Azacitidine – Uses, Dosage, Side Effects, Interactions

Dr. Harun Ar Rashid, MD - Arthritis, Bones, Joints Pain, Trauma, and Internal Medicine Specialist Dr. Harun Ar Rashid, MD - Arthritis, Bones, Joints Pain, Trauma, and Internal Medicine Specialist
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Drugs (A - Z)

Azacitidine is a cytosine analog and antineoplastic agent used in the therapy of myelodysplastic syndromes. Azacitidine is associated with a low rate of transient serum enzyme elevations during therapy and has only rarely been implicated in cases of clinically apparent acute liver injury with jaundice.

Azacitidine is a Nucleoside Metabolic Inhibitor. The mechanism of action of azacitidine is as a Nucleic Acid Synthesis Inhibitor. Azacitidine is a pyrimidine nucleoside analog used to treat certain subtypes of myelodysplastic syndrome. A pyrimidine nucleoside analog that inhibits DNA methyltransferase, impairing DNA methylation. It is also an antimetabolite of cytidine, incorporated primarily into RNA. Azacytidine has been used as an antineoplastic agent.

Mechanism of Action

Azacitidine (5-azacytidine) is a chemical analog of the cytosine nucleoside used in DNA and RNA. Azacitidine may induce antineoplastic activity by inhibition of DNA methyltransferase at low doses and cytotoxicity through incorporation into RNA and DNA at high doses. Covalent binding to DNA methyltransferase results in the hypomethylation of DNA and prevents DNA synthesis. As azacitidine is a ribonucleoside, it incorporates into RNA to a larger extent than into DNA. The incorporation into RNA leads to the disassembly of polyribosomes, defective methylation and acceptor function of transfer RNA, and inhibition of the production of protein, resulting in cell death.

Telomerase activation is thought to be a critical step in cellular immortality and oncogenesis. Several reagents including differentiation-inducing and antineoplastic agents are known to inhibit telomerase activity, although the molecular mechanisms through which they inhibit telomerase activity remain unclear. Demethylating reagents have recently been used as potential antineoplastic drugs for some types of cancers including those of the prostate. In the present study, we examined the effect of the demethylating reagent 5-azacytidine (5-aza-CR) on telomerase activity using cells of two prostate cancer cell lines, DU-145 and TSU-PR1. 5-aza-CR treatment significantly reduced telomerase activity in TSU-PR1 cells, but not in DU-145 cells, although growth inhibition was observed to a similar extent in both cell lines. Reverse transcription-PCR analyses revealed that inhibition of telomerase activity was accompanied by down-regulation of telomerase catalytic subunit (hTERT) mRNA expression. Transient expression assays showed that 5-aza-CR repressed the transcriptional activity of the hTERT promoter and that the E-box within the core promoter was responsible for this down-regulation. Western blot analyses revealed that 5-aza-CR reactivated p16 expression and repressed c-Myc expression in TSU-PR1 cells but not in DU-145 cells. Overexpression of p16 in TSU-PR1 cells led to significant repression of c-Myc transcription. These findings suggest that 5-aza-CR inhibits telomerase activity via transcriptional repression of hTERT, in which p16 and c-Myc may play a key role.

or

Azacitidine is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine. Upon uptake into cells, azacitidine is phosphorylated to the 5-azacytidine monophosphate by uridine–cytidine kinase, then to diphosphate by pyrimidine monophosphate kinases and triphosphate by diphosphate kinases. 5-Azacitidine triphosphate is incorporated into RNA, leading to the disruption of nuclear and cytoplasmic RNA metabolism and inhibition of protein synthesis. 5-Azacytidine diphosphate is reduced to 5-aza-deoxycytidine diphosphate by ribonucleotide reductase. The resultant metabolite is phosphorylated to 5-aza deoxycytidine triphosphate by nucleoside diphosphate kinases. 5-aza deoxycytidine triphosphate is then incorporated into DNA, leading to the inhibition of DNA synthesis. Azacitidine is most toxic during the S-phase of the cell cycle.

Indications

  • For treatment of patients with the following French-American-British myelodysplastic syndrome subtypes: refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation (now classified as acute myelogenous leukemia with multilineage dysplasia), and chronic myelomonocytic leukemia.
  • Azacitidine Mylan is indicated for the treatment of adult patients who are not eligible for hematopoietic stem cell transplantation (HSCT) with intermediate 2 and high-risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS), chronic myelomonocytic leukemia (CMML) with 10 29% marrow blasts without myeloproliferative disorder acute myeloid leukemia (AML) with 20 30% blasts and multi-lineage dysplasia, according to World Health Organisation (WHO) classification, AML with > 30% marrow blasts according to the WHO classification.
  • Azacitidine betapharm is indicated for the treatment of adult patients who are not eligible for hematopoietic stem cell transplantation (HSCT) with intermediate-2 and high-risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS), chronic myelomonocytic leukemia (CMML) with 10 % to 29 % marrow blasts without the myeloproliferative disorder,  acute myeloid leukemia (AML) with 20 % to 30 % blasts and multi-lineage dysplasia, according to World Health Organization (WHO) classification, AML with > 30 % marrow blasts according to the WHO classification.
  • Azacitidine Accord is indicated for the treatment of adult patients who are not eligible for hematopoietic stem cell transplantation (HSCT) with intermediate-2 and high-risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS), chronic myelomonocytic leukemia (CMML) with 10-29 % marrow blasts without the myeloproliferative disorder, acute myeloid leukemia (AML) with 20-30 % blasts and multi-lineage dysplasia, according to World Health Organisation (WHO) classification, AML with > 30% marrow blasts according to the WHO classification.
  • Azacitidine Celgene is indicated for the treatment of adult patients who are not eligible for hematopoietic stem cell transplantation (HSCT) with intermediate 2 and high-risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS), chronic myelomonocytic leukemia (CMML) with 10 29 % marrow blasts without the myeloproliferative disorder, acute myeloid leukemia (AML) with 20 30 % blasts and multi-lineage dysplasia, according to World Health Organisation (WHO) classification, AML with > 30% marrow blasts according to the WHO classification.
  • Vidaza is indicated for the treatment of adult patients who are not eligible for hematopoietic stem cell transplantation (HSCT) with intermediate 2 and high-risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS), chronic myelomonocytic leukemia (CMML) with 10 29 % marrow blasts without the myeloproliferative disorder, acute myeloid leukemia (AML) with 20-30 % blasts and multi-lineage dysplasia, according to World Health Organisation (WHO) classification.
  • Vidaza is indicated for the treatment of adult patients aged 65 years or older who are not eligible for HSCT with AML with > 30% marrow blasts according to the WHO classification.
  • Treatment of myelodysplastic syndrome (including juvenile myelomonocytic leukemia), Treatment of acute myeloid leukemia
  • Anurag is indicated as maintenance therapy in adult patients with acute myeloid leukemia (AML) who achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following induction therapy with or without consolidation treatment and who are not candidates for, including those who choose not to proceed to, hematopoietic stem cell transplantation (HSCT).
  • The anticancer agent used to treat acute myelogenous leukemia
  • Acute Myeloid Leukemia (AML)
  • Chronic Myelomonocytic Leukemia (CMML)
  • Refractory Anemia
  • Refractory Anemia With Excess Blasts in Transformation
  • Refractory Anemia With Excess Blasts (RAEB)
  • Refractory Anemia With Ringed Sideroblasts
  • Newly diagnosed Juvenile Myelomonocytic Leukaemias (JMML)

Use in Cancer

Azacitidine is approved to treat:

  • Acute myeloid leukemia in adults who had a first complete remission after intensive induction therapy and who are not able to finish intensive curative therapy. This use is approved for the Onureg brand of azacitidine.
  • Myelodysplastic syndromes (MDS).
    • It is used in adults with certain types of myelodysplastic syndromes, including chronic myelomonocytic leukemia.
    • It is used in children aged 1 month and older with newly diagnosed juvenile myelomonocytic leukemia.

    This use is approved for the Vidaza brand of azacitidine.

Azacitidine is also being studied in the treatment of other conditions and types of cancer.

Contraindications

The following conditions are contraindicated with this drug. Check with your physician if you have any of the following:

  • anemia
  • decreased blood platelets
  • low levels of a type of white blood cell called neutrophils
  • severe liver disease
  • decreased kidney function
  • abnormal liver function tests
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • advanced liver cancer
  • Hypersensitivity to the active component or any of the ingredients
  • Hypersensitivity to mannitol
  • Advanced malignant hepatic tumors

Dosage

Strengths: 100 mg; 200 mg; 300 mg

Myelodysplastic Syndrome

  • FIRST TREATMENT CYCLE: 75 mg/m2 IV or subcutaneously daily for 7 days; repeat cycles every 4 weeks
  • SUBSEQUENT CYCLES: After 2 cycles, may increase the dose to 100 mg/m2 if no beneficial effect is seen and if no toxicity other than nausea and vomiting has occurred
  • DURATION OF THERAPY: Minimum of 4 to 6 cycles; may continue treatment if the patient continues to benefit

Acute Myeloid Leukemia

  • FIRST TREATMENT CYCLE: 75 mg/m2 IV or subcutaneously daily for 7 days; repeat cycles every 4 weeks
  • SUBSEQUENT CYCLES: After 2 cycles, may increase the dose to 100 mg/m2 if no beneficial effect is seen and if no toxicity other than nausea and vomiting has occurred
  • DURATION OF THERAPY: Minimum of 4 to 6 cycles; may continue treatment if the patient continues to benefit

Renal Dose Adjustments

  • Unexplained reductions in serum bicarbonate levels to less than 20 mEq/L: Reduce dose by 50% for the next course.
  • Unexplained elevations of BUN or serum creatinine: Delay the next cycle until values return to normal or baseline and reduce the dose by 50% for the next course.

Dose Adjustments

Baseline WBC 3 x 10(9)/L or greater, absolute neutrophil count (ANC) 1.5 x 10(9)/L or greater, AND platelets 75 x 10(9)/L or greater:

  • ANC less than 0.5 x 10(9)/L and platelets less than 25 x 10(9)/L: Administer 50% of the dose in the next course.
  • ANC 0.5 to 1.5 x 10(9)/L and platelets 25 to 50 x 10(9)/L: Administer 67% of the dose in the next course.
  • ANC greater than 1.5 x 10(9)/l and platelets greater than 50 x 10(9)/L: Administer 100% of the dose in the next course.

Baseline WBC less than 3 x 10(9)/L, ANC less than 1.5 x 10(9)/L, OR platelets less than 75 x 10(9)/L, base dose adjustments on nadir counts and bone marrow biopsy cellularity at the time of the nadir unless there is a clear improvement in differentiation (percentage of mature granulocytes is higher and ANC is higher than at the onset of that course) at the time of the next cycle, in which case continue the current dose:

  • Bone marrow biopsy cellularity (BMBC) of 30% to 60% at the time of nadir: Administer 100% of the dose in the next course.
  • BMBC of 15% to 30% at the time of nadir: Administer 50% of the dose in the next course.
  • BMBC Less Than 15% at the time of nadir: Administer 33% of the dose in the next course.

BASELINE WBC less than 3 x 10(9)/L, ANC less than 1.5 x 10(9)/L, OR platelets less than 75 x 10(9)/L AND WBC or platelet nadir 50% to 75% decrease in counts from baseline:

  • BMBC of 30% to 60% at nadir time: Administer 100% of the dose in the next course.
  • BMBC of 15% to 30% at nadir time: Administer 50% of the dose in the next course.
  • BMBC Less Than 15% at nadir time: Administer 33% of the dose in the next course.

BASELINE WBC less than 3 x 10(9)/L, ANC less than 1.5 x 10(9)/L, OR platelets less than 75 x 10(9)/L AND WBC or platelet nadir greater than 75% decrease in counts from baseline:

  • BMBC of 30% to 60% at nadir time: Administer 75% of the dose in the next course.
  • BMBC of 15% to 30% at nadir time: Administer 50% of the dose in the next course.
  • BMBC Less Than 15% at nadir time: Administer 33% of the dose in the next course.
  • Give the next course 28 days after the start of the preceding course provided that both the WBC and platelet counts are greater than 25% above the nadir and rising.
  • At the time of the next cycle, continue the current dose if there is a clear improvement in differentiation (i.e., the percentage of mature granulocytes and ANC is higher than at the onset of that course).
  • If a greater than 25% increase above the nadir is not seen by Day 28: Reassess counts every 7 days.
  • If 25% increase is not seen by Day 42: Reduce the scheduled dose by 50%.

Side Effects

The Most Common

  • nausea
  • vomiting
  • diarrhea
  • constipation
  • sores on the mouth or tongue
  • hemorrhoids
  • stomach pain or tenderness
  • heartburn
  • loss of appetite
  • weight loss
  • headache
  • dizziness
  • weakness
  • excessive tiredness
  • difficulty falling asleep or staying asleep
  • depression
  • anxiety
  • back, muscle, or joint pain
  • muscle cramps
  • sweating
  • night sweats
  • difficulty urinating or pain when urinating
  • swelling of the hands, feet, ankles, or lower legs
  • dry skin
  • redness, pain, bruising, swelling, itching, lump, or change in the skin color in the place where the medication was injected
  • severe ongoing nausea, vomiting, or diarrhea;
  • redness, swelling, warmth, oozing, or other signs of skin infection;
  • low blood cell counts–fever, chills, tiredness, mouth sores, skin sores, easy bruising, unusual bleeding, pale skin, cold hands, and feet, feeling light-headed or short of breath;
  • signs of a lung infection–fever, cough with mucus, chest pain, feeling short of breath;
  • kidney problems–pain in your lower back, blood in your urine, little or no urination, swelling in your feet or ankles;
  • liver problems–upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
  • low potassium level–leg cramps, constipation, irregular heartbeats, fluttering in your chest, increased thirst or urination, numbness or tingling, muscle weakness or limp feeling; or
  • signs of tumor cell breakdown–tiredness, weakness, muscle cramps, nausea, vomiting, diarrhea, fast or slow heart rate, tingling in your hands and feet or around your mouth.

More Common

  • pale skin
  • shortness of breath
  • fast heartbeat
  • chest pain
  • cough
  • unusual bruising or bleeding
  • nosebleeds
  • bleeding gums
  • small red or purple dots on the skin
  • sore throat, fever, chills, or other signs of infection
  • hives
  • rash
  • itching
  • difficulty breathing or swallowing

Rare

  • constipation
  • decreased appetite
  • diarrhea
  • dizziness
  • gas
  • joint, back, arm, or leg pain
  • nausea
  • stomach pain
  • tiredness
  • vomiting
  • weakness
  • anxiety
  • fainting
  • increased frequency of infection symptoms (symptoms may include fever or chills, severe diarrhea, shortness of breath, prolonged dizziness, headache, stiff neck, weight loss, or listlessness)
  • signs of anemia (low red blood cells; e.g., dizziness, pale skin, unusual tiredness or weakness, shortness of breath)
  • signs of clotting problems (e.g., unusual nosebleeds, bruising, blood in urine, coughing blood, bleeding gums, cuts that don’t stop bleeding)
  • symptoms of an upper respiratory tract infection (colds or cases of flu; runny or stuffy nose, sore throat, cough, nasal congestion, body aches, headache, sneezing, fever, general feeling of being unwell)
  • symptoms of a urinary tract infection (e.g. pain when urinating, urinating more often than usual, low back or flank pain)
  • symptoms of a lung infection (e.g., chest pain when you breathe or cough, confusion, cough producing phlegm, nausea, shortness of breath)

Drug Interactions

Pregnancy and Lactation

Pregnancy Category D

Pregnancy

Azacitidine may cause harm to the developing baby if it is taken by the mother during pregnancy or it is taken by either the man or the woman at the time of conception. If you or your partner become pregnant while taking this medication, contact your doctor immediately. Effective birth control should be practiced by both men and women while using this medication and for at least 6 months after taking the last dose.

Lactation

Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy. It might be possible to breastfeed safely during intermittent azacitidine therapy with an appropriate period of breastfeeding abstinence; the manufacturer recommends an abstinence period of 1 week after the last dose. Avoid breastfeeding while taking azacitidine and for at least 1 week after taking your last dose of azacitidine. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breast milk. Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant.

How should this medicine be used?

Azacitidine comes as a powder to be mixed with water and injected subcutaneously (under the skin) or intravenously (into a vein) by a doctor or nurse in a medical office or hospital outpatient department. It is usually injected once a day for 7 days. This treatment may be repeated every 4 weeks for as long as your doctor recommends. Treatment should usually be given for at least four cycles.

Your doctor may increase your dose of azacitidine after two cycles if your condition has not improved and if you have not experienced serious side effects of the medication. Your doctor may also need to delay your treatment or reduce your dose if you experience certain side effects. Be sure to tell your doctor how you are feeling during your treatment with azacitidine.

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

What special precautions should I follow?

Before using azacitidine,

  • tell your doctor and pharmacist if you are allergic to azacitidine, mannitol (Osmitrol, Resectisol), or any other medications.
  • tell your doctor and pharmacist what 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 a liver tumor. Your doctor may tell you not to take azacitidine.
  • tell your doctor if you have or have ever had liver or kidney disease.
  • tell your doctor if you are pregnant or plan to become pregnant, or if you plan to father a child. You or your partner should not become pregnant while you are using azacitidine. You should use birth control to prevent pregnancy in yourself or your partner during your treatment with azacitidine. Talk to your doctor about birth control methods that will work for you. If you or your partner become pregnant while using azacitidine, call your doctor. Azacitidine may harm the fetus.
  • do not breastfeed while you are using azacitidine.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are using azacitidine.

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    5-Azacytidine
    https://spectrabase.com/spectrum/JTudjAlUHud
    5-Azacytidine
    https://spectrabase.com/spectrum/8SntjqXhiJQ
  42. International Agency for Research on Cancer (IARC)
    https://publications.iarc.fr/Terms-Of-Use
    Azacitidine
    https://monographs.iarc.who.int/list-of-classifications
    IARC Classification
    https://www.iarc.fr/
  43. NCI Cancer Drugs
    LICENSE
    https://www.cancer.gov/policies/copyright-reuse
    Azacitidine
    https://www.cancer.gov/about-cancer/treatment/drugs/azacitidine
  44. NIPH Clinical Trials Search of Japan
    https://rctportal.niph.go.jp/en/
  45. NLM RxNorm Terminology
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
    https://rxnav.nlm.nih.gov/id/rxnorm/1251
  46. NMRShiftDB
    https://pubchem.ncbi.nlm.nih.gov/substance/114918057
  47. Protein Data Bank in Europe (PDBe)
    http://www.ebi.ac.uk/pdbe-srv/pdbechem/chemicalCompound/show/5AE
  48. PubChem
    https://pubchem.ncbi.nlm.nih.gov
  49. RCSB Protein Data Bank (RCSB PDB)
    https://www.rcsb.org/pages/policies
    https://www.rcsb.org/
  50. Springer Nature
    https://pubchem.ncbi.nlm.nih.gov/substance/?source=15745&sourceid=17048602-445380347
  51. Wikidata
    LICENSE
    CCZero
    https://creativecommons.org/publicdomain/zero/1.0/
    Azacitidine
    https://www.wikidata.org/wiki/Q416451
  52. Medical Subject Headings (MeSH)
    https://www.nlm.nih.gov/copyright.html
    Azacitidine
    https://www.ncbi.nlm.nih.gov/mesh/68001374
    MeSH Tree
    http://www.nlm.nih.gov/mesh/meshhome.html
    Antimetabolites, Antineoplastic
    https://www.ncbi.nlm.nih.gov/mesh/68000964
    Enzyme Inhibitors
    https://www.ncbi.nlm.nih.gov/mesh/68004791
  53. KEGG
    https://www.kegg.jp/kegg/legal.html
    Therapeutic category of drugs in Japan
    http://www.genome.jp/kegg-bin/get_htext?br08301.keg
    USP drug classification
    http://www.genome.jp/kegg-bin/get_htext?br08302.keg
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  54. 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
  55. PATENTSCOPE (WIPO)
    SID 388556103
    https://pubchem.ncbi.nlm.nih.gov/substance/388556103
  56. NCBI
    https://www.ncbi.nlm.nih.gov/projects/linkout

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