Decitabine: Package Insert and Label Information (Page 2 of 3)

6.2 Post-marketing Experience

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.

Sweet’s Syndrome (acute febrile neutrophilic dermatosis)
Differentiation Syndrome

7 DRUG INTERACTIONS

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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings from human data, animal studies, and the mechanism of action, Decitabine for Injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)]

Limited published data on Decitabine for Injection use throughout the first trimester during pregnancy describe adverse developmental outcomes including major birth defects (structural abnormalities). In animal reproduction studies, administration of decitabine to pregnant mice and rats during organogenesis caused adverse developmental outcomes including malformations and embryo-fetal lethality starting at doses approximately 7% of the recommended human dose on a mg/m2 basis (see Data). Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage in the U.S. general populations is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively.

Data

Human Data

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

Animal Data

In utero exposure to decitabine causes temporal related defects in the rat and/or mouse, which include growth suppression, exencephaly, defective skull bones, rib/sternabrae defects, phocomelia, digit defects, micrognathia, gastroschisis, micromelia. Decitabine inhibits proliferation and increases apoptosis of neural progenitor cells of the fetal CNS and induces palatal clefting in the developing murine fetus. Studies in mice have also shown that decitabine administration during osteoblastogenesis (day 10 of gestation) induces bone loss in offspring. In mice exposed to single IP (intraperitoneal) injections (0.09 and 3.0 mg/m2 , approximately 2% and 7% of the recommended daily clinical dose, respectively) over gestation days 8, 9, 10 or 11, no maternal toxicity was observed but reduced fetal survival was observed after treatment at 3 mg/m2 and decreased fetal weight was observed at both dose levels. The 3 mg/m2 dose elicited characteristic fetal defects for each treatment day, including supernumerary ribs (both dose levels), fused vertebrae and ribs, cleft palate, vertebral defects, hind-limb defects and digital defects of fore- and hind-limbs.

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

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

8.2 Lactation

Risk Summary

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

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

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

Contraception

Females

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

Males

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

Infertility

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

8.4 Pediatric Use

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

8.5 Geriatric Use

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.

10 OVERDOSAGE

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.

11 DESCRIPTION

Decitabine is a nucleoside metabolic inhibitor. Decitabine is a fine, white to almost white powder with the molecular formula of C8 H12 N4 O4 and a molecular weight of 228.21. Its chemical name is 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one and it has the following structural formula:

structure

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, for intravenous use, is a sterile, white to almost white lyophilized powder supplied in a clear colorless glass single-dose vial. Each 20 mL vial contains 50 mg decitabine, 68 mg monobasic potassium phosphate (potassium dihydrogen phosphate) and 11.6 mg sodium hydroxide. Sodium hydroxide and/or hydrochloric acid are used for pH adjustment.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

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

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

Dose

Cmax (ng/mL)

AUC0-° (ng•h/mL)

T1/2( h)

CL (L/h/m2)

AUCCumulative *** (ng•h/mL)

15 mg/m2 3-hr infusion every 8 hours for 3 days (Option 1)*

73.8 (66)

163 (62)

0.62 (49)

125 (53)

1332 (1010-1730)

20 mg/m2 1-hr infusion daily for 5 days (Option 2)**

147 (49)

115 (43)

0.54 (43)

210 (47)

570 (470-700)

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

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

Specific Populations

Patients with Renal Impairment

There are no data on the use of Decitabine for Injection in patients with renal impairment.

Patients with Hepatic Impairment

There are no data on the use of Decitabine for Injection in patients with hepatic impairment.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies with decitabine have not been conducted.

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

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

14 CLINICAL STUDIES

14.1 Controlled Trial in Myelodysplastic Syndrome

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.

Table 4 Baseline Demographics and Other Patient Characteristics (ITT)

Demographic or Other Patient Characteristic

Decitabine for Injection N = 89

Supportive Care N= 81

Age (years) Mean (±SD) Median (IQR) (Range: min-max)

69±10 70 (65-76) (31-85)

67±10 70 (62-74) (30-82)

Gender n (%) Male Female

59 (66) 30 (34)

57 (70) 24 (30)

Race n (%) White Black Other

83 (93) 4 (4) 2 (2)

76 (94) 2 (2) 3 (4)

Weeks Since MDS Diagnosis Mean (±SD) Median (IQR) (Range: min-max)

86±131 29 (10-87) (2-667)

77±119 35 (7-98) (2-865)

Previous MDS Therapy n (%) Yes No

27 (30) 62 (70)

19 (23) 62 (77)

RBC Transfusion Status n (%) Independent Dependent

23 (26) 66 (74)

27 (33) 54 (67)

Platelet Transfusion Status n (%) IndependentDependent

69 (78) 20 (22)

62 (77) 19 (23)

IPSS Classification n (%) Intermediate-1 Intermediate-2 High Risk

28 (31) 38 (43) 23 (26)

24 (30) 36 (44) 21 (26)

FAB Classification n (%) RA RARS RAEB RAEB-t CMML

12 (13) 7 (8) 47 (53) 17 (19) 6 (7)

12 (15) 4 (5) 43 (53) 14 (17) 8 (10)

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

Table 5 Response Criteria for the Controlled Trial in MDS *
*
Cheson BD, Bennett JM, et al. Report of an International Working Group to Standardize Response Criteria for MDS. Blood. 2000; 96:3671-3674.

Complete Response (CR) ≥8 weeks

Bone Marrow

On repeat aspirates: • < 5% myeloblasts • No dysplastic changes

Peripheral Blood

In all samples during response: • Hgb > 11 g/dL (no transfusions or erythropoietin

• ANC ≥1500/ µL (no growth factor) • Platelets ≥ 100,000/ µL (no thrombopoietic agent) • No blasts and no dysplasia

Partial Response (PR) ≥8 weeks

Bone Marrow

On repeat aspirates: • ≥ 50% decrease in blasts over pretreatment values OR • Improvement to a less advanced MDS FAB classification

Peripheral Blood

Same as for CR

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.

Table 6 Analysis of Response (ITT)

Parameter

Decitabine for Injection N=89

Supportive Care N=81

Overall Response Rate (CR+PR) Complete Response (CR) Partial Response (PR)

15 (17%)**

8 (9%) 7 (8%)

0 (0%)

0 (0%) 0 (0%)

Duration of Response Median time to (CR+PR) response — Days (range) Median Duration of (CR+PR) response — Days (range)

93 (55-272)

288 (116-388)

NA

NA

**p-value <0.001 from two-sided Fisher’s Exact Test comparing Decitabine For Injection vs. Supportive Care.

In the statistical analysis plan, a p-value of ≤ 0.024 was required to achieve statistical significance.

All patients with a CR or PR were RBC and platelet transfusion independent in the absence of growth factors. Responses occurred in patients with an adjudicated baseline diagnosis of AML.

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