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 through 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 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).
- Cedazuridine is a cytidine deaminase inhibitor coadministered with the hypomethylating agent decitabine for the treatment of variable forms of myelodysplastic syndrome (MDS).
- Chronic Myelomonocytic Leukemia
- Myelodysplastic Syndromes (MDS)
- Decitabine/cedazuridine is indicated for the treatment of adults with 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.[rx][rx][rx]
- MDS is a type of blood cancer in which blood cells in the bone marrow are defective leading to a low number of one or more types of 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
Use in Cancer
Decitabine and cedazuridine is approved to treat adults with:
- Myelodysplastic syndromes (MDS), including chronic myelomonocytic leukemia (CMML).
Decitabine and cedazuridine is 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.
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 mouth, or on 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, painful, 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
Rare
- Fever sores on the skin
- blue lips, fingernails, or skin
- Joint pain, stiffness, or swelling
- stomach pain
- Constipation
- decreased appetite
- difficulty in moving
- falls
- muscle pain, cramps, or stiffness
- skin rash
- trouble sleeping
- unsteadiness or awkwardness
- weakness in the arms, hands, legs, or feet
Drug Interactions
| DRUG | INTERACTION |
|---|---|
| Azacitidine | The serum concentration of Azacitidine can be increased when it is combined with Cedazuridine. |
| Capecitabine | The serum concentration of Capecitabine can be increased when it is combined with Cedazuridine. |
| Cytarabine | The serum concentration of Cytarabine can be increased when it is combined with Cedazuridine. |
| Gemcitabine | The serum concentration of Gemcitabine can be increased when it is combined with Cedazuridine. |
Pregnancy and Lactation
US FDA pregnancy category: Not assigned.
Pregnancy
Based on findings from human data, animal studies, and its mechanism of action [see Clinical Pharmacology (12.1)], INQOVI can cause fetal harm when administered to a pregnant woman. A single published case report of intravenous decitabine use throughout the first trimester of pregnancy describes adverse developmental outcomes, including major birth defects (structural abnormalities). In animal reproduction studies, intravenous administration of decitabine to pregnant mice and rats during organogenesis at doses approximately 7% of the recommended human dose on a body surface area (mg/m2 ) basis caused adverse developmental outcomes, including increased embryo-fetal mortality, alterations to growth, and structural abnormalities (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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Lactation
There are no data on the presence of cedazuridine, decitabine, or their metabolites in human milk or on their effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with INQOVI and for at least 2 weeks after the last dose.
Why is this medication prescribed?
The combination of decitabine and cedazuridine is used to treat certain types of myelodysplastic syndrome (conditions in which the bone marrow produces blood cells that are misshapen and does not produce enough healthy blood cells), including chronic myelomonocytic leukemia (CMML) in adults. Decitabine is in a class of medications called hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. Cedazuridine is in a class of medications called cytidine deaminase inhibitors. It helps to increase the amount of decitabine in the body so that the medication will have a greater effect.
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.
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.
What special dietary instructions should I follow?
Unless your doctor tells you otherwise, continue your normal diet.
What should I do if I forget a dose?
If it has been less than 12 hours since you were scheduled to take the dose, take the missed dose on an empty stomach as soon as you remember it. If it has been more than 12 hours, skip the missed dose and continue your regular dosing schedule to complete the 5 daily doses in the cycle. Do not take a double dose to make up for a missed one.