Cedazuridine – Uses, Dosage, Side Effects, Interaction Cedazuridine is an orally available synthetic nucleoside analog derived from tetrahydrouridine (THU) and cytidine deaminase inhibitor (CDAi), that can potentially be used to prevent the breakdown of cytidines. Upon oral administration, cedazuridine binds to and inhibits CDA, an enzyme primarily found in the gastrointestinal (GI) tract and liver that catalyzes the deamination of cytidine and cytidine analogs. Given in combination with a cytidine, such as the antineoplastic hypomethylating agent decitabine, it specifically prevents its breakdown and increases its bioavailability and efficacy. In addition, this allows for lower doses of decitabine to be administered, which results in decreased decitabine-associated GI toxicity. Myelodysplastic syndromes (MDS) are a group of hematopoietic neoplasms that give rise to variable cytopenias progressing to secondary acute myeloid leukemia (SAML), which is invariably fatal if untreated. Hypomethylating agents such as [decitabine] and [azacitidine] are used to treat MDS by inducing DNA hypomethylation and apoptosis of cancerous cells. Although effective, these compounds are rapidly metabolized by cytidine deaminase (CDA) prior to reaching systemic circulation when administered orally, necessitating intramuscular or intravenous administration routes. Cedazuridine is a fluorinated tetrahydrouridine derivative specifically designed to inhibit CDA and facilitate the oral administration of hypomethylating agents. Cedazuridine was first reported in 2014 and was subsequently approved by the FDA on July 7, 2020, in combination with [decitabine] for sale by Astex Pharmaceuticals Inc under the name INQOVI®. 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: Myelodysplastic syndromes (MDS), including chronic myelomonocytic leukemia (CMML). You Might Also Read Lenalidomide; Uses, Dosage, Side Effects, Drug InteractionsDecitabine 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 You Might Also Read Neratinib Maleate; Dosage, Side Effect, Drug InteractionsRare 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. You Might Also Read Coenzyme Q10 - Uses, Dosage, Side Effects, InteractionsSwallow 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 https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212576s000lbl.pdf https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-oral-combination-decitabine-and-cedazuridine-myelodysplastic-syndromes https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-oral-combination-decitabine-and-cedazuridine- https://www.cancer.gov/about-cancer/treatment/drugs/decitabineandcedazuridine https://pubchem.ncbi.nlm.nih.gov/compound/Cedazuridine https://medlineplus.gov/druginfo/meds/a620050.html https://go.drugbank.com/drugs/DB15694 https://www.mayoclinic.org/drugs-supplements/decitabine-and-cedazuridine-oral-route/side-effects/drg-20490770?p=1 https://www.drugs.com/mtm/cedazuridine-and-decitabine.html https://www.webmd.com/drugs/2/drug-179701/decitabine-cedazuridine-oral/details/list-contraindications ChEMBL http://www.ebi.ac.uk/Information/termsofuse.html https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL3237547/ ChEMBL Protein Target Tree https://www.ebi.ac.uk/chembl/g/#browse/targets IUPHAR/BPS Guide to PHARMACOLOGY https://www.guidetopharmacology.org/about.jsp#license cedazuridine https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=11101 Guide to Pharmacology Target Classification https://www.guidetopharmacology.org/targets.jsp ChemIDplus LICENSE https://www.nlm.nih.gov/copyright.html Cedazuridine [USAN:INN] https://chem.nlm.nih.gov/chemidplus/sid/1141397809 ChemIDplus Chemical Information Classification https://chem.nlm.nih.gov/chemidplus/ DrugBank) https://www.drugbank.ca/legal/terms_of_use Cedazuridine https://www.drugbank.ca/drugs/DB15694 European Chemicals Agency (ECHA) https://echa.europa.eu/web/guest/legal-notice https://echa.europa.eu/information-on-chemicals https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/264882 FDA Global Substance Registration System (GSRS) https://www.fda.gov/about-fda/about-website/website-policies#linking CEDAZURIDINE https://gsrs.ncats.nih.gov/ginas/app/beta/substances/39IS23Q1EW ClinicalTrials.gov https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use https://clinicaltrials.gov/ DailyMed LICENSE https://www.nlm.nih.gov/copyright.html CEDAZURIDINE https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=CEDAZURIDINE CEDAZURIDINE; DECITABINE https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=CEDAZURIDINE;+DECITABINE NCI Thesaurus (NCIt) https://www.cancer.gov/policies/copyright-reuse https://ncithesaurus.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=ncit&code=C164146 NCI Thesaurus Tree https://ncit.nci.nih.gov EU Clinical Trials Register https://www.clinicaltrialsregister.eu/ FDA Orange Book https://www.fda.gov/about-fda/about-website/website-policies#linking https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book National Drug Code (NDC) Directory https://www.fda.gov/about-fda/about-website/website-policies#linking CEDAZURIDINE https://www.fda.gov/drugs/drug-approvals-and-databases/national-drug-code-directory NIPH Clinical Trials Search of Japan https://rctportal.niph.go.jp/en/ NLM RxNorm Terminology https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html cedazuridine https://rxnav.nlm.nih.gov/id/rxnorm/2384449 Springer Nature https://pubchem.ncbi.nlm.nih.gov/substance/?source=15745&sourceid=18049777-656739522 The Cambridge Structural Database https://www.ccdc.cam.ac.uk/structures/Search?Ccdcid=974853 Wikidata https://creativecommons.org/publicdomain/zero/1.0/ https://www.wikidata.org/wiki/Q76534202 PubChem https://pubchem.ncbi.nlm.nih.gov PFAS and Fluorinated Compounds in PubChem https://gitlab.lcsb.uni.lu/eci/pubchem-docs/-/raw/main/pfas-tree/PFAS_Tree.pdf?inline=false Medical Subject Headings (MeSH) https://www.nlm.nih.gov/copyright.html cedazuridine https://www.ncbi.nlm.nih.gov/mesh/2029896 MeSH Tree http://www.nlm.nih.gov/mesh/meshhome.html UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS) GHS Classification Tree http://www.unece.org/trans/danger/publi/ghs/ghs_welcome_e.html PATENTSCOPE (WIPO) SID 391740003 https://pubchem.ncbi.nlm.nih.gov/substance/391740003 Show More