Cedazuridine – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

Myelodysplastic syndromes (MDS) represent a heterogeneous group of hematopoietic neoplasms arising from a variety of underlying mutations that manifest in peripheral cytopenias and may eventually progress to secondary acute myeloid leukemia (SAML). There are over 45 genes commonly mutated in MDS patients, including those involved in DNA methylation and repair, histone modification, RNA splicing, transcription, signal transduction, and cellular adhesion. It is hypothesized that initial clonal founder mutations give rise to the progressive acquisition of secondary mutations and facilitate disease progression to SAML. Hypomethylating agents such as [decitabine] are metabolized into triphosphate derivatives that are subsequently incorporated into DNA. Once incorporated, these agents inhibit the activity of DNA methylases such as DNMT1, leading to progressive DNA hypomethylation and eventual activation of tumor suppression genes and apoptotic pathways. However, hypomethylating agents given orally are vulnerable to first-pass metabolism by cytidine deaminase, and hence typically have to be administered through intramuscular or intravenous routes. Co-administration with cedazuridine, which is an efficient inhibitor of cytidine deaminase, drastically increases the oral bioavailability of [decitabine], allowing for combination oral therapy.

Cedazuridine is a cytidine deaminase inhibitor that is co-administered with hypomethylating agents such as [decitabine] in order to increase their oral bioavailability. In combination with hypomethylating agents, cedazuridine may cause myelosuppression and embryo-fetal toxicity and should be administered with appropriate monitoring.

Indications

  • Cedazuridine, in combination with decitabine, is indicated for the treatment of myelodysplastic syndromes (MDS), including MDS with refractory anemia, MDS with refractory anemia and ringed sideroblasts, MDS with refractory anemia and excess blasts, MDS scoring intermediate-1, intermediate-2, or high-risk on the International Prognostic Scoring System (IPSS), and chronic myelomonocytic leukemia (CMML).
  • Decitabine and cedazuridine combination is used to treat myelodysplastic syndromes (MDS), including chronic myelomonocytic leukemia (CMML), and certain types of anemia. Myelodysplastic syndromes are a group of cancers, in which immature blood cells in the bone marrow do not mature and do not become healthy blood cells.
  • For myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups
  • Chronic Myelomonocytic Leukemia (CMML)
  • Myelodysplastic Syndromes (MDS)

Use in Cancer

Decitabine and cedazuridine are approved to treat adults with:

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Decitabine and cedazuridine are also being studied in the treatment of other types of cancer.

Decitabine and cedazuridine is a tablet form of decitabine combined with cedazuridine. For more information about the form of decitabine that is given by infusion, see the Drug Information Summary for Decitabine.

Contraindications

  • decreased blood platelets
  • low levels of a type of white blood cell called neutrophils
  • pregnancy
  • a patient who is producing milk and breastfeeding

Dosage

Strengths: 100 mg-35 mg

Myelodysplastic Syndrome

  • 1 tablet (containing 100 mg cedazuridine and 35 mg decitabine) orally once daily on Days 1 through 5 of each 28-day cycle for a minimum of 4 cycles until disease progression or unacceptable toxicity; a complete or partial response may take longer than 4 cycles
  • Consider administering antiemetics prior to each dose to minimize nausea and vomiting.

Renal Dose Adjustments

  • Mild (CrCl 60 to less than 90 mL/min) or moderate (CrCl 30 to less than 60 mL/min): No adjustment is recommended.
    Severe (15 to less than 30 mL/min) or end-stage (CrCl less than 15 mL/min) renal impairment: Data not available

Dose Adjustments

  • Obtain complete blood cell counts prior to initiating therapy and before each cycle; delay the next cycle if absolute neutrophil count (ANC) is less than 1000/microliter and platelets are less than 50,000/microliter in the absence of active disease. Monitor complete blood cell counts until ANC is 1000/microliter or greater and platelets are 50,000/microliter or greater.

Administration advice:

  • Do not substitute this drug combination for an IV decitabine product within a cycle.
  • Take this drug at the same time each day.
  • Swallow tablets whole; do not cut, crush, or chew tablets.
  • Take this drug on an empty stomach 2 hours before or 2 hours after food.
  • If a dose is missed within 12 hours of the time it is usually taken, take the missed dose as soon as possible and then to resume the normal daily dosing schedule.
  • Extend the dosing period by one day for every missed dose to complete 5 daily doses for each cycle.
  • Do not take an additional dose if vomiting occurs but continue with the next schedule dose.

Side Effects

The Most Common

  • excessive tiredness
  • pale skin
  • constipation
  • diarrhea
  • nausea
  • vomiting
  • stomach pain
  • weight loss
  • loss of appetite
  • joint or muscle pain
  • dizziness
  • falling down
  • headache
  • difficulty falling asleep or staying asleep
  • painful sores in the mouth, or on the tongue or lips
  • swelling of the hands, feet, ankles, lower legs, or stomach
  • tingling, numbness, and pain in hands or feet
  • fever, chills, cough, body aches, or other signs of infection
  • unusual bleeding or bruising, nose bleeds, or bleeding gums
  • fast or pounding heartbeat
  • shortness of breath
  • rash

More Common

  • Black, tarry stools
  • bleeding gums
  • bloating or swelling of the face, arms, hands, lower legs, or feet
  • bloody urine
  • blurred vision
  • body aches or pain
  • burning, numbness, pain, or tingling sensations
  • chest pain
  • chills
  • confusion
  • cough
  • coughing up blood
  • cracked lips
  • decreased frequency or amount of urine
  • diarrhea
  • difficult or labored breathing
  • difficulty in swallowing
  • dizziness, fainting, or lightheadedness when getting up suddenly from a lying or sitting position
  • ear congestion
  • fainting
  • fast, slow, or irregular heartbeat
  • fever
  • headache
  • increased menstrual flow or vaginal bleeding
  • increased thirst
  • itching, pain, redness, swelling, tenderness, or warmth on the skin
  • loss of appetite
  • loss of voice
  • lower back or side pain
  • nausea
  • nosebleeds
  • painful or difficult urination
  • pale skin
  • paralysis
  • pinpoint red spots on the skin
  • prolonged bleeding from cuts
  • rapid, shallow breathing
  • runny or stuffy nose
  • sneezing
  • sore throat
  • sores, ulcers, or white spots on the lips, tongue, or inside the mouth
  • sweating
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • unusual weight gain or loss
  • vomiting
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Rare

  • Fever sores on the skin
  • blue lips, fingernails, or skin
  • Joint pain, stiffness, or swelling
  • stomach pain
  • easy bruising, unusual bleeding, purple or red spots under your skin;
  • low red blood cells (anemia)–pale skin, unusual tiredness, feeling light-headed or short of breath, cold hands and feet;
    low white blood cell counts–fever, mouth sores, skin sores, sore throat, cough, trouble breathing; or
  • signs of a lung infection–fever, chills, cough with mucus, chest pain, feeling short of breath.
  • abnormal liver function tests;
  • headache, dizziness, feeling tired;
  • swelling in your arms or legs; fever, low blood cell counts;
  • bruising or bleeding;

Drug Interaction

  • adalimumab
  • adenovirus vaccine
  • aldesleukin
  • alefacept
  • alemtuzumab
  • anakinra
  • anthrax vaccine adsorbed
  • azacitidine
  • azathioprine
  • baricitinib
  • bcg
  • bcg vaccine
  • bendamustine
  • bifidobacterium infantis
  • bleomycin
  • brewer’s yeast
  • busulfan
  • canakinumab
  • candida albicans extract
  • capecitabine
  • carboplatin
  • certolizumab
  • chlorambucil
  • chloramphenicol
  • chloramphenicol ophthalmic
  • cholera vaccine
  • cholera vaccine, live
  • cisplatin
  • cladribine
  • clozapine
  • coccidioidin skin test
  • cytarabine
  • cytarabine liposomal
  • dacarbazine
  • daunorubicin
  • daunorubicin liposomal
  • deferiprone
  • dengue vaccine
  • denosumab
  • dimethyl fumarate
  • diroximel fumarate
  • efalizumab
  • eflapegrastim
  • etanercept
  • etoposide
  • filgrastim
  • fingolimod
  • floxuridine
  • fluorouracil
  • ganciclovir
  • gemcitabine
  • golimumab
  • haemophilus b conjugate (hboc) vaccine
  • haemophilus b conjugate (prp-omp) vaccine
  • haemophilus b conjugate (prp-t) vaccine
  • hepatitis a adult vaccine
  • hepatitis a pediatric vaccine
  • hepatitis b adult vaccine
  • hepatitis b pediatric vaccine
  • histoplasmin
  • human papillomavirus vaccine
  • hydroxyurea
  • ibritumomab
  • idarubicin
  • idelalisib
  • ifosfamide
  • imatinib
  • infliximab
  • influenza virus vaccine, h1n1, inactivated
  • influenza virus vaccine, h1n1, live
  • influenza virus vaccine, h5n1
  • influenza virus vaccine, inactivated
  • influenza virus vaccine, live, trivalent
  • interferon alfa-2a
  • interferon alfa-2b
  • isatuximab
  • japanese enceph vacc sa14-14-2, inactivated
  • japanese encephalitis virus vaccine nakayama
  • lactobacillus acidophilus
  • lactobacillus reuteri
  • lactobacillus rhamnosus
  • lactobacillus rhamnosus gg
  • leflunomide
  • lomustine
  • loncastuximab tesirine
  • lurbinectedin
  • lyme disease vaccine
  • measles virus vaccine
  • melphalan
  • melphalan flufenamide
  • meningococcal conjugate vaccine
  • meningococcal group B vaccine
  • meningococcal polysaccharide vaccine
  • mercaptopurine
  • mitomycin
  • mitoxantrone
  • mixed respiratory vaccine
  • monomethyl fumarate
  • mumps skin test antigen
  • mumps virus vaccine
  • natalizumab
  • naxitamab
  • niraparib
  • ocrelizumab
  • olaparib
  • omacetaxine
  • oxaliplatin
  • ozanimod
  • palifermin
  • pegfilgrastim
  • plague vaccine
  • pneumococcal 13-valent vaccine
  • pneumococcal 15-valent conjugate vaccine
  • pneumococcal 20-valent conjugate vaccine
  • pneumococcal 23-polyvalent vaccine
  • pneumococcal 7-valent vaccine
  • poliovirus vaccine, inactivated
  • poliovirus vaccine, live, trivalent
  • ponesimod
  • rabies vaccine, human diploid cell
  • rabies vaccine, purified chick embryo cell
  • radium 223 dichloride
  • rilonacept
  • roflumilast
  • ropeginterferon alfa-2b
  • rotavirus vaccine
  • rubella virus vaccine
  • ruxolitinib
  • saccharomyces boulardii lyo
  • samarium sm 153 lexidronam
  • skin test antigens, multiple
  • smallpox and monkeypox vaccine
  • smallpox vaccine
  • sodium phosphate p32
  • staphage lysate (spl)
  • streptozocin
  • strontium-89 chloride
  • talimogene laherparepvec
  • tbo-filgrastim
  • teclistamab
  • teriflunomide
  • tetanus toxoid
  • thalidomide
  • thiotepa
  • tiagabine
  • topotecan
  • trichophyton skin test
  • tuberculin purified protein derivative
  • typhoid vaccine, inactivated
  • typhoid vaccine, live
  • upadacitinib
  • ustekinumab
  • valganciclovir
  • varicella virus vaccine
  • vinblastine
  • vinorelbine
  • vitamin e
  • voclosporin

Pregnancy and Lactation

US FDA pregnancy category Not Assigned

Pregnancy

There are no controlled data on human pregnancy. This drug combination can harm a developing fetus. Adequate methods of contraception should be encouraged. Verify negative pregnancy status in females of reproductive potential prior to initiating therapy. Advise females of reproductive potential to use effective contraception during therapy and for 6 months after. Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during therapy and for 3 months after. This drug combination may impair male fertility; the reversibility of the effect on fertility is unknown.

Lactation

Use should be avoided. Excreted into human milk: Unknown. Excreted into animal milk: Data not available The effects on the nursing infant are unknown. Women should not breastfeed during therapy and for at least 2 weeks after.

How should this medicine be used?

The combination of decitabine and cedazuridine comes as a tablet to take by mouth. It is usually taken on an empty stomach for the first 5 days of a 28-day cycle. Do not eat food for 2 hours before and 2 hours after each dose. The 28-day cycle regimen may be repeated as recommended by your doctor based on your body’s response to this medication. Treatment should usually be given for at least 4 cycles but may be continued if your doctor decides that you will benefit from additional treatment.

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Swallow the tablets whole; do not split, chew, or crush them.

If you vomit after taking decitabine and cedazuridine, do not take another dose. Continue your regular dosing schedule.

Your doctor will give you medication to prevent nausea and vomiting before you receive each dose of decitabine and cedazuridine.

Your doctor may decrease your dose or temporarily or permanently stop your treatment if you experience certain side effects. Be sure to tell your doctor how you are feeling during your treatment with decitabine and cedazuridine. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

What special precautions should I follow?

Before taking decitabine and cedazuridine,

  • tell your doctor and pharmacist if you are allergic to decitabine, cedazuridine, any other medications, or any of the ingredients in decitabine and cedazuridine tablets. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have or have ever had kidney or liver disease.
  • tell your doctor if you are pregnant or plan to become pregnant, or if you plan to father a child. If you are female, you will need to take a pregnancy test before you start treatment and use birth control to prevent pregnancy during your treatment and for at least 6 months after your final dose. If you are male, you and your female partner should use effective birth control while you are taking decitabine and cedazuridine and for 3 months after the final dose. If you or your partner becomes pregnant while taking this medication, call your doctor. Decitabine and cedazuridine may harm the fetus.
  • tell your doctor if you are breastfeeding. Do not breastfeed while you are taking decitabine and cedazuridine and for 2 weeks after your final dose.
  • you should know that this medication may decrease fertility in men. Talk to your doctor about the risks of taking decitabine and cedazuridine.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking decitabine and cedazuridine.

References

  1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212576s000lbl.pdf
  2. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-oral-combination-decitabine-and-cedazuridine-myelodysplastic-syndromes
  3. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-oral-combination-decitabine-and-cedazuridine-
  4. https://www.cancer.gov/about-cancer/treatment/drugs/decitabineandcedazuridine
  5. https://pubchem.ncbi.nlm.nih.gov/compound/Cedazuridine
  6. https://medlineplus.gov/druginfo/meds/a620050.html
  7. https://go.drugbank.com/drugs/DB15694
  8. https://www.mayoclinic.org/drugs-supplements/decitabine-and-cedazuridine-oral-route/side-effects/drg-20490770?p=1
  9. https://www.drugs.com/mtm/cedazuridine-and-decitabine.html
  10. https://www.webmd.com/drugs/2/drug-179701/decitabine-cedazuridine-oral/details/list-contraindications
  11. Guide to Pharmacology Target Classification
  12. ChemIDplus Chemical Information Classification
  13. NCI Thesaurus Tree
  14. PubChem