Azacitidine

L01B - Antimetabolites ATC L01BC07 Small molecule approved 2004 Oral Parenteral Prodrug Natural product

Active form: 5-Aza-Ctp.

JFDA label: Vidaza 100mg

Mechanism of Action

Inhibitor of DNA (cytosine-5)-methyltransferase 3A — DNA (cytosine-5)-methyltransferase 3A inhibitor; Inhibitor of DNA (cytosine-5)-methyltransferase 1 — DNA (cytosine-5)-methyltransferase 1 inhibitor; Inhibitor of DNA — DNA inhibitor; Inhibitor of RNA — RNA inhibitor

Target	Action	Gene / class
DNA efficacy	INHIBITOR
DNA (cytosine-5)-methyltransferase 1 efficacy	INHIBITOR	DNMT1
DNA (cytosine-5)-methyltransferase 3A efficacy	INHIBITOR	DNMT3A
RNA efficacy	INHIBITOR

Indications

Approved

Myelodysplastic syndromes

Off-label

Acute myeloid leukemia (AML) in patients requiring low-intensity therapy

Contraindications

Source: Lexicomp

Hypersensitivity to azacitidine, mannitol, or any component of the formulation Absolute
advanced malignant hepatic tumors Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (8)

Very Common chest pain · Peripheral edema

Common chest wall pain · Heart murmur · hypertension · hypotension · syncope · tachycardia

Nervous system disorders (12)

Very Common anxiety · depression · dizziness · Fatigue · headache · insomnia · malaise · pain · rigors

Common hypoesthesia · Lethargy · postoperative pain

Renal and urinary disorders (3)

Common dysuria · hematuria · Urinary tract infection

Blood and lymphatic system disorders (13)

Very Common anemia · bone marrow depression (nadir: days 10 to 17; recovery: days 28 to 31) · bruise · febrile neutropenia · leukopenia · neutropenia · petechia · Thrombocytopenia

Common hematoma · Lymphadenopathy · oral hemorrhage · oral mucosal petechiae · postprocedural hemorrhage

Immune system disorders (1)

Common Transfusion reaction

Metabolism and nutrition disorders (3)

Very Common hypokalemia · pitting edema · Weight loss

Gastrointestinal disorders (15)

Very Common abdominal pain · abdominal tenderness · anorexia · constipation · diarrhea · Nausea · vomiting

Common abdominal distention · dyspepsia · dysphagia · Gingival hemorrhage · hemorrhoids · loose stools · stomatitis · tongue ulcer

Skin and subcutaneous tissue disorders (12)

Very Common diaphoresis · Erythema · pallor · pruritus · skin lesion · skin rash

Common cellulitis · Night sweats · rash at injection site · skin nodules · urticaria · xeroderma

Musculoskeletal and connective tissue disorders (6)

Very Common arthralgia · back pain · limb pain · myalgia · Weakness

Common Muscle cramps

Infections and infestations (1)

Common Herpes simplex infection

General disorders and administration site conditions (11)

Very Common bruising · Fever · Injection site reactions: Erythema

Common hematoma at injection site · herpes simplex · induration at injection site · injection site granuloma · Itching at injection site · mouth hemorrhage · skin discoloration at injection site · swelling at injection site

Respiratory, thoracic and mediastinal disorders (19)

Very Common Cough · dyspnea · epistaxis · nasopharyngitis · pharyngitis · pneumonia · rales · upper respiratory infection

Common abnormal breath sounds · atelectasis · nasal congestion · pharyngolaryngeal pain · pleural effusion · post nasal drip · rhinitis · Rhinorrhea · rhonchi · sinusitis · wheezing

Dosing

Source: Lexicomp

Note: Azacitidine is associated with a moderate emetic potential (Hesketh 2017; Roila 2016); antiemetics are recommended to prevent nausea and vomiting. Myelodysplastic syndromes (MDS): IV, SubQ: Initial cycle: 75 mg/m2/day for 7 days. Subsequent cycles: 75 mg/m2/day for 7 days every 4 weeks; dose may be increased to 100 mg/m2/day if no benefit is observed after 2 cycles and no toxicity other than nausea and vomiting have occurred. Patients should be treated for a minimum of 4 to 6 cycles; treatment may be continued as long as patient continues to benefit. Note: Alternate (off-label) schedules (which have produced hematologic response) have been used for convenience in community oncology centers (Lyons 2009): SubQ: 75 mg/m2/day for 5 days (Mon-Fri), 2 days rest (Sat, Sun), then 75 mg/m2/day for 2 days (Mon, Tues); repeat cycle every 28 days or 50 mg/m2/day for 5 days (Mon-Fri), 2 days rest (Sat, Sun), then 50 mg/m2/day for 5 days (Mon-Fri); repeat cycle every 28 days or 75 mg/m2/day for 5 days (Mon-Fri), repeat cycle every 28 days Acute myeloid leukemia (AML) (off-label use): SubQ: 75 mg/m2/day for 7 days every 4 weeks for at least 6 cycles; treatment may be continued as long as patient continues to benefit or until disease progression or unacceptable toxicity (Fenaux 2010). Dose reductions and/or therapy interruption may be required for hematologic toxicity. Dosage adjustment based on serum electrolytes: If serum bicarbonate falls to

Refer to adult dosing. Due to the potential for decreased renal function in the elderly, select dose carefully and closely monitor renal function.

Renal impairment at baseline: Mild to moderate impairment (CrCl ≥30 mL/minute): No dosage adjustment necessary (Douvali 2012). Severe impairment (CrCl Renal toxicity during treatment: Unexplained increases in BUN or serum creatinine: Delay next cycle until values reach baseline or normal, then reduce dose by 50% for next treatment course.

No dosage adjustment provided in the manufacturer’s labeling (has not been studied). Use is contraindicated in patients with advanced malignant hepatic tumors.

Warnings & Precautions

Source: Lexicomp

Bone marrow suppression

Neutropenia, thrombocytopenia, and anemia are common; may cause therapy delays and/or dosage reductions. Monitor blood counts prior to each cycle (at a minimum), and as clinically indicated. Adjust dose in subsequent cycles based on nadir counts and hematologic response.

Hepatotoxicity

May cause hepatotoxicity in patients with preexisting hepatic impairment. Progressive hepatic coma leading to death has been reported in patients with extensive tumor burden due to metastatic disease, especially those with a baseline albumin • Gastrointestinal toxicity: Azacitidine is associated with a moderate emetic potential (Dupuis 2011; Hesketh 2017; Roila 2016); antiemetics are recommended to prevent nausea and vomiting.

Injection site reactions

Injection site reactions commonly occurred with subcutaneous administration.

Nephrotoxicity

Renal toxicities, including serum creatinine elevations, renal tubular acidosis (serum bicarbonate decrease to • Tumor lysis syndrome: May cause serious or fatal tumor lysis syndrome (TLS). TLS has occurred in patients despite receiving antihyperuricemic therapy (eg, allopurinol). Assess TLS risk at baseline and monitor for TLS symptoms; treat accordingly. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Dosage form specific issues:

Polysorbate 80

Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.

Pregnancy & Lactation

Pregnancy

Adverse events were observed in animal reproduction studies. Based on its mechanism of action, azacitidine may cause fetal harm if administered during pregnancy. Women of childbearing potential should be advised to avoid pregnancy during treatment; verify pregnancy status prior to therapy initiation. In addition, males should be advised to avoid fathering a child while on azacitidine therapy and should use effective contraception during therapy.

Lactation

Avoid

It is not known if azacitidine is present in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer.

Monitoring

Clinical pearl	Monitor liver function tests, electrolytes, CBC with differential and platelets, renal function (BUN and serum creatinine) at baseline, prior to each cycle, and more frequently if indicated. Also monitor for hematologic response, nausea/vomiting, and for injection site reactions.

Chemistry & Properties

Formula	C8H12N4O5
Molecular weight	244.21 g/mol
IUPAC name	4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,3,5-triazin-2-one
CAS	320-67-2
PubChem CID	9444
InChIKey	`NMUSYJAQQFHJEW-KVTDHHQDSA-N`
logP	-3.17 (XLogP -2.2)
Polar surface area	143.72 Å²
H-bond acceptors / donors	9 / 4
Drug-likeness (QED)	0.43
Lipinski violations	0

SMILES

Nc1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	35.0%
Half-life	2.237 h
Volume of distribution	0.517 L/kg
Protein binding	30.4%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP3A4	Substrate	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MATE1 (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)CNT1 (Substrate)P-gp (Substrate)

Drug–drug interactions (85, DDInter)

Interacting drug	Severity	Management
Adalimumab	major
Bacillus calmette-guerin substrain tice live antigen	major
Baricitinib	major
Certolizumab pegol	major
Cladribine	major
Clozapine	major
Deferiprone	major
Etanercept	major
Fingolimod	major
Golimumab	major
Infliximab	major
Leflunomide	major
Measles virus vaccine live attenuated	major
Mumps virus strain B level jeryl lynn live antigen	major
Natalizumab	major
Ozanimod	major
Rotavirus vaccine	major
Rubella virus vaccine	major
Samarium (153Sm) lexidronam	major
Siponimod	major
Smallpox (Vaccinia) Vaccine, Live	major
Talimogene laherparepvec	major
Teriflunomide	major
Thalidomide	major
Tofacitinib	major
Typhoid vaccine (live)	major
Upadacitinib	major
Varicella Zoster Vaccine (Recombinant)	major
Yellow Fever Vaccine	major
Alefacept	moderate
Alemtuzumab	moderate
Anakinra	moderate
Anthrax vaccine	moderate
Azathioprine	moderate
Bifidobacterium longum infantis	moderate
Canakinumab	moderate
Candida albicans	moderate
Cedazuridine	moderate
Chloramphenicol	moderate
Chloramphenicol (ophthalmic)	moderate

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Registered Products (3)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
AZACITIDINE NEAPOLIS	Vial Azacitidine 100 mg	1 vial	Professional Drug Store	—
Vidaza	Vial 100 mg	1 vial	Petra Drug Store	—
Zydrome 100mg Lyophilized Powder For injection Vials	Powder for Injection 100 mg	1 vial	Hikma Pharmaceuticals Co.Ltd/Jordan	—