Bisni Narayanan, PharmD, MS

 is a fixed-dose oral combination tablet comprised of hypomethylating agent decitabine (35 mg) and cytidine deaminase inhibitor cedazuridine (100 mg).

The FDA approved decitabine/cedazuridine in 2020 for treatment of adults with myelodysplastic syndromes (MDS), including previously treated and untreated de novo and secondary MDS with the American-British-French subtypes of refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia (CMML), as well as intermediate-1, intermediate- 2, and high-risk International Prognostic Scoring System groups.

The approval of decitabine/cedazuridine was supported by findings from 2 open-label, multicenter, randomized crossover trials, ASTX727-01-B and ASTX727-02.

 Researchers assessed study efficacy as complete response (Hb ≥ 11g/dL, ANC ≥ 1000/mm

, 0% blasts in blood, and <5% myeloblasts with normal maturation of all cell lines) and the rate of conversion from transfusion dependence to transfusion independence.

In the ASTX727-01-B trial (N=80), 18% of participants achieved completed response with a median duration of complete response of 8.7 months. Among patients who were transfusion-dependent, 49% (20/41) became transfusion-independent and among patients who were transfusion-independent, 64% (25/39) remained so during the post-baseline period.

In the ASTX727-02 study (N=133), 21% of patients achieved complete response, with a median duration of complete response of 7.5 months.

 Of the patients who were transfusion-dependent, 53% (30/57) became transfusion-independent and 63% (48/76) remained transfusion-independent during the post baseline period.

Decitabine is a nucleoside metabolic inhibitor.

 Decitabine induces cell death by inhibiting the enzyme DNA methyltransferase, resulting in DNA hypomethylation and cell differentiation.

Hypomethylation in cancer cells may restore normal function to genes regulating cell proliferation and differentiation. Non-proliferating cells are insensitive to decitabine.

Decitabine is a prodrug analogue of the natural nucleotide 2-deoxycytidine. Cytidine deaminase, an enzyme highly expressed in the gastrointestinal tract and liver, degrades cytidine and its analogues, including decitabine.

When cytidine deaminase degrades decitabine, it limits the oral bioavailability. Cedazuridine is a cytidine deaminase inhibitor. Administration of decitabine with cedazuridine inhibits the cytidine deaminase enzyme, increasing decitabine’s oral bioavailability.

Decitabine/cedazuridine is taken as 1 tablet containing 35 mg decitabine and 100 mg cedazuridine orally once daily for 5 days on days 1 through 5 of each 28-day cycle for a minimum of 4 cycles until disease progression or toxicity.

Pharmacists must advise patients to take the tablets the same time each day and to swallow them whole without crushing or chewing.

Patients must take decitabine/cedazuridine on an empty stomach, which denotes no food for 2 hours before and 2 hours after each dose. Administration of antiemetics may minimize nausea and vomiting prior to each dose.

If the patient misses a dose within 12 hours of the usual dose time, pharmacists must advise them to take the missed dose as soon as possible and then to resume the normal daily dosing. Labeling guidelines do not recommend an additional dose if the patient vomits after decitabine/cedazuridine administration; instead patients must continue with the next scheduled dose.

The most common AEs with decitabine/cedazuridine are fatigue, constipation, hemorrhage, myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, edema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia, and transaminase increase.

 The common grade 3 or 4 laboratory abnormalities are decreased leukocytes, platelets, neutrophils, and hemoglobin.

Health care providers must obtain a complete blood cell count prior to decitabine/cedazuridine initiation and before each cycle.

 If the patient’s ANC is less than 1000/mcL and platelets are less than 50,000/mcL, then the next cycle is delayed until hematologic recovery (ANC at least 1000/mcL, and platelets at least 50,000/mcL). In clinical trials, AEs led to dose reductions in 19% of patients and dose interruptions in 41% of patients on decitabine/cedazuridine.

The manufacturer recommends the following dosing modification for hematological AEs:

Continue decitabine/cedazuridine tablets at same dose upon hematological recovery (ANC at least 1000/mcL, and platelets at least 50,000/mcL) within 2 weeks of achieving remission.

If a patient’s cell count does not recover within 2 weeks of achieving remission:

Delay decitabine/cedazuridine for up to 2 additional weeks

Resume at a reduced dose on days 1 through 4. If myelosuppression persists after reduced dose follow the dose reduction listed in below (

Decitabine/Cedazuridine Dose Reductions During Hematological AEs

Patients with mild to moderate renal or hepatic impairment require no dosing adjustment.

Patients with severe renal or hepatic impairment have no specific recommendations, as decitabine/cedazuridine has not been studied in this population.

Myelosuppression (thrombocytopenia, neutropenia, anemia, and febrile neutropenia) is the most frequent cause of decitabine/cedazuridine dose reduction or interruption.

 Patients in the first and second treatment cycles may experience myelosuppression and neutropenia more frequently.

Patients on decitabine/cedazuridine may experience serious and fatal infectious complications of pneumonia and sepsis. Pharmacists must counsel patients to report any signs or symptoms of an infection to their health care provider immediately during treatment.

Decitabine/cedazuridine can cause fetal harm when administered to a pregnant woman. Pharmacists must counsel women of reproductive age to use effective contraception during treatment and for 6 months after last dose.

Males with female partners of reproductive potential must be counseled to use effective contraception during treatment and for 3 months after last dose. Women should be advised not to breastfeed during treatment and for at least 2 weeks after last dose.

Health care providers must verify pregnancy status in females of reproductive potential prior to initiating therapy. Decitabine/cedazuridine may impair fertility in males.

 Intravenous decitabine products should not be substituted for oral decitabine within a cycle.

Cedazuridine inhibits cytidine deaminase. Drugs metabolized by cytidine deaminase should be avoided to decrease the risk of increased exposure and toxicity.

Bisni Narayanan, PharmD, MS, Supervisor Pharmacy Operations, Outpatient Pharmacy Services, Yale New Haven Health System, Hamden, CT.

1. Inqovi prescribing information. July 2020. Accessed May 30, 2022. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212576s000lbl.pdf

2. Kim N, Norsworthy KJ, Subramaniam S, et al. FDA approval summary: decitabine and cedazuridine tablets for myelodysplastic syndromes [published online ahead of print, 2022 Apr 18]. 

Articles

The FDA approved decitabine/cedazuridine in 2020 for treatment of adults with myelodysplastic syndromes.