Dacogen

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 forthe control of cellulardifferentiation 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.

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.

Pharmacokinetics

Pharmacokinetic 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 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)	AUC 0-∞ (ng•h/mL)	T½ (h)	CL (L/h/m²)	AUC Cumulative*** (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.

Clinical Studies

Controlled Trial

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 Dacogen therapy plus supportive care (only 83 received Dacogen), 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 Dacogen 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	Dacogen N = 89	Supportive Care N = 81
Age (years)
Mean (±SD)	69±10	67±10
Median (IQR)	70 (65-76)	70 (62-74)
(Range: min-max)	(31-85)	(30-82)
Gender n (%)
Male	59 (66)	57 (70)
Female	30 (34)	24 (30)
Race n (%)
White	83 (93)	76 (94)
Black	4 (4)	2 (2)
Other	2 (2)	3 (4)
Weeks Since MDS Diagnosis
Mean (±SD)	86±131	77±119
Median (IQR)	29 (10-87)	35 (7-98)
(Range: min-max)	(2-667)	(2-865)
Previous MDS Therapy n (%)
Yes	27 (30)	19 (23)
No	62 (70)	62 (77)
RBC Transfusion Status n (%)	23 (26)	27 (33)
ndependent Dependent	66 (74)	54 (67)
Platelet Transfusion Status n (%)	69 (78)	62 (77)
Independent Dependent	20 (22)	19 (23)
IPSS Classification n (%)
Intermediate-1	28 (31)	24 (30)
Intermediate-2	38 (43)	36 (44)
High Risk	23 (26)	21 (26)
FAB Classification n (%)
RA	12 (13)	12 (15)
RARS	7 (8)	4 (5)
RAEB	47 (53)	43 (53)
RAEB-t	17 (19)	14 (17)
CMML	6 (7)	8 (10)

Patients randomized to the Dacogen arm received Dacogen 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 Phase 3 MDS Trial*

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/pL (no growth factor) Platelets ≥ 100,000/pL (no thrombopoietic agent) No blasts and no dysplasia
Partial Res ponse (PR) ≥ 8 weeks	Bone Marrow	On repeat as pirates : ≥ 50% decrease in blasts over pretreatment values OR Improvement to a less advanced MDS FAB
	Peripheral Blood	Same as for CR
*Cheson BD, Bennett JM, et al. Report of an International Working Group to Standardize Response Criteria for MDS. Blood. 2000; 96:3671-3674.

The overall response rate (CR+PR) in the ITT population was 17% in Dacogen-treated patients and 0% in the SC group (p < 0.001). (SeeTable 6) The overall response rate was 21% (12/56) in Dacogentreated 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 Dacogen was 288 days (116-388) and median time to response (range) was 93 days (55-272). All but one of the Dacogen-treated patients who responded did so by the fourth cycle. Benefit was seen in an additional 13% of Dacogen-treated patients who had hematologic improvement, defined as a response less than PR lasting at least 8 weeks, compared to 7% of SC patients. Dacogen treatment did not significantly delay the median time to AML or death versus supportive care.

Table 6: Analysis of Response (ITT)

Parameter	Dacogen N=89	Supportive Care N=81
Overall Response Rate (CR+PR)†	15 (17%)**	0 (0%)
Complete Response (CR)	8 (9%)	0 (0%)
Partial Response (PR)	7 (8%)	0 (0%)
Duration of Response
Median time to (CR+PR) response - Days (range)	93 (55-272)	NA
Median Duration of (CR+PR) response - Days (range)	288 (116-388)	NA
**p-value < 0.001 from two-sided Fisher's Exact Test comparing Dacogen 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.

Single-arm Studies

Three open-label, single-arm, multicenter studies were conducted to evaluate the safety and efficacy of Dacogen 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 Dacogen by intravenous infusion at a dose of 20 mg/m IV over 1-hour daily, on days 1-5 of week 1 every 4 weeks (1 cycle). The results were consistent with the results of the controlled trial and summarized in Table 8.

Table 7 : Baseline Demographics and Other Patient Characteristics (ITT)

Demographic or Other Patient Characteristic	Dacogen N = 99
Age (years)
Mean (±SD)	71±9
Median (Range: min-max)	72 (34-87)
Gender n (%)
Male	71(72)
Female	28(28)
Race n (%)
White	86 (87)
Black	6 (6)
Asian	4 (4)
Other	3 (3)
Days From MDS Diagnosis to First Dose
Mean (±SD)	444±626
Median (Range: min-max)	154 (7-3079)
Previous MDS Therapy n (%)
Yes	27 (27)
No	72 (73)
RBC Transfusion Status n (%)
Independent	33 (33)
Dependent	66 (67)
Platelet Transfusion Status n (%)
Independent	84 (85)
Dependent	15 (15)
IPSS Classification n (%)
Low Risk	1 (1)
Intermediate-1	52 (53)
Intermediate-2	23 (23)
High Risk	23 (23)
FAB Classification n (%)
RA	20 (20)
RARS	17 (17)
RAEB	45 (45)
RAEB-t	6 (6)
CMML	11 (11)

Table 8 : Analysis of Response (ITT)*

Parameter	Dacogen N=99
Overall Response Rate (CR+PR)	16 (16%)
Complete Response (CR)	15 (15%)
Partial Response (PR)	1 (1%)
Duration of Response
Median time to (CR+PR) response - Days (range)	162 (50-267)
Median Duration of (CR+PR) response - Days (range)	443 (72-722+)
+ indicates censored observation * Cheson BD, Bennett JM, et al. Report of an International Working Group to Standardize Response Criteria for MDS. Blood. 2000; 96:3671-3674.

Contraindications

Hypersensitivity

Cautions

Use caution in renal/hepatic impairment

Avoid pregnancy

Bone marrow suppression may occur (dose limiting); dose adjustment may be necessary

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category D. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Dacogen may cause harm to an unborn baby.

It is recommended to avoid pregnancy while receiving treatment with Dacogen and for I month afterwards, and to use effective contraception during this time.

It is recommended for men not to father a child while receiving treatment with Dacogen, and for 2 months afterwards. During these times, men with female partners of childbearing potential should use effective contraception.

This medication is available in an injectable form to be given directly into a vein (IV) by a healthcare professional.
 

Myelodysplastic Syndrome

Treatment of myelodysplastic syndrome (MDS);1 3 4 designated an orphan drug by FDA for this use.2

Used in patients with previously treated or untreated, de novo or secondary MDS of all French-American-British (FAB) subtypes (i.e., refractory anemia [RA], RA with ringed sideroblasts [RARS], RA with excess blasts [RAEB], RAEB in transformation to leukemia [RAEB-T], chronic myelomonocytic leukemia [CMML]) and International Prognostic Scoring System (IPSS) risk groups with scores of ≥0.5 (i.e., intermediate-1, intermediate-2, and high-risk groups).1 3 4

In the U.S.

• Dacogen

Available Dosage Forms:

• Powder for Solution

Therapeutic Class: Antineoplastic Agent

Decitabine is used to treat myelodysplastic syndromes (diseases of the blood and bone marrow; MDS) and certain types of anemia. This medicine is an antineoplastic (cancer medicine) .

This medicine is available only with your doctor's prescription .

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

More common

• Black, tarry stools
• bladder pain
• bleeding after defecation
• bleeding gums
• blood in urine or stools
• bloody or cloudy urine
• blue lips and fingernails
• blurred vision
• body aches or pain
• chest pain
• chills
• coma
• congestion
• convulsions
• cough
• coughing that sometimes produces a pink frothy sputum
• decreased urination
• difficult, burning, or painful urination
• difficult, fast, noisy breathing, sometimes with wheezing
• dizziness, faintness, or lightheadedness when getting up from a lying or sitting position
• drowsiness
• dry mouth
• dryness of throat
• facial swelling
• fainting
• fast or irregular heartbeat
• feeling unusually cold
• fever
• flushed, dry skin
• frequent urge to urinate
• fruit-like breath odor
• headache
• hives or welts
• hoarseness
• increased hunger
• increased sweating
• increased thirst
• increased urination
• itching, pain, redness, swelling, tenderness, or warmth on skin
• lightheadedness
• loss of appetite
• lower back or side pain
• mood or mental changes
• muscle pain or cramps
• muscle spasms or twitching
• nausea or vomiting
• nervousness
• numbness or tingling in hands, feet, or lips
• pale skin
• pinpoint red spots on skin
• redness or pain at the catheter site
• runny nose
• seizures
• shivering
• shortness of breath
• skin rash
• small clicking, bubbling, or rattling sounds in the lung when listening with a stethoscope
• small red or purple spots on skin, lips or in mouth
• sneezing
• sore mouth or tongue
• sore throat
• sores, ulcers, or white spots on lips or in mouth
• stomach pain and bloating
• sunken eyes
• swelling of face, hands, ankles, feet, or lower legs
• swollen, painful, or tender lymph glands in neck, armpit, or groin
• tightness in chest
• trembling
• trouble in swallowing
• troubled breathing with exertion
• uncomfortable swelling around anus
• unexplained weight loss
• unusual bleeding or bruising
• unusual tiredness or weakness
• voice changes
• weakness or heaviness of legs
• wheezing
• white patches in mouth and/or on tongue
• wrinkled skin
• yellow eyes or skin

Less common

• Collection of blood under skin
• deep, dark purple bruise
• diarrhea
• pain or tenderness around eyes and cheekbones
• pain, warmth, or burning in fingers, toes, and legs
• problems with vision or hearing
• skin scrape or burn
• stuffy nose
• swelling at injection site

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Acid or sour stomach
• anxiety
• back pain
• belching
• bumps on skin
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• chest discomfort
• constipation
• difficulty swallowing
• fall
• hair loss, thinning of hair
• heartburn
• indigestion
• loose stools
• muscle stiffness
• pain in arms or legs
• pain in joints
• sleeplessness
• stomach discomfort or upset
• swelling or inflammation of the mouth
• trouble sleeping
• unable to sleep
• unusual drowsiness, dullness, or feeling of sluggishness

Less common

• Difficulty in moving
• general feeling of discomfort or illness
• muscle aching
• pain in the tongue
• postnasal drip
• pressure in the stomach
• swollen joints

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• It is used to treat a health problem called myelodysplastic syndrome (MDS).
• It may be given to you for other reasons. Talk with the doctor.

• Tell all of your health care providers that you take Dacogen. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• You may have more chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
• Very bad and sometimes deadly bleeding problems have happened with this medicine. Talk with the doctor.
• If you have upset stomach, throwing up, loose stools (diarrhea), or are not hungry, talk with your doctor. There may be ways to lower these side effects.
• If you have high blood sugar (diabetes), talk with your doctor. This medicine may raise blood sugar.
• Check your blood sugar as you have been told by your doctor.
• If you are a man and have sex with a female who could get pregnant, protect her from pregnancy during care and for 2 months after stopping Dacogen. Use birth control that you can trust.
• If you are a man and your sex partner gets pregnant while you take this medicine or within 2 months after your last dose, call your doctor right away.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant.
• Use birth control that you can trust to prevent pregnancy while taking Dacogen and for 1 month after stopping this medicine.
• If you get pregnant while taking Dacogen or within 1 month after your last dose, call your doctor right away.

• If you need to store this medicine at home, talk with your doctor, nurse, or pharmacist about how to store it.

    None

Clinical Studies 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.

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 in the Phase 3 Trials in the Dacogen Arm:

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

Discussion of Adverse Reactions Information
    Dacogen was studied in 3 single-arm studies (N = 66, N = 98, N = 99) and 1 controlled supportive care study (N = 83 Dacogen, N = 81 supportive care ).  The data described below reflect exposure to Dacogen in 83 patients in the MDS trial.  In the trial, patients received 15 mg/m2 intravenously every 8 hours for 3 days every 6 weeks.  The median number of Dacogen cycles was 3 (range 0 to 9).

Table 1 presents all adverse events regardless of causality occurring in at least 5% of patients in the Dacogen group and at a rate greater than supportive care.

Table 1 Adverse Events Reported in ≥ 5% of Patients in the Dacogen Group and at a Rate Greater than Supportive Care in Phase 3 MDS Trial

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

    Discussion of Clinically Important Adverse Reactions

    In the controlled trial using Dacogen dosed at 15 mg/m2, administered by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days, the highest incidence of Grade 3 or Grade 4 adverse events in the Dacogen arm were neutropenia (87%), thrombocytopenia (85%), febrile neutropenia (23%) and leukopenia (22%).  Bone marrow suppression was the most frequent cause of dose reduction, delay and discontinuation.  Six patients had fatal events associated with their underlying disease and myelosuppression (anemia, neutropenia, and thrombocytopenia) that were considered at least possibly related to drug treatment [See Warnings and Precautions (5.1)]. Of the 83 Dacogen-treated patients, 8 permanently discontinued therapy for adverse events; compared to 1 of 81 patients in the supportive care arm.

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

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

	Dacogen N = 99 (%)
* In this single arm study, investigators reported adverse events based on clinical signs and symptoms rather than predefined laboratory abnormalities. Thus not all laboratory abnormalities were recorded as adverse events.
Blood and lymphatic system disorders
Anemia	31 (31%)
Febrile neutropenia	20 (20%)
Leukopenia	6 (6% )
Neutropenia	38 (38% )
Pancytopenia	5 (5% )
Thrombocythemia	5 (5% )
Thrombocytopenia	27 (27%)
Cardiac disorders
Cardiac failure congestive	5 (5% )
Tachycardia	8 (8% )
Ear and labyrinth disorders
Ear pain	6 (6% )
Gastrointestinal disorders
Abdominal pain	14 (14%)
Abdominal pain upper	6 (6% )
Constipation	30 (30%)
Diarrhea	28 (28%)
Dyspepsia	10 (10%)
Dysphagia	5 (5% )
Gastro-esophageal reflux disease	5 (5% )
Nausea	40 (40%)
Oral pain	5 (5% )
Stomatitis	11 (11%)
Toothache	6 (6% )
Vomiting	16 (16%)
General disorders and administration site conditions
Asthenia	15 (15%)
Chest pain	6 (6% )
Chills	16 (16%)
Fatigue	46 (46%)
Mucosal inflammation	9 (9% )
Edema	5 (5% )
Edema peripheral	27 (27%)
Pain	5 (5% )
Pyrexia	36 (36%)
Infections and infestations
Cellulitis	9 (9% )
Oral candidiasis	6 (6% )
Pneumonia	20 (20%)
Sinusitis	6 (6% )
Staphylococcal bacteremia	8 (8% )
Tooth abscess	5 (5% )
Upper respiratory tract infection	10 (10%)
Urinary tract infection	7 (7% )
Injury, poisoning and procedural complications
Contusion	9 (9% )
Investigations
Blood bilirubin increased	6 (6% )
Breath sounds abnormal	5 (5% )
Weight decreased	9 (9% )
Metabolism and nutrition disorders
Anorexia	23 (23%)
Decreased appetite	8 (8% )
Dehydration	8 (8% )
Hyperglycemia	6 (6% )
Hypokalemia	12 (12%)
Hypomagnesemia	5 (5% )
Musculoskeletal and connective tissue disorders
Arthralgia	17 (17%)
Back pain	18 (18%)
Bone pain	6 (6% )
Muscle spasms	7 (7% )
Muscular weakness	5 (5% )
Musculoskeletal pain	5 (5% )
Myalgia	9 (9% )
Pain in extremity	18 (18%)
Nervous system disorders
Dizziness	21 (21%)
Headache	23 (23%)
Psychiatric disorders
Anxiety	9 (9% )
Confusional state	8 (8% )
Depression	9 (9% )
Insomnia	14 (14%)
Respiratory, thoracic and mediastinal disorders
Cough	27 (27%)
Dyspnea	29 (29%)
Epistaxis	13 (13%)
Pharyngolaryngeal pain	8 (8% )
Pleural effusion	5 (5% )
Sinus congestion	5 (5% )
Skin and subcutaneous tissue disorders
Dry skin	8 (8% )
Ecchymosis	9 (9% )
Erythema	5 (5% )
Night sweats	5 (5% )
Petechiae	12 (12%)
Pruritus	9 (9% )
Rash	11 (11%)
Skin lesion	5 (5% )
Vascular disorders
Hypertension	6 (6% )
Hypotension	11 (11%)

    Discussion of Clinically Important Adverse Reactions

    In the single-arm study (N=99) when Dacogen was dosed at 20 mg/m2 intravenous, infused over one hour daily for 5 consecutive days, the highest incidence of Grade 3 or Grade 4 adverse events were neutropenia (37%), thrombocytopenia (24%) and anemia (22%).  Seventy-eight percent of patients had dose delays, the median duration of this delay was 7 days and the largest percentage of delays was due to hematologic toxicities.  Hematologic toxicities and infections were the most frequent causes of dose delays and discontinuation.  Eight patients had fatal events due to infection and/or bleeding (seven of which occurred in the clinical setting of myelosuppression) that were considered at least possibly related to drug treatment.  Nineteen of 99 patients permanently discontinued therapy for adverse events.

    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 Events that occurred in patients receiving Dacogen 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 Dacogen has been reported in a Phase 2 trial.

Post-marketing Experience

    The following adverse reactions have been identified during post-approval use of Dacogen.  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.

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.

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.

Pharmacokinetics

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

    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.

Get emergency medical help if you have any signs of an allergic reaction to Dacogen: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• fever, chills, body aches, cough, sore throat, flu symptoms;

• easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

• pale skin, feeling light-headed, rapid heart rate, trouble concentrating;

• white patches or sores inside your mouth or on your lips; or

• stabbing chest pain, wheezing, feeling short of breath, cough with yellow or green mucus;

• swelling, pain, tenderness, or redness anywhere on your body; or

• electrolyte imbalance (confusion, uneven heart rate, extreme thirst, increased urination, jerking muscle movements, leg discomfort, muscle weakness or limp feeling).

Common Dacogen side effects may include:

• headache, dizziness, drowsiness;

• nausea, vomiting, stomach pain, diarrhea, constipation;

• cough, dry mouth;

• joint pain; or

• sleep problems (insomnia).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Common side effects of Dacogen include: neutropenia and thrombocytopenia. See below for a comprehensive list of adverse effects.