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AZACITIDINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Azacitidine, a pyrimidine nucleoside analog of cytidine, is an antimetabolite antineoplastic agent.

Specific Substances

    1) 4-Amino-1-beta-D-ribofuranosyl-1,3,5-triazin-2(1H)-one
    2) s-Triazin-2(1H)-one, 4-amino-1-beta-D-ribofuranosyl-(8CI)
    3) Azacitidina
    4) 5-Azacytidine
    5) AZA-CR
    6) Ladakamycin
    7) NCI-C01569
    8) NSC-102816
    9) U-18496
    10) WR-183027
    1.2.1) MOLECULAR FORMULA
    1) C8-H12-N4-O5

Available Forms Sources

    A) FORMS
    1) Azacitidine is available as lyophilized powder in 100 mg single-use vials for parenteral administration (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).
    B) USES
    1) Azacitidine is indicated for the treatment of various myelodysplastic syndrome subtypes including refractory anemia with or without ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Azacitidine is indicated for the treatment of various myelodysplastic syndrome subtypes including refractory anemia with or without ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia.
    B) PHARMACOLOGY: Appears to restore normal growth and differentiation of bone marrow cells by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. Hypomethylation may permit the normal functioning of genes that regulate differentiation and proliferation.
    C) EPIDEMIOLOGY: Overdoses are rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly occurring events (greater than 30%) following use include effects related to myelosuppression (ie, neutropenia, thrombocytopenia, anemia), fatigue, pyrexia, gastrointestinal symptoms (ie, nausea, vomiting, constipation or diarrhea), injection site reactions, petechiae, and hypokalemia.
    2) LESS FREQUENT: Other effects occurring less frequently include hypotension, myocarditis, mucositis, renal dysfunction, hepatic abnormalities, myalgias, rhabdomyolysis, headache, dyspnea, and coma.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Gastrointestinal effects (nausea, vomiting, diarrhea) occurred following administration of a single IV dose of approximately 290 mg/m(2), approximately 4 times the recommended starting dose.
    2) SEVERE TOXICITY: Severe toxicity following overdose has not been reported. It is anticipated that clinical effects will likely be an extension of adverse events (ie, myelosuppression, fatigue, nausea, vomiting, diarrhea).
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever has been reported following therapeutic administration of azacitidine.
    0.2.20) REPRODUCTIVE
    A) Azacitidine is classified as FDA pregnancy category D. Embryotoxicity, including embryonal death and fetal anomalies (ie, CNS and limb anomalies, micrognathia, gastroschisis, edema, and rib abnormalities), have been reported with azacitidine use in animals. It is not known whether azacitidine is excreted into breast milk.

Laboratory Monitoring

    A) Monitor CBC with differential and platelet count periodically for several weeks after overdose. Neutrophil nadir occurs approximately 20 days after therapeutic doses.
    B) Monitor renal function and liver enzymes.
    C) Monitor vital signs.
    D) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    E) Monitor for fever or other clinical evidence of infection.
    F) Evaluate patient for signs and symptoms of mucositis.

Treatment Overview

    0.4.4) EYE EXPOSURE
    A) Irrigate eyes with 0.9% saline or water. Perform an eye exam, including slit lamp, if irritation persists.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Wash exposed skin well with soap and water and remove contaminated clothing.
    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids. Treat persistent nausea and vomiting with several antiemetics of different classes. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat hypotension with IV fluids, dopamine, or norepinephrine. For severe neutropenia/neutropenic sepsis, administer colony stimulating factor (eg, filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding. Myelosuppression may be prolonged, protective isolation may help avoid infections complications. Severe nausea and vomiting may respond to a combination of agents from different drug classes.
    C) INTRATHECAL INJECTION
    1) No clinical reports available, information derived from experience with other antineoplastics. Neurotoxicity has been reported following IV administration; severe neurotoxicity may be expected after intrathecal injection. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free saline). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 18 to 24 hr). Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.
    D) DECONTAMINATION
    1) Decontamination is not necessary; azacitidine is administered parenterally.
    E) AIRWAY MANAGEMENT
    1) Intubate if patient is unable to protect airway or if CNS depression develops.
    F) ANTIDOTE
    1) None
    G) MYELOSUPPRESSION
    1) Administer colony stimulating factors in patients who develop severe neutropenia or neutropenic sepsis. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    H) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
    I) FEBRILE NEUTROPENIA
    1) If fever (38.3 C) develops during the neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
    J) HYPOTENSIVE EPISODE
    1) IV 0.9% NaCl at 10 mL to 20 mL/kg, dopamine, norepinephrine.
    K) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. Agents to consider: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol, olanzapine).
    L) STOMATITIS
    1) Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Consider prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection. Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. It has not been studied in the setting of chemotherapy overdose. In patients with azacitidine overdose, consider administering palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
    M) ENHANCED ELIMINATION
    1) Azacitidine has a small volume of distribution, suggesting that early hemodialysis might be effective, but its use after overdose has not been reported.
    N) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management.
    2) ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    4) TRANSFER CRITERIA: Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    O) PITFALLS
    1) Symptoms of overdose are similar to reported side effects at therapeutic doses. Early symptoms of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable follow-up is imperative. Patients also may have severe co-morbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression, neurotoxicity).
    P) PHARMACOKINETICS
    1) Rapidly absorbed following subcutaneous administration; the bioavailability of subcutaneous azacitidine relative to intravenous azacitidine is approximately 89%. Mean volume of distribution is 76 liters +/- 26 liters following intravenous administration of single doses of azacitidine (75 mg/m(2)) in 6 myelodysplastic syndrome patients. Urinary excretion is the primary route of elimination. After a single subcutaneous dose (75 mg/m(2)) of azacitidine was administered to myelodysplastic syndrome patients, the mean half-life was 41 +/- 8 minutes.
    Q) DIFFERENTIAL DIAGNOSIS
    1) May include other agents that cause myelosuppression.

Range Of Toxicity

    A) TOXICITY: A specific minimum toxic dose has not been established. A single IV dose of 290 mg/m(2) (approximately 4 times the recommended starting dose) has resulted in nausea, vomiting, and diarrhea.
    B) THERAPEUTIC DOSE: The recommended azacitidine starting dose is 75 mg/m(2) subQ or IV daily for 7 days. The dose may be increased to 100 mg/m(2) if needed.

Clinical Effects

Summary Of Exposure

    A) USES: Azacitidine is indicated for the treatment of various myelodysplastic syndrome subtypes including refractory anemia with or without ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia.
    B) PHARMACOLOGY: Appears to restore normal growth and differentiation of bone marrow cells by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. Hypomethylation may permit the normal functioning of genes that regulate differentiation and proliferation.
    C) EPIDEMIOLOGY: Overdoses are rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly occurring events (greater than 30%) following use include effects related to myelosuppression (ie, neutropenia, thrombocytopenia, anemia), fatigue, pyrexia, gastrointestinal symptoms (ie, nausea, vomiting, constipation or diarrhea), injection site reactions, petechiae, and hypokalemia.
    2) LESS FREQUENT: Other effects occurring less frequently include hypotension, myocarditis, mucositis, renal dysfunction, hepatic abnormalities, myalgias, rhabdomyolysis, headache, dyspnea, and coma.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Gastrointestinal effects (nausea, vomiting, diarrhea) occurred following administration of a single IV dose of approximately 290 mg/m(2), approximately 4 times the recommended starting dose.
    2) SEVERE TOXICITY: Severe toxicity following overdose has not been reported. It is anticipated that clinical effects will likely be an extension of adverse events (ie, myelosuppression, fatigue, nausea, vomiting, diarrhea).

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever has been reported following therapeutic administration of azacitidine.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) FEVER
    a) In pooled data from 2 clinical studies in patients with myelodysplastic syndromes or acute myelogenous leukemia, pyrexia was reported in 51.8% of azacitidine-treated patients (n=220) and 30.4% of observation only patients (n=92) (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).
    b) In an international, multicenter, randomized trial in patients with myelodysplastic syndrome, pyrexia (any grade) occurred in 30.3% of patients who received azacitidine plus best supportive care (BSC) (n=175) compared with 17.6% of patients who received BSC only (n=102) (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension has been reported as a rare side effect following rapid intravenous infusion of azacitidine (Fischer & Knobf, 1989).
    b) In pooled data from 2 clinical studies in patients with myelodysplastic syndromes or acute myelogenous leukemia, hypotension was reported in 6.8% of azacitidine-treated patients (n=220) and 2.2% of observation only patients (n=92) (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).
    c) In a large study sponsored by the Southwest Oncology Group, 6 of the 9 hypotensive episodes that were observed occurred in patients who were receiving large doses (300 to 750 mg/m(2)/day in divided doses). The other 3 episodes of hypotension were observed with lower daily doses (150 to 200 mg/m(2)) (Saiki et al, 1981).
    d) An early study reported hypotension following the administration of azacitidine in 4 of 28 patients treated for acute and chronic leukemias (McCredie et al, 1973). In one patient, administration of the drug was associated with the development of hypotension, tachypnea, and cyanosis. Oliguric renal failure and severe diarrhea also occurred, and the patient died 5 days after the administration of 5-azacitidine. Disseminated Candida tropicalis was found at autopsy.
    e) When azacitidine was administered in combination with pyrazofurin for the treatment of acute leukemia, hypotension was reported in 47% of the patients (Van Echo et al, 1981).
    B) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) In pooled data from 2 clinical studies in patients with myelodysplastic syndromes or acute myelogenous leukemia, chest pain was reported in 16.4% of azacitidine-treated patients (n=220) and 5.4% of observation only patients (n=92) (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).
    C) THROMBOPHLEBITIS
    1) WITH THERAPEUTIC USE
    a) Phlebitis was reported in a patient treated with azacitidine for acute leukemia (Gaynon & Baum, 1983).
    D) MYOCARDITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 50-year-old man, receiving azacitidine (175 mg/day for 7 days), developed chest pain the second day after beginning the second cycle of azacitidine treatment. An ECG revealed ST segment elevation and his troponin concentration increased to 13.7 ng/mL (normal less than 0.1 ng/mL). A transthoracic echocardiogram showed no evidence of regional wall motion abnormality or global hypokinesia, and coronary catheterization showed no abnormalities. Within 1 week, the patient's chest pain resolved and his troponin concentration normalized, and he was discharged home. On the fourth day after beginning the third cycle of azacitidine treatment, the patient's chest pain recurred with similar ECG abnormalities as the previous episode, and an increase in the troponin concentration (0.3 ng/mL). A cardiac MRI demonstrated signs of myocarditis. With supportive care and cessation of azacitidine treatment, the patient's chest pain resolved with normalization of his troponin concentration (Bibault et al, 2011).
    E) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In an international, multicenter, randomized trial in patients with myelodysplastic syndrome, hypertension (any grade) occurred in 8.6% of patients who received azacitidine plus best supportive care (BSC) (n=175) compared with 3.9% of patients who received BSC only (n=102) (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) In pooled data from 2 clinical studies in patients with myelodysplastic syndrome or acute myelogenous leukemia, dyspnea was reported in 29.1% of azacitidine-treated patients (n=220) and 12% of observation only patients (n=92) (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).
    b) In an international, multicenter, randomized trial in patients with myelodysplastic syndrome, dyspnea occurred in 14.9% of patients who received azacitidine plus best supportive care (BSC) (n=175) compared with 4.9% of patients who received BSC only (n=102) (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) FATIGUE
    1) WITH THERAPEUTIC USE
    a) In an international, multicenter, randomized trial in patients with myelodysplastic syndrome, fatigue (any grade) occurred in 24% of patients who received azacitidine plus best supportive care (BSC) (n=175) compared with 11.8% of patients who received BSC only (n=102) (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).
    b) An unusual syndrome of myalgia, weakness, and lethargy with progression to somnolence, stupor, and coma has been observed in a number of patients receiving azacitidine (Fischer & Knobf, 1989).
    c) In an early comparative clinical trial of 5-azacitidine and guanazole in previously treated adults with acute nonlymphocytic leukemia, neuromuscular toxicity was observed in 17 of 18 patients receiving azacitidine 200 to 250 mg/m(2)/ day intravenously for 5 days. The syndrome usually began by day 3 of therapy, was maximal by day 5 and slowly abated 5 to 7 days after therapy was complete. Initially, there was generalized muscle tenderness, weakness, and lethargy. The serum potassium levels showed a moderate fall, with oral and intravenous potassium supplements failing to reverse the toxicity. As the severity of the syndrome increased, patients were unable to sit up, mental status deteriorated further to irritability, confusion, and somnolence. Although 10 patients had preexisting hepatic dysfunction, there was no definitive evidence of further deterioration in liver function tests that could account for the neuromuscular effects (Levi & Weirnik, 1976).
    B) COMA
    1) WITH THERAPEUTIC USE
    a) One patient, who received azacitidine during a comparative clinical trial, became comatose on 2 consecutive occasions after receiving the drug. A diffuse dysrhythmia consistent with a toxic encephalopathy was noted on the EEG in this patient and in a second patient who experienced marked somnolence following administration of 5-azacitidine. These tracings returned to normal, in both patients, 7 days after therapy (Levi & Weirnik, 1976).
    b) Researchers noted a disturbing complication of coma in 15 of 154 leukemia patients (9.7%) treated with azacitidine. Significant associated medical problems including CNS leukemia, sepsis, cerebrovascular hemorrhage, and/or marked azotemia were present in 13 of the 15 patients. A review committee for the Southwest Oncology Group found explanations other than drug toxicity for 10 patients, but concluded that azacitidine may occasionally contribute to central nervous system toxicity in a small proportion of patients. Significantly, coma developed in 22% of patients treated with high doses of azacitidine (300 to 750 mg/m(2)/day) and in 4.6% of patients treated with lower doses (150 to 200 mg/m(2)/day) (Saiki et al, 1981).
    c) CASE REPORT: An acute life-threatening toxic neuromuscular reaction occurred in a 10-year-old boy who was receiving maintenance therapy with 5-azacitidine for acute nonlymphocytic leukemia. The patient received 266 mg/m(2)/day azacitidine by continuous infusion. Onset of the neuromuscular syndrome was observed on day 3 of therapy with progression from mild muscle pain and tenderness to somnolence, apathy and severe muscle tenderness on day 5 of the infusion. By day 7, he was unarousable, unresponsive to noxious stimulation, and had very shallow respirations. Over the next 25 days, he had gradual clearing of his sensorium with persistent severe myalgias. A serum CPK, obtained on day 7, was elevated at 266 international units/liter (normal 50 to 180 international units/liter). By day 9, the serum CPK was normal. Although this patient had other serious medical disorders (previous cerebrovascular accident) and had received extensive prior chemotherapy (including intrathecal methotrexate), the authors concluded that a temporal relationship existed and that azacitidine was probably responsible for the toxicity (Weisman et al, 1985).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache was reported in approximately 22% of the patients (n=220) who received azacitidine subcutaneously for treatment of myelodysplastic syndrome (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).
    D) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) In pooled data from 2 clinical studies in patients with myelodysplastic syndromes or acute myelogenous leukemia, insomnia was reported in 10.9% of azacitidine-treated patients (n=220) and 4.3% of observation only patients (n=92) (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).
    b) In an international, multicenter, randomized trial in patients with myelodysplastic syndrome, insomnia (any grade) occurred in 8.6% of patients who received azacitidine plus best supportive care (BSC) (n=175) compared with 2.9% of patients who received BSC only (n=102) (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, and diarrhea occurred in 70.5%, 54.1%, and 36.4% of the patients (n=220), respectively, following subcutaneous administration of azacitidine for treatment of myelodysplastic syndrome. The symptoms appeared to be dose-related, and were generally more pronounced during the first 1 to 2 cycles of treatment as compared with later treatment cycles (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).
    b) Severe nausea and vomiting associated with diarrhea were the dose-limiting toxicities in a phase II study of azacitidine administered by intravenous bolus. The severity of the gastrointestinal effects prompted the investigators to alter the dosage schedule twice during the study, dividing the daily dosage and then extending the treatment period from 5 to 10 days. The overall incidence of nausea and vomiting was not altered by extension of the treatment period, but the severity of the gastrointestinal distress was decreased. Antiemetic therapy (prochlorperazine 10 mg given rectally or intramuscularly) was ineffective (Moertel et al, 1972). Practitioners noted profound nausea, vomiting, and diarrhea in virtually all patients given doses greater than 150 mg/m(2) (Karon et al, 1973). The severity could be reduced by administering the drug in divided doses.
    c) When administered by continuous infusion for acute leukemia, azacitidine produces moderate nausea and vomiting, which may be controlled by conventional antiemetics (Case, 1982; Larson et al, 1982). The incidence of severe nausea and vomiting was lowered significantly in 108 of 154 patients who were treated by continuous infusion as compared with patients who received azacitidine by intravenous bolus (Saiki et al, 1981).
    d) In a limited study of azacitidine in children (10 months to 13 years of age) with acute nonlymphocytic leukemia, nausea and vomiting were not troublesome, but diarrhea occurred in 3 of 5 patients (Gaynon & Baum, 1983).
    e) Significant gastrointestinal toxicity has occurred when azacitidine was used in combination with other antineoplastics. Azacitidine and zorubicin produced nausea and vomiting in 16 of 29 patients (55%) and diarrhea in 4 of 29 patients (14%) treated (Peterson et al, 1981). The incidence of nausea and vomiting was also high (83%) in a study of azacitidine and pyrazofurin, although the gastrointestinal distress was not severe and was fairly well controlled with antiemetics(Van Echo et al, 1981).
    f) The combination of 5-azacitidine and VP-16 (etoposide) administered daily for the treatment of chronic myelogenous leukemia produced moderate-to-severe nausea and vomiting in 17 of 27 patients (63%). In many patients this tended to decrease with subsequent courses of therapy (Schiffer et al, 1982).
    2) WITH POISONING/EXPOSURE
    a) Nausea, vomiting, and diarrhea occurred in a patient who received a single IV azacitidine dose of approximately 290 mg/m(2) (almost 4 times the recommended starting dose). The patient recovered without sequelae (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).
    B) ACUTE MUCOSITIS
    1) WITH THERAPEUTIC USE
    a) Mucocutaneous toxicity (mucositis, stomatitis, proctitis, and rash) were the dose-limiting toxicities following concomitant administration of azacitidine and pyrazofurin (Chahinian et al, 1981; Martelo et al, 1981; Van Echo et al, 1981).
    b) Mucositis developed in 5 patients but was clinically severe in only 2; in one of these patients, bleeding from the hypopharynx with subsequent pulmonary aspiration was the immediate cause of death (Schiffer et al, 1982).
    c) In pooled data from 2 clinical studies in patients with myelodysplastic syndromes or acute myelogenous leukemia, stomatitis was reported in 7.7% of azacitidine-treated patients (n=220) and 0% of observation only patients (n=92) (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).
    C) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation has been reported in approximately 34% of the patients (n=220) who received azacitidine subcutaneously for treatment of myelodysplastic syndrome, and appeared to be dose-related. Constipation seemed to be more pronounced during the first 1 to 2 cycles of treatment as compared with later treatment cycles (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) Acute hepatic failure and death were reported in early phase I studies of azacitidine, 0.8 to 2.2 mg/kg/day administered for 10 consecutive days. Of 20 patients evaluated, 7 (35%) had liver function abnormalities. These consisted of elevations of total bilirubin and/or SGOT to at least 3 times pretreatment values (baseline bilirubin was less than 1.5 mg% and SGOT less than 120 units). Four patients who developed both abnormal total bilirubin and SGOT levels died in hepatic coma. There were no significant or consistent differences between pre-and posttreatment liver biopsy specimens. In several instances, the second biopsy appeared better than the first, apparently due to improved nutritional status of the patient during the interim. Drug effect on the liver parenchyma of patients with metastases in both fatal and surviving groups could not be evaluated since the biopsies consisted mostly of tumor. Comparison of patients dying in hepatic coma and a surviving group with hepatic metastases showed that serum bilirubin, prothrombin time, SGOT, and alkaline phosphatase were not reliable criteria for predicting poor tolerance of 5-azacitidine. Those patients dying in hepatic coma had baseline serum albumin less than 2.8 gm% while survivors with hepatic metastases had baseline serum albumin greater than 3 gm%. The authors suggested that the presence of hepatic metastasis with serum albumin less than 3 gm% was a contraindication to the use of azacitidine (Bellett et al, 1973).
    B) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Alteration of liver function has been noted in numerous studies of azacitidine in solid tumors and leukemias. Investigators noted reversible rises in serum glutamic oxaloacetic transaminase (SGOT) levels in several patients treated in a phase I study. The same authors noted an overall incidence of hepatic dysfunction in 7% of 148 patients with a variety of primary tumors (Weiss et al, 1972). A significant observation was that hepatic abnormalities occurred only in those patients receiving azacitidine by IV push. None of the 29 patients receiving the drug by IV infusion developed this complication. Abnormal liver function tests with cholestasis was noted in 2 of 8 patients treated for refractory acute leukemia. Azacitidine was continued in both patients with doses reduced in half. Liver function tests improved with continuation of the drug at reduced doses (Case, 1982).
    C) HYPERBILIRUBINEMIA
    1) WITH THERAPEUTIC USE
    a) Hyperbilirubinemia occurred in one patient treated with azacitidine and VP-16 for blast crisis of chronic myelogenous leukemia. A massive tumor lysis with significant and persistent abnormalities in hepatic and renal function occurred following the treatment and had begun to improve prior to his death from pharyngeal hemorrhage (Schiffer et al, 1982).
    b) Bilirubin elevation was the most consistent laboratory abnormality pertaining to hepatic dysfunction in 15 of 23 patients given DATA (daunorubicin, azacitidine, 6-thioguanine, cytarabine) therapy for the blastic transformation of chronic myelogenous leukemia. These patients had serum bilirubin elevations greater than 2 mg/dL (range 2.1 to 16 mg/dL, mean 6.9 mg/dL) during the first 2 to 4 weeks of therapy. The peak values were related to death within 2 to 3 days in 7 patients (Winton et al, 1981).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL RENAL FUNCTION
    1) WITH THERAPEUTIC USE
    a) Abnormal renal function parameters were noted during DATA therapy (daunorubicin, 5-azacitidine, 6-thioguanine and cytarabine) for blastic transformation of chronic myelogenous leukemia. Serum creatinine increased to greater than 2 mg/dL (maximum 7.3 mg/dL) and/or the blood urea nitrogen (BUN) increased to greater than 50 mg/dL in 8 of 26 evaluable patients. All but one of these patients had normal pretreatment values and all were receiving cephalosporins and/or aminoglycosides at the time renal toxic effects were noted; the direct relationship of renal dysfunction to DATA chemotherapy is uncertain (Winton et al, 1981).
    b) Azotemia was reported in 4 consecutive courses of azacitidine administered to 3 patients with acute leukemia. The patients, ranging in age from 63 to 68 years, had all received extensive prior chemotherapy and were treated with azacitidine 150 to 200 mg/m(2)/day by continuous infusion for a duration of 5 days. Reversible serum creatinine elevations as high as 3.1 mg% were reported with significant proteinuria found in one patient. All patients received concomitant allopurinol, gentamicin, and oxacillin. Interstitial leukemic infiltrates were found in the kidneys of 2 patients at postmortem examination (Greenberg, 1979). Although there were multiple causes for renal dysfunction (infection, nephrotoxic drugs, underlying disease), the author concluded that azacitidine should be considered a risk factor in patients with acute leukemia.
    c) Renal tubular acidosis, defined as a fall in serum bicarbonate to less than 20 mEq/L in association with an alkaline urine and hypokalemia (serum potassium less than 3 mEq/L) developed in 5 patients with chronic myelogenous leukemia treated with azacitidine and VP-16 (etoposide). Some of these patients also developed muscle pain and weakness, but these symptoms were not clearly correlated. Significant and persistent abnormalities in hepatic and renal function occurred in only 1 patient in whom massive tumor lysis occurred during the first course of therapy; severe hyperphosphatemia, hypocalcemia, azotemia, and hyperbilirubinemia occurred and had begun to improve prior to his death from pharyngeal hemorrhage (Schiffer et al, 1985; Schiffer et al, 1982).
    d) Significant unexpected acid-base, and fluid and electrolyte abnormalities occurred during 29 courses (88%) of azacitidine administered to 22 patients with advanced acute leukemia. These abnormalities contributed to the deaths of 2 patients early in the study. Polyuria, glucosuria, and/or transient changes in the serum concentrations of bicarbonate or phosphorus were detected. Spontaneous polyuria with demonstrable salt wasting and orthostatic hypotension occurred during 7 courses (21%) of treatment. Inappropriate glucosuria was observed in 9 courses (27%). Hypophosphatemia with serum phosphorus concentrations as low as 0.3 mg/dL occurred in 21 of 32 evaluable courses (66%). The authors concluded that the renal abnormalities that were observed suggested both proximal and distal tubular damage from azacitidine (Peterson et al, 1981).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) Bone marrow suppression with leukopenia and thrombocytopenia has been a major side effect of azacitidine. Marrow suppression appears to be dose-related with severe leukopenia observed in the majority of patients being treated for leukemia. The granulocytic nadir from azacitidine administration usually occurs on days 14 to 17 with a median duration of approximately 2 weeks (Fischer & Knobf, 1989). Thrombocytopenia is also dose-dependent, but with a lower incidence than leukopenia. The bone marrow suppression is reversible but necessitates the use of rigorous support (antibiotics, platelet transfusions) (Von Hoff & Slavik, 1977). The overall incidence of leukopenia (total white blood cell count less than 1500/mm(3)) in phase I studies was 34%. Leukopenia was dose-related with an increasing incidence in those patients treated with maximally tolerated doses (Von Hoff et al, 1976).
    b) INCIDENCE: Anemia, thrombocytopenia, leukopenia, and neutropenia were reported in 69.5%, 65.5%, 48.2%, and 32.3% of the patients (n=220), respectively, who received azacitidine subcutaneously for treatment of myelodysplastic syndrome (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).
    c) In an early phase I study of daily intravenous bolus azacitidine for 8 to 10 days, researchers found that nadirs of white blood cells and platelets occurred at 20 to 30 days after the initiation of therapy (range 12 to 31 days) (Weiss et al, 1972). The marrow suppression lasted 1 to 5 weeks and was fully reversible.
    d) Azacitidine, 2 mg/kg/day, administered orally with tetrahydrouridine (THU) in 2 patients with sickle cell anemia produced significant suppression of white blood cells, platelets, and reticulocytes. The nadir occurred 10 to 15 days after beginning azacitidine therapy with recovery occurring within 3 weeks of the initial dose (Dover et al, 1985).
    e) Azacitidine, 2 mg/kg/day, was administered by continuous infusion to 3 patients with beta-thalassemia. Decreased total white blood cell count and neutrophil count occurred at 20 days after initiation of therapy and persisted for at least 40 days (Ley et al, 1983; Ley et al, 1982).
    f) In phase II studies of azacitidine in patients with solid tumors, variable degrees of marrow suppression were reported. All patients treated had advanced malignancies refractory to other modes of therapy and most had received prior chemotherapy. In doses of 50 to 150 mg/m(2)/day IV for 5 to 7 days, mild-to-moderate marrow suppression (total WBC count less than 3000/mm(3)) occurred in the majority of patients. The nadir of the white blood cells occurred at 15 to 25 days from initiation of therapy with recovery within 7 to 14 days from the nadir (Srinivasan et al, 1982; Weiss et al, 1977; Moertel et al, 1972). The mean nadir and recovery of thrombocytopenia were similar. Another group of investigators noted that cumulative hematologic toxicity with repeated courses of 5-azacitidine was not detected (Moertel et al, 1972). Severe myelosuppression leading to fatalities secondary to sepsis and cerebral hemorrhage occurred in 13 of 167 (8%) patients treated by the Southwest Oncology Group (SWOG). At doses of 225 mg/m(2)/day IV for 5 days, moderate-to-severe leukopenia occurred in 63% of patients. Eleven of the 13 deaths during the study occurred on the higher dose schedule (225 mg/m(2)/day) (Quagliana et al, 1977).
    g) The goal of therapy in acute nonlymphocytic leukemia is complete marrow ablation in an effort to eliminate the malignant clone of cells. This has been achieved successfully in numerous trials using azacitidine as a single agent or in combination with other antineoplastics. Doses have ranged from 50 to 100 mg/m(2)/day by divided intravenous boluses or continuous infusion for 5 to 10 days. In all cases, myelosuppression was severe (total white blood cell count less than 500). The nadir of white blood cells ranged from 8 to 45 days, depending on the dosage regimen used. The duration of leukopenia was as long as 56 days after the beginning of the infusion (Gaynon & Baum, 1983; Larson et al, 1982; Saiki et al, 1981; Saiki et al, 1978; Armitage & Burns, 1977; Vogler et al, 1976; Karon et al, 1973; McCredie et al, 1973; Hrodek & Vessely, 1971).
    B) FEBRILE NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In pooled data from 2 clinical studies in patients with myelodysplastic syndromes or acute myelogenous leukemia, febrile neutropenia was reported in 16.4% of azacitidine-treated patients (n=220) and 4.3% of observation only patients (n=92) (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).
    b) In an international, multicenter, randomized trial in patients with myelodysplastic syndrome, febrile neutropenia (any grade) occurred in 13.7% of patients who received azacitidine plus best supportive care (BSC) (n=175) compared with 9.8% of patients who received BSC only (n=102) (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) INJECTION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) Subcutaneous injections of azacitidine produced moderately severe burning pain and slightly raised violaceous tender skin lesions at the injection site in 8 or 10 patients treated for refractory leukemia. The lesions appeared within 1 to 3 hours and subsided in 5 to 10 days. There was no permanent induration or scarring at the sites; however, most patients had a persistent brown skin discoloration in the area of the rash (Armitage & Burns, 1977).
    b) INCIDENCE: Injection site erythema and pain were reported in 35% and 22.7% of the patients (n=220), respectively, who received azacitidine subcutaneously for treatment of myelodysplastic syndrome (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012). The injection site reactions appeared to be more pronounced during the first 1 to 2 cycles of treatment as compared with later treatment cycles.
    c) CASE REPORTS: Two patients developed well-demarcated erythematous lesions on their abdomen, which corresponded to the sites of subcutaneous azacitidine injections. The lesions gradually resolved over the course of several days (Goldsmith et al, 1991).
    B) PETECHIAE
    1) WITH THERAPEUTIC USE
    a) In pooled data from 2 clinical studies in patients with myelodysplastic syndromes or acute myelogenous leukemia, petechiae was reported in 23.6% of azacitidine-treated patients (n=220) and 8.7% of observation only patients (n=92) (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).
    b) In an international, multicenter, randomized trial in patients with myelodysplastic syndrome, petechiae (any grade) occurred in 11.4% of patients who received azacitidine plus best supportive care (BSC) (n=175) compared with 3.9% of patients who received BSC only (n=102) (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).
    C) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) In pooled data from 2 clinical studies in patients with myelodysplastic syndromes or acute myelogenous leukemia, petechiae was reported in 23.6% of azacitidine-treated patients (n=220) and 8.7% of observation only patients (n=92) (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).
    b) In an international, multicenter, randomized trial in patients with myelodysplastic syndrome, petechiae (any grade) occurred in 11.4% of patients who received azacitidine plus best supportive care (BSC) (n=175) compared with 3.9% of patients who received BSC only (n=102) (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).
    D) ERUPTION
    1) WITH THERAPEUTIC USE
    a) In pooled data from 2 clinical studies in patients with myelodysplastic syndromes or acute myelogenous leukemia, rash was reported in 14.1% of azacitidine-treated patients (n=220) and 9.8% of observation only patients (n=92) (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).
    b) In an international, multicenter, randomized trial in patients with myelodysplastic syndrome, rash (any grade) occurred in 10.3% of patients who received azacitidine plus best supportive care (BSC) (n=175) compared with 1% of patients who received BSC only (n=102) (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgias have been reported in 15.9% of the patients (n=220) who received azacitidine subcutaneously for treatment of myelodysplastic syndrome (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).
    b) One report noted the appearance of muscle cramps in 3 of 11 leukemia patients (27%) that were unrelated to electrolyte disturbances or renal tubular defects. The symptoms occurred after 3 or 4 days of azacitidine therapy and had subsided before the next course of treatment (Case, 1982). A similar syndrome that occurred in 2 patients was related to hypophosphatemia. Severe generalized muscle aching and tenderness without demonstrable muscle weakness was associated with hypophosphatemia (serum phosphorus less than 1 mg/dL). A diagnosis of drug-induced myositis was made in one patient who suffered the same syndrome on 2 subsequent courses of azacitidine. In this patient, pain and tenderness involving the tongue and jaw muscles resulted in dysphagia. She had difficulty rising from a sitting position and developed a shuffling gait because of pain associated with leg movement. The serum phosphorus returned to normal over 8 days following therapy with abatement of the muscular symptoms (Ho et al, 1976). The authors postulated that azacitidine may influence the gastrointestinal absorption or intracellular migration of phosphorus.
    c) One group reported the presence of myalgias in 93% of all courses of pyrazofurin and azacitidine (Van Echo et al, 1981). The incidence of muscle aches and tenderness was lower (40%) when azacitidine was combined with VP-16 (etoposide) (Schiffer et al, 1982).
    d) In an early comparative clinical trial of 5-azacitidine and guanazole in previously treated adults with acute nonlymphocytic leukemia, neuromuscular toxicity was observed in 17 of 18 patients receiving azacitidine 200 to 250 mg/m(2)/ day intravenously for 5 days. The syndrome usually began by day 3 of therapy, was maximal by day 5 and slowly abated 5 to 7 days after therapy was complete. Initially, there was generalized muscle tenderness, weakness, and lethargy. The serum potassium levels showed a moderate fall, with oral and intravenous potassium supplements failing to reverse the toxicity. As the severity of the syndrome increased, patients were unable to sit up, mental status deteriorated further to irritability, confusion, and somnolence. Although 10 patients had pre-existing hepatic dysfunction, there was no definitive evidence of further deterioration in liver function tests that could account for the neuromuscular effects (Levi & Weirnik, 1976).
    e) CASE REPORT: An acute life-threatening toxic neuromuscular reaction occurred in a 10-year-old boy who was receiving maintenance therapy with 5-azacitidine for acute nonlymphocytic leukemia. The patient received 266 mg/m(2)/day azacitidine by continuous infusion. Onset of the neuromuscular syndrome was observed on day 3 of therapy with progression from mild muscle pain and tenderness to somnolence, apathy and severe muscle tenderness on day 5 of the infusion. By day 7, he was unarousable, unresponsive to noxious stimulation, and had very shallow respirations. Over the next 25 days, he had gradual clearing of his sensorium with persistent severe myalgias. A serum CPK, obtained on day 7, was elevated at 266 international units/liter (normal 50 to 180 international units/liter). By day 9, the serum CPK was normal. Although this patient had other serious medical disorders (previous cerebrovascular accident) and had received extensive prior chemotherapy (including intrathecal methotrexate), the authors concluded that a temporal relationship existed and that azacitidine was probably responsible for the toxicity (Weisman et al, 1985).
    B) RHABDOMYOLYSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Practitioners described an episode of rhabdomyolysis in a 26-year-old woman with refractory leukemia who was treated with azacitidine. The syndrome presented as extremely painful generalized muscle tenderness and weakness. It was associated with oliguria, lethargy, confusion, and agitation. The blood creatine phosphokinase (CPK), blood aldolase, urine myoglobin, and serum creatinine dramatically increased over the 2- to 3-day period of drug therapy. By day 5 after chemotherapy, the muscle tenderness was markedly diminished, the blood CPK and urine output returned to normal and serum creatinine decreased to 1 mg/dL (Koeffler & Haskell, 1978).

Reproductive

    3.20.1) SUMMARY
    A) Azacitidine is classified as FDA pregnancy category D. Embryotoxicity, including embryonal death and fetal anomalies (ie, CNS and limb anomalies, micrognathia, gastroschisis, edema, and rib abnormalities), have been reported with azacitidine use in animals. It is not known whether azacitidine is excreted into breast milk.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RATS: Embryotoxicity occurred in rat offspring with exposures of approximately 8% of the recommended human daily dose on gestation days 4 to 8, although no effect was noted with preimplantation exposure (gestation days 1 to 3). Multiple fetal anomalies (ie, CNS anomalies, limb anomalies, micrognathia, gastroschisis, edema, rib abnormalities) developed after single doses of approximately 8% of the human daily dose on gestation day 9, 10, 11, or 12. Fetal deaths reduced live pups per litter to 9% of control when exposed on gestation days 9 and 10 (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified azacitidine as FDA pregnancy category D. Based on animal data, azacitidine may cause fetal harm when administered to a pregnant woman. The manufacturer advises that women of childbearing potential not become pregnant while undergoing treatment with azacitidine, and that men should not father a child while receiving azacitidine treatment. If azacitidine is used during pregnancy, or if the patient becomes pregnant while on azacitidine, apprise the patient of the potential hazard to the fetus (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2014). In general, antineoplastic agents are believed to cause increases in the risk of congenital malformations when given during the first trimester, but are believed to only increase the risk of growth retardation when given during the second or third trimesters (Glantz, 1994; Doll et al, 1988). Depending upon the nature of the malignancy, the progression of the disease, and how advanced the gestation, chemotherapy can in some cases be deferred allowing fetal maturation to occur, and in some cases earlier-than-term delivery provides an acceptable compromise between maternal and fetal risk (Cunningham et al, 1993; Doll et al, 1988).
    B) ANIMAL STUDIES
    1) MICE: A 44% frequency of intrauterine embryonal death was reported following a single exposure of approximately 8% of the recommended human daily dose on gestation day 10. Developmental brain abnormalities were detected in mice following administration of azacitidine on or before gestation day 15 at doses approximately 4% to 16% of the recommended human daily dose (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Lactation studies with azacitidine have not been conducted in humans, and it is unknown whether azacitidine is excreted in human breast milk. Until further data are available, a decision should be made whether to discontinue azacitidine or to discontinue nursing, taking into consideration the importance of the drug to the mother (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) MICE: Decreased fertility and loss of offspring occurred when male mice received azacitidine at doses approximately 9% the recommended human daily dose for 3 days prior to mating with untreated female mice (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2014).
    2) RATS: Decreased weight of the testes and epididymides and reduced sperm counts occurred in male rats treated with azacitidine doses approximately 20% to 40% the recommended human daily dose 3 times per week for 11 or 16 weeks. Fewer pregnancies and greater embryotoxicity also occurred. In a related study, an increase in abnormal embryos was seen in the offspring of male rats treated for 16 weeks with 24 mg/m(2) doses (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2014).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS320-67-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Azacitidine
    b) Carcinogen Rating: 2A
    1) The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans. This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.
    3.21.4) ANIMAL STUDIES
    A) NEOPLASMS
    1) MICE - Tumors of the hematopoietic system were reported in female mice who received azacitidine at 2.2 mg/kg (6.6 mg/m(2), approximately 8% of the recommended human daily dose on a mg/m(2) basis) intraperitoneally three times per week for 1 year. An increased incidence of tumors in the lymphoreticular system, lung, mammary gland, and skin occurred in mice who also received azacitidine at 2 mg/kg (6 mg/m(2)) once a week for 50 weeks (Prod Info Vidaza, 2004).
    2) RATS - An increased incidence of testicular tumors was reported in rats who were given azacitidine, 15 mg/m(2) or 60 mg/m(2) (approximately 20% to 80% of the recommended human daily dose on a mg/m(2) basis) twice weekly (Prod Info Vidaza, 2004).

Genotoxicity

    A) Azacitidine was mutagenic in the bacterial and mammalian cell systems and was clastogenic in the mouse L5178Y lymphoma cells and in the Syrian hamster embryo cells .

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor CBC with differential and platelet count periodically for several weeks after overdose. Neutrophil nadir occurs approximately 20 days after therapeutic doses.
    B) Monitor renal function and liver enzymes.
    C) Monitor vital signs.
    D) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    E) Monitor for fever or other clinical evidence of infection.
    F) Evaluate patient for signs and symptoms of mucositis.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) CBC with differential should be regularly monitored for several weeks after overdose. Neutrophil nadir occurred at 20 days after initiation of therapy and persisted for at least 40 days (Ley et al, 1983; Ley et al, 1982).
    B) BLOOD/SERUM CHEMISTRY
    1) Monitor renal function and hepatic enzymes after overdose.
    2) Monitor electrolytes and fluid status as clinically indicated in patients with significant gastrointestinal symptoms following exposure.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs.
    b) Monitor for fever or other clinical evidence of infection.
    c) Evaluate patient for signs and symptoms of mucositis

Methods

    A) CHROMATOGRAPHY
    1) High performance liquid chromatography has been used for determination of azacitidine in human plasma. The limit of detection, with this method, was 80 ng/mL (Rustum & Hoffman, 1987).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.

Monitoring

    A) Monitor CBC with differential and platelet count periodically for several weeks after overdose. Neutrophil nadir occurs approximately 20 days after therapeutic doses.
    B) Monitor renal function and liver enzymes.
    C) Monitor vital signs.
    D) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    E) Monitor for fever or other clinical evidence of infection.
    F) Evaluate patient for signs and symptoms of mucositis.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Decontamination is not necessary; azacitidine is administered parenterally.

Range Of Toxicity

Summary

    A) TOXICITY: A specific minimum toxic dose has not been established. A single IV dose of 290 mg/m(2) (approximately 4 times the recommended starting dose) has resulted in nausea, vomiting, and diarrhea.
    B) THERAPEUTIC DOSE: The recommended azacitidine starting dose is 75 mg/m(2) subQ or IV daily for 7 days. The dose may be increased to 100 mg/m(2) if needed.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended starting dose of azacitidine is 75 mg/m(2) subcutaneously or intravenously daily for 7 days. Treatment cycles should be repeated every 4 weeks. The dose may be increased to 100 mg/m(2) if there has been no beneficial effect after two treatment cycles and if no toxicity, other than nausea and vomiting, has occurred. A minimum of 4 to 6 treatment cycles is recommended (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).
    7.2.2) PEDIATRIC
    A) Safety and efficacy in pediatric patients have not been established (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).

Maximum Tolerated Exposure

    A) During a clinical trial, nausea, vomiting, and diarrhea occurred in one patient who received a single IV azacitidine dose of 290 mg/m(2) (approximately 4 times the recommended starting dose). The patient recovered without sequelae (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).

Workplace Standards

    A) ACGIH TLV Values for CAS320-67-2 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS320-67-2 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS320-67-2 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 2A ; Listed as: Azacitidine
    a) 2A : The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans. This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): R ; Listed as: Azacitidine (5-Azacytidine)
    a) R : RAHC = Reasonably anticipated to be a human carcinogen

    D) OSHA PEL Values for CAS320-67-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 68 mg/kg (RTECS, 2004)
    B) LD50- (ORAL)MOUSE:
    1) 572 mg/kg (RTECS, 2004)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Azacitidine appears to interfere with nucleic acid metabolism prior to the steps involving cytidine and uridine since these pyrimidines reverse the antimicrobial activity of the drug. More specifically, 4 mechanisms of action for this interference with nucleic acid metabolism have been proposed (Chabner, 1982; Von Hoff et al, 1976):
    1) After preliminary phosphorylation to a triphosphate, azacitidine may become directly incorporated into DNA. Spontaneous degradation of the symmetrical triazine molecule of 5-azacitidine makes the DNA less stable and more liable to disruption of the secondary structure leading to chromosomal breakage.
    2) After conversion to a triphosphate, azacitidine competes with endogenous cytosine triphosphate for incorporation into RNA. Incorporation into newly synthesized messenger RNA produces defective mRNA that cannot code properly for protein synthesis leading to an inhibition of protein synthesis. Transfer RNA is also structurally and functionally modified contributing to the inhibition of protein synthesis.
    3) Azacitidine also competes with uridine and cytidine for uridine kinase, the enzyme that catalyzes the phosphorylation of azacitidine, uridine, and cytidine. It is the first enzyme taking part in the metabolic change of azacitidine and is regarded as the rate-limiting step in the pyrimidine salvage pathway. Azacitidine binding to uridine kinase is probably competitive as uridine, cytidine, and thymidine (but not uracil or cytosine) reverse the bacteriostatic effects of azacitidine.
    4) Azacitidine monophosphate inhibits orotidylic acid decarboxylase leading to a decreased synthesis of pyrimidines by the de novo pathway. The drug has greatest cytotoxicity for cells in the DNA synthetic phase of the cell cycle (S phase), a finding consistent with a cytotoxic lesion related to DNA synthesis.
    B) In patients with myelodysplastic syndrome, azacitidine appears to restore normal growth and differentiation of bone marrow cells by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. Hypomethylation may permit the normal functioning of genes that regulate differentiation and proliferation (Prod Info VIDAZA(R) subcutaneous injection, intravenous injection, 2012).
    C) Azacitidine may have a delayed cytotoxic effect in acute leukemia. Delayed remission and marrow repopulation have been seen in vivo and in patients with acute nonlymphoblastic leukemia. The authors postulated that azacitidine affected the stem cells of abnormal myeloblasts (Lampkin, 1985; Presant et al, 1975).
    D) Concomitant use of pyrazofurin and azacitidine result in more rapid accumulation of 5-azacitidine into and enhanced killing of rapidly dividing leukemia cells. Pyrazofurin is an inhibitor of orotidylate decarboxylase and produces marked reductions in intracellular levels of uridine triphosphate (UTP) and cytidine-5'triphosphate (CTP). These triphosphate ribonucleotides are known inhibitors of uridine-cytidine kinase, the enzyme that catalyzes the conversion of azacitidine to its monophosphate derivative. Pyrazofurin followed by azacitidine has been used for the treatment of rapidly proliferating leukemias when patients have failed more standard forms of antileukemic therapy (Cadman et al, 1978).

Physicochemical

Physical Characteristics

    A) Azacitidine is a white to off-white solid that is soluble in dimethylsulfoxide; sparingly soluble in water, water-saturated octanol, 5% dextrose in water, N-methyl-2-pyrrolidone, normal saline, and 5% Tween 80 in water; slightly soluble in ethanol/water (50/50), propylene glycol, and polyethylene glycol; and insoluble in acetone, ethanol, and methyl ethyl ketone (Prod Info VIDAZA(R) injection, 2008).

Molecular Weight

    A) 244 (Prod Info VIDAZA(R) injection, 2008)

References

General Bibliography

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