The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.
1.1 Myelodysplastic Syndromes (Mds)
Azacitidine for injection is indicated for treatment of patients with the following French-American-British (FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL).
2.1 First Treatment Cycle
- Therecommendedstartingdoseforthefirsttreatment cycle, for all patients regardless of baseline hematology laboratory values, is 75 mg/m
- 2 subcutaneously or intravenously, daily for 7 days. Premedicate patients for nausea and vomiting.
- Obtain complete blood counts, liver chemistries and serum creatinine prior to the first dose.
2.2 Subsequent Treatment Cycles
- Repeat cycles every 4 weeks. The dose may be increased to 100 mg/m
- 2 if no beneficial effect isseen after2treatmentcyclesandifnotoxicityotherthannausea and vomiting has occurred. It is recommended that patients be treated for a minimumof 4to6 cycles. However, complete or partial response may require additional treatment cycles. Treatment may be continued as long as the patient continues to benefit.
- Monitor patients for hematologic response and renal toxicities
- Warnings and Precautions (5.3)]
- , and delay or reduce dosage if necessary as described below.
2.3 Dosage Adjustment Based On Hematology Laboratory Values
- Forpatientswith baseline (start of treatment) WBCgreater thanor equalto3.0 ×10
- 9/L, ANC greater than or equal to 1.5 ×10
- 9/L, and platelets greater than or equal to 75.0 ×10
- 9/L, adjust the dose as follows, based on nadir counts for any given cycle:
- Nadir Counts% Dose in the Next CourseANC (×10
- Platelets (×10
- Less than 0.5Less than 2550%0.5 –1.525-5067%Greater than 1.5Greater than 50100%Forpatientswhose baseline counts are WBC lessthan 3.0 ×10
- 9/L, ANC less than 1.5 ×10
- 9/L, or platelets less than 75.0 ×10
- 9/L, base dose adjustments on nadir counts and bone marrow biopsy cellularity at the time of the nadir as noted below, unless there is clear improvement in differentiation (percentage of mature granulocytes is higher and ANC is higher than at onset of that course) at the time of the next cycle, in which case continue the current dose.
- WBC or Platelet Nadir
- % decrease in counts from baseline
- Bone Marrow
- Biopsy Cellularity at Time of Nadir
- 30-6015-30Less than 15% Dose in the Next Course50 - 751005033greater than 75755033Ifa nadir as defined in the table above has occurred, give the next course 28 daysafter thestart of the preceding course, provided thatboth theWBC and the plateletcounts are greater than 25% above the nadir and rising. If a greater than 25% increase above the nadir is not seen by day 28, reassess counts every 7 days. If a 25% increase is not seen by day 42, reduce the scheduled dose by 50%.
2.4 Dosage Adjustment Based On Serum Electrolytes And Renal Toxicity
If unexplained reductions in serum bicarbonate levels to less than 20 mEq/L occur, reduce the dosage by 50% for the next course. Similarly, if unexplained elevations of BUN or serum creatinine occur, delay the next cycle until values return to normal or baseline and reduce the dose by 50% for the next course
Warnings and Precautions (5.3)]
2.5 Use In Geriatric Patients
Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, select the dose carefully and monitor renal function
Warnings and Precautions (5.3) and
Use in Specific Populations (8.5)]
2.6 Preparation Of Azacitidine For Injection
Azacitidine for injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.
1The azacitidine for injection vial is single-dose and does not contain any preservatives. Discard unused portions of each vial properly
How Supplied/Storage and Handling (16)]
. Do not save any unused portions for later administration.
2.7 Instructions For Subcutaneous Administration
- Reconstitute azacitidine for injection aseptically with 4 mL sterile water for injection. Inject thediluentslowlyintothevial. Vigorouslyshakeorrollthevialuntilauniformsuspension is achieved. The suspension will be cloudy. The resulting suspension willcontainazacitidine 25 mg/mL. Donotfilter thesuspensionafter reconstitution.Doing so could remove the active substance.
Preparation for Immediate Subcutaneous Administration: For doses requiring more than 1 vial, divide the dose equally between the syringes (e.g., dose 150 mg = 6 mL, 2 syringes with 3 mL in each syringe) and inject into two separate sites. Due to retention in the vial and needle, it may not be feasible to withdraw all of the suspension from the vial. The product may be held at room temperature for up to 1 hour, but must be administered within 1 hour after reconstitution.
- Preparation for Delayed Subcutaneous Administration: The reconstituted product may be kept in the vial or drawn into a syringe. For doses requiring more than 1 vial, divide the dose equally between the syringes (e.g., dose 150 mg = 6 mL, 2 syringes with 3 mL in each syringe) and inject into two separate sites. Due to retention in the vial and needle, it may not be feasible to withdraw all of the suspensionfrom thevial.Theproductmust berefrigerated immediately.WhenAzacitidine for injection is reconstituted using water for injection that has not been refrigerated, the reconstituted product may be held under refrigerated conditions (2°C - 8°C, 36°F - 46°F) for up to8 hours. When Azacitidine for injection is reconstitutedusingrefrigerated (2°C - 8°C, 36°F - 46°F) water for injection, the reconstituted product may be stored under refrigerated conditions (2°C - 8°C, 36°F - 46°F) for up to 22 hours. After removal from refrigerated conditions, the suspension may be allowed to equilibrate to room temperature for up to 30 minutes prior to administration.
Subcutaneous AdministrationTo provide a homogeneous suspension, the contents of the dosing syringe must be re-suspended immediately prior to administration. To re-suspend, vigorously roll the syringe between the palms until a uniform, cloudy suspension is achieved.Azacitidine for injection suspension is administered subcutaneously. Rotate sites for each injection (thigh, abdomen, or upper arm). New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, red, or hard.
- Suspension Stability: Azacitidine for injection reconstituted with non-refrigerated water for injection for subcutaneous administration may be stored for up to 1 hour at25°C (77°F) or for up to8 hoursbetween 2°C and 8°C (36°F and46°F);whenreconstituted with refrigerated (2°C - 8°C, 36°F - 46°F) water for injection, it may be stored for 22 hours between 2°C and 8°C (36°F and 46°F).
- Intravenous Solution IncompatibilityAzacitidine forinjection is incompatible with5% Dextrose solutions, Hespan, or solutions that contain bicarbonate. These solutions have the potential to increase the rate of degradation of azacitidine for injection and should therefore be avoided.
Intravenous Administration Azacitidine for injection solution is administered intravenously. Administer the total dose over a period of 10 - 40 minutes. The administration must be completed within 1 hour of reconstitution of the azacitidine for injection vial.
Solution Stability: Azacitidine for injection reconstituted for intravenous administration may be stored at 25°C (77°F), but administration must be completed within 1 hour of reconstitution.
- Risk Summary Based on its mechanismof action and findings in animals,azacitidine can cause fetal harm when administered to a pregnant woman
- Clinical Pharmacology (12.1)]
- . There are no data on the use of azacitidine in pregnant women. Azacitidine was teratogenic and caused embryo-fetal lethality in animals at doses lower than the recommended human daily dose
- . Advise pregnant women of the potential risk to the fetus.
- The background rate of major birth defects and miscarriage is unknown for the indicated population. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.
- Animal DataEarly embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single IP (intraperitoneal) injection of 6 mg/m
- 2 (approximately 8% of the recommended human daily dose on a mg/m
- 2 basis) azacitidine on gestation day 10. Developmental abnormalities in the brain have been detected in mice given azacitidine on or before gestation day 15 at doses of ~3-12 mg/m
- 2 (approximately 4%-16% the recommended human daily dose on a mg/m
- 2 basis).
- In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4-8 (postimplantation) at a dose of 6 mg/m
- 2 (approximately 8% of the recommended human daily dose on a mg/m
- 2 basis), although treatment in the preimplantation period (on gestation days 1-3) had no adverse effect on the embryos. Azacitidine caused multiple fetal abnormalities in rats after a single IP dose of 3 to 12 mg/m
- 2 (approximately 8% the recommended human daily dose on a mg/m
- 2 basis) given on gestation day 9, 10, 11 or 12. In this study azacitidine caused fetal death when administered at 3-12 mg/m
- 2 on gestationdays 9 and10; averageliveanimalsperlitterwasreducedto9%of control at the highest dose on gestation day 9. Fetal anomalies included: CNS anomalies (exencephaly/encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly), and others (micrognathia, gastroschisis, edema, and rib abnormalities).
Risk SummaryThere is no information regarding the presence of azacitidine in human milk, the effects of azacitidine on the breastfed infant, or the effects of azacitidine on milk production. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for azacitidine in animal studies
Nonclinical Toxicology (13.1)]
and the potential for serious adverse reactions in nursing infants from azacitidine advise patients not to breastfeed during treatment with azacitidine.
- Pregnancy TestingVerifythe pregnancy status of females of reproductive potential prior to initiating azacitidine for injection.
FemalesAdvise females of reproductive potential to avoid pregnancy during treatment with azacitidine for injection.
MalesMales with female sexual partners of reproductive potential should not father a child and should use effective contraception during treatment with azacitidine for injection.
InfertilityBased on animal data, azacitidine could have an effect on male or female fertility
Nonclinical Toxicology (13.1)]
- AbsorptionAzacitidine is rapidly absorbedafter subcutaneous administration; the peak plasma azacitidine concentration of 750 ± 403 ng/ml occurred in 0.5 hour.
DistributionThe bioavailability of subcutaneous azacitidine relative to intravenous azacitidine is approximately 89%, based on area under the curve. Mean volume of distribution following intravenous dosing is 76 ± 26 L. Mean apparent subcutaneous clearance is 167 ± 49 L/hour and mean half-life after subcutaneous administration is 41 ± 8 minutes. The AUC and C
max of subcutaneous administration of azacitidine in 21 patients with cancer were approximately dose proportional within the 25 to 100 mg/m
2 dose range. Multiple dosing at the recommended dose regimen does not result in drug accumulation.
EliminationPublished studies indicate that urinary excretion is the primary route of elimination of azacitidine and its metabolites. Following intravenous administration of radioactive azacitidine to 5 cancer patients, the cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for <1% of administered radioactivity over 3 days. Mean excretion of radioactivity in urine following subcutaneous administration of
14C-azacitidine was 50%. The mean elimination half-lives of total radioactivity (azacitidine and its metabolites) were similar after intravenous and subcutaneous administrations, about 4 hours.
- Specific PopulationsIn patients with cancer the pharmacokinetics of azacitidine in 6 patients with normal renal function (CLcr > 80 mL/min) and 6 patients with severe renal impairment (CLcr < 30 mL/min) were compared following daily subcutaneous dosing (Days 1 through 5) at 75 mg/m
- 2/day. Severe renal impairment increased azacitidine exposure by approximately 70% after single and 41% after multiple subcutaneous administrations. This increase in exposure was not correlated with an increase in adverse events. The exposure was similar to exposure in patients with normal renal function receiving 100 mg/m
- 2 . Therefore, a Cycle 1dose modification is not recommended.
- The effects of hepatic impairment, gender, age, or race on the pharmacokinetics of azacitidine have not been studied.
- Drug-Drug InteractionsNo formal clinical drug interaction studies with azacitidine have been conducted.An
- In vitro study of azacitidine incubation in human liver fractions indicated thatazacitidine may bemetabolizedby the liver.Whether azacitidine metabolism may be affected by known microsomal enzyme inhibitors or inducers has not been studied.
- In vitro study with cultured human hepatocytes indicated that azacitidine at concentrations up to 100 µM (IV C
- Max=10.6µM) does not cause any inhibition of CYP2B6 and CYP2C8. The potential of azacitidine to inhibit other cytochrome P450 (CYP) enzymes is not known.
- In vitro studies with human cultured hepatocytes indicate that azacitidine atconcentrations of 1.0 µM to 100 µM does not induceCYP 1A2, 2C19, or 3A4/5.
- Myelodysplastic Syndromes (MDS)Study 1 was a randomized, open-label, controlled trial carried out in 53 U.S. sites compared the safetyandefficacyofsubcutaneousazacitidine forinjection plus supportive care with supportive care alone ("observation") in patientswith any of the fiveFAB subtypesofmyelodysplasticsyndromes(MDS): refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL). RA and RARS patients were included if they met one or more of the following criteria: required packed RBC transfusions;hadplatelet counts ≤50.0 × 10
- 9/L;required platelettransfusions; or were neutropenic (ANC <1.0 × 10
- 9/L) with infections requiring treatment with antibiotics. Patients with acute myelogenous leukemia (AML) were not intended to be included. Supportive care allowed in this study included blood transfusion products, antibiotics, antiemetics, analgesics and antipyretics. The use of hematopoietic growth factors was prohibited. Baseline patient anddiseasecharacteristics aresummarizedinTable 3;the2groupsweresimilar.
- Azacitidine for injection was administered at a subcutaneous dose of 75 mg/m
- 2 daily for 7 days every 4 weeks. The dose was increased to 100 mg/m
- 2 ifnobeneficialeffectwasseen after 2 treatment cycles.Thedose was decreased and/or delayed based on hematologic response or evidence of renal toxicity. Patients in the observation arm were allowed by protocol to cross over to azacitidine for injection if they had increases in bone marrow blasts, decreases in hemoglobin, increases in red cell transfusion requirements, or decreases in platelets, or if they required a platelet transfusion or developed a clinical infection requiring treatment with antibiotics. For purposes of assessing efficacy, the primary endpoint was response rate (as defined in Table 4).
- Of the 191 patients included in the study, independent review (adjudicated diagnosis) found that 19 had the diagnosis of AML at baseline. These patients were excluded from the primary analysis of response rate, although they were included in an intent-to-treat (ITT) analysis of all patients randomized. Approximately 55% of the patients randomized to observation crossed over to receive azacitidine for injection treatment.Table 3. Baseline Demographics and Disease CharacteristicsAzacitidine for Injection(N=99)Observation(N=92)Gender (n%)Male72 (72.7)60 (65.2)Female27 (27.3)32 (34.8)Race (n%) White93 (93.9)85 (92.4)Black1 (1.0)1 (1.1)Hispanic3 (3.0)5 (5.4)Asian/Oriental2 (2.0)1 (1.1)Age (years)N9991Mean ± SD67.3 ± 10.3968.0 ± 10.23Range31 - 9235 - 88Adjudicated MDS diagnosis at study entry (n%) RA21 (21.2)18 (19.6)RARS6 (6.1)5 (5.4)RAEB38 (38.4)39 (42.4)RAEB-T16 (16.2)14 (15.2)CMMoL8 (8.1)7 (7.6)AML10 (10.1)9 (9.8)Transfusion product used in 3 months before study entry (n%)Any transfusion product70 (70.7)59 (64.1)Blood cells, packed human 66 (66.7)55 (59.8)Platelets, human blood15 (15.2)12 (13.0)Hetastarch0 (0.0)1 (1.1)Plasma protein fraction1 (1.0)0 (0.0)Other2 (2.0)2 (2.2)Table 4. Response CriteriaRARARSRAEBRAEB-TCMMoLComplete Response (CR), duration ≥4 weeks
- Marrow <5% blastsPeripheral BloodNormal CBC if abnormal at baseline
- Absence of blasts in the peripheral circulation
- Partial Response (PR), duration ≥4 weeks
- Marrow No marrow requirements≥50% decrease in blasts
- Improvement of marrow dyspoiesis
- Peripheral Blood≥50% restoration in the deficit from normal levels of baseline white cells, hemoglobin and platelets if abnormal at baseline
- No blasts in the peripheral circulation
- For CMMoL, if WBC is elevated at baseline, a ≥75% reduction in the excess count over the upper limit of normal
- The overall response rate (CR + PR) of 15.7% in azacitidine for injection-treated patients without AML (16.2% for all azacitidine for injection randomizedpatientsincludingAML)wasstatisticallysignificantlyhigher than the response rate of 0% in the observation group (p<0.0001) (Table 5). The majority of patients who achieved either CR or PR had either 2 or 3 cell lineabnormalities at baseline (79%;11/14)andhadelevated bonemarrowblasts or were transfusion dependent at baseline. Patients responding to azacitidine for injection had a decrease in bone marrow blasts percentage, or an increaseinplatelets, hemoglobin or WBC. Greater than 90%of theresponders initially demonstrated these changes by the 5
- Th treatment cycle. All patients who had been transfusion dependent became transfusion independent during PR or CR. The mean and median duration of clinical response of PR or better was estimated as 512 and 330 days, respectively; 75% of theresponding patients were still in PR or better at completion of treatment. Response occurred in all MDS subtypes as well as in patients with adjudicated baseline diagnosis of AML.
- Table 5. Response RatesAzacitidine for Injection(N=89)Observation Before Crossover(N=83)Responsen (%)n (%)P valueOverall (CR+PR)14 (15.7)0 ( 0.0)(<0.0001)Complete (CR)5 ( 5.6)0 ( 0.0)(0.06)Partial (PR)9 (10.1)0 ( 0.0)--Patients in the observation group who crossed over to receive azacitidine for injection treatment (47 patients) had a response rate of 12.8%.Study 2, a multi-center, open-label, single-arm study of 72 patients with RAEB, RAEB-T, CMMoL, or AML was also carried out. Treatment with subcutaneous azacitidine for injection resulted in a response rate (CR + PR) of 13.9%, using criteria similar to those described above. The mean and median duration of clinical response of PR or better was estimated as 810 and430 days,respectively; 80% of therespondingpatientswere still in PRor better at the time of completion of study involvement. In Study 3, another open-label, single-arm study of 48 patients with RAEB, RAEB-T, or AML, treatment with intravenous azacitidine for injection resulted in a response rate of 18.8%, again using criteria similar to those described above. The mean and median duration of clinical response of PR or better was estimated as389and281days, respectively; 67% of the responding patients werestillin PR or better at the time of completion of treatment. Response occurred in all MDS subtypes as well as in patients with adjudicated baseline diagnosis of AML in both of these studies. Azacitidine for injection dosage regimens in these 2 studies were similar to the regimen used in the controlled study.
- Benefit was seen in patients who did not meet the criteria for PR or better,butwere considered "improved." About 24% of azacitidine for injection-treated patients were considered improved, and about 2/3 of those lost transfusion dependence. In the observation group, only 5/83 patients met criteria for improvement; nonelosttransfusiondependence. In all3 studies,about19% of patients met criteria for improvement with a median duration of 195 days. Study 4 was an international, multicenter, open-label, randomized trial in MDSpatientswith RAEB, RAEB-T or modifiedCMMoLaccordingtoFABclassificationandIntermediate-2andHighriskaccordingtoIPSSclassification. Of the 358 patients enrolled in the study, 179 were randomized to receive azacitidine plus best supportive care (BSC) and 179 were randomized to receive conventional care regimens (CCR) plus BSC (105 to BSC alone, 49 to low dose cytarabine and 25 to chemotherapy with cytarabine and anthracycline). The primaryefficacyendpoint was overallsurvival.
- The azacitidine and CCR groups were comparable for baseline parameters. The median age of patients was 69 years (range was 38-88 years), 98% were Caucasian, and 70% were male. At baseline, 95% of the patients were higher risk by FABclassification:RAEB(58%), RAEB-T (34%), and CMMoL (3%).By IPSSclassification,87% werehigher risk: Int-2(41%), High (47%).Atbaseline, 32% of patientsmetWHO criteria for AML.
- Azacitidine was administered subcutaneously at a dose of 75 mg/m
- 2 daily for 7 consecutive days every 28 days (which constituted one cycle of therapy). Patients continued treatment until disease progression, relapse after response, or unacceptable toxicity. Azacitidine patients were treated for a median of 9 cycles (range 1 to 39), BSC only patients for a median of 7 cycles (range 1 to 26), low dose cytarabine patients for a median of 4.5 cycles (range 1 to 15), and chemotherapy with cytarabine and anthracycline patients for a median of 1 cycle (range 1 to 3, i.e. induction plus 1 or 2 consolidation cycles).
- In the Intent-to-Treat analysis, patients treated with azacitidine demonstrated astatistically significant difference in overall survival as compared to patients treated with CCR(mediansurvivalof 24.5 months vs. 15.0 months; stratified log-rank p=0.0001). The hazard ratio describing this treatment effect was 0.58 (95% CI: 0.43, 0.77).
- Kaplan-Meier Curve of Time to Death from Any Cause: (Intent-to-Treat Population)
- Key: AZA = azacitidine; CCR = conventional care regimens; CI = confidence interval; HR = Hazard RatioAzacitidine treatment led to a reduced need for red blood cell transfusions (see
- Table 6). In patients treated with azacitidine who were RBC transfusion dependent at baseline and became transfusion independent, the median duration of RBC transfusion independence was 13.0 months.
- Table 6. Effect of Azacitidine on RBC Transfusions in MDS PatientsEfficacy ParameterAzacitidine plus BSC(n= 179)Conventional Care Regimens(n= 179)Number and percent of patients who were transfusion dependent at baseline who became transfusion independent on treatment
- A patient was considered RBC transfusion independent during the treatment period if the patient had no RBC transfusions during any 56 consecutive days or more during the treatment period. Otherwise, the patient was considered transfusion dependent.50/111 (45.0%)
- (95% CI: 35.6%, 54.8%)
- 13/114 (11.4%)
- (95% CI: 6.2%, 18.7%)
- Number and percent of patients who were transfusion-independent at baseline who became transfusion-dependent on treatment10/68 (14.7%)
- (95% CI: 7.3%, 25.4%)
- 28/65 (43.1%)
- (95% CI: 30.9%, 56.0%)
How SuppliedAzacitidine for injection is supplied as a lyophilized powder in 100 mg single-dose vials packaged in cartons of 1 vial (NDC 68001-504-54).
Handling and DisposalAzacitidine for injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.
- HepatotoxicityinPatientswith Severe Pre-Existing Hepatic ImpairmentInstruct patients to inform their physician about any underlying liver disease
- Warnings and Precautions (5.2)]
Renal ToxicityInstruct patients to inform their physician about any underlying renal disease
Warnings and Precautions (5.3)]
Embryo-Fetal RiskAdvise pregnant women of the potential risk to a fetus
Warnings and Precautions (5.5) and
Use in Specific Populations (8.1)]
Advise females of reproductive potential to avoid pregnancy during treatment with azacitidine for injection. Advise males with female sexual partners of reproductive potential to not father a child and to use effective contraception during treatment with azacitidine for injection. Advise patients to report pregnancy to their physicians immediately
Warnings and Precautions (5.5) and
Use in Specific Populations (8.3)]
LactationAdvise patients to avoid breastfeeding while receiving azacitidine for injection
Use in Specific Populations (8.2)]
Panacea Biotec Pharma LimitedBaddi- 173 205, India.
For BluePoint Laboratories Rev 05/21
2.8 Instructions For Intravenous Administration
- Reconstitute the appropriate number of azacitidine for injection vials to achieve the desired dose. Reconstitute each vial with 10 mL sterile water for injection. Vigorouslyshakeor rollthe vial until all solidsaredissolved.Theresulting solution will contain azacitidine 10 mg/mL. The solution should be clear. Parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- Withdraw the required amount ofazacitidine for injectionsolutiontodeliver the desired dose and inject into a 50 -100 mL infusion bag of either 0.9% Sodium Chloride Injection or Lactated Ringer's Injection.
3 Dosage Forms And Strengths
Azacitidine for injection is supplied as lyophilized powder in 100 mg single-dose vials.
4.1 Advanced Malignant Hepatic Tumors
Azacitidine for injection is contraindicated in patients with advanced malignant hepatic tumors
Warnings and Precautions (5.2)]
4.2 Hypersensitivity To Azacitidine Or Mannitol
Azacitidine for injection is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol.
5.1 Anemia, Neutropenia And Thrombocytopenia
- Azacitidine causes anemia, neutropenia and thrombocytopenia. Monitor complete blood counts frequently for response and/or toxicity, at a minimum, prior to each dosingcycle.Afteradministrationoftherecommendeddosageforthefirstcycle,adjust dosage for subsequent cycles based on nadir counts and hematologic response
- Dosage and Administration (2.3)]
5.2 Hepatotoxicity In Patients With Severe Pre-Existing Hepatic Impairment
Because azacitidine is potentially hepatotoxic in patients with severe pre-existing hepatic impairment, caution is needed in patients with liver disease. Patients with extensive tumor burden due to metastatic disease have been reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline albumin <30 g/L. Azacitidine is contraindicated in patients with advanced malignant hepatic tumors
Monitor liver chemistries prior to initiation of therapy and with each cycle.Safety and effectiveness of azacitidine in patients with MDS and hepatic impairment have not been studied as these patients were excluded from the clinical trials.
5.3 Renal Toxicity
- Renal toxicity ranging from elevated serum creatinine to renal failure and death have been reported in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for nonMDS conditions. In addition, renal tubular acidosis, definedas afall inserum bicarbonateto <20 mEq/L in association with an alkaline urine and hypokalemia (serum potassium <3 mEq/L) developed in 5 patients with CML treated with azacitidine and etoposide. Monitor serum creatinine and electrolytes prior to initiation of therapy and with each cycle. If unexplained reductions in serum bicarbonate <20 mEq/L or elevations of BUN or serum creatinine occur, reduce or hold the dose
- Dosage and Administration (2.4)]
- Patients with renal impairment may be at increased risk for renal toxicity. Also, azacitidine and its metabolites are primarily excreted by the kidney. Therefore, monitor these patients closely for toxicity
- Dosage and Administration (2.4,
- . Patients with MDS and renal impairment were excluded from the clinical studies.
5.4 Tumor Lysis Syndrome
Azacitidine for injection may cause fatal or serious tumor lysis syndrome, including in patients with MDS. Tumor lysis syndrome may occur despite concomitant use of allopurinol. Assess baseline risk and monitor and treat as appropriate.
5.5 Embryo-Fetal Risk
- Based on the mechanism of action and findingsinanimals,azacitidine for injection can cause fetal harm when administered to a pregnant woman. Azacitidine administered to pregnant rats via a single intraperitoneal (IP) dose approximating 8% of the recommended human daily dose caused fetal death and anomalies
- Use in Specific Populations (8.1)]
- Advise females with reproductive potential to avoid pregnancy during treatment with azacitidine for injection
- Use in Specific Populations (8.3)]
- . Men should be advised to not father a child while receiving treatment with azacitidine for injection.
6 Adverse Reactions
- The following adverse reactions are described in other labeling sections:Anemia, Neutropenia and Thrombocytopenia
- Warnings and Precautions (5.1)]
- Warnings and Precautions (5.2)]
- Renal Toxicity
- Warnings and Precautions (5.3)]
- Tumor Lysis Syndrome
- Warnings and Precautions (5.4)]
- Embryo-Fetal Risk
- Warnings and Precautions (5.5)]
- Most Commonly Occurring Adverse Reactions (Subcutaneous or Intravenous Route): nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia, ecchymosis. The most common adverse reactions by intravenous route also included petechiae, rigors, weakness and hypokalemia.
- Adverse Reactions Most Frequently (>2%) Resulting in Clinical Intervention (Subcutaneous or Intravenous Route):Discontinuation: leukopenia, thrombocytopenia, neutropenia.DoseHeld:leukopenia,neutropenia,thrombocytopenia, pyrexia, pneumonia, febrile neutropenia.
- Dose Reduced: leukopenia, neutropenia, thrombocytopenia.
6.1 Adverse Reactions In Clinical Trials
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared toratesintheclinicaltrialsofanotherdrug and may not reflectthe rates observed in practice.
- Thedata describedbelowreflectexposuretoazacitidine in 443 MDS patients from 4 clinical studies. Study 1 was a supportive-care controlled trial (subcutaneous administration), Studies 2 and 3 were single arm studies (one with subcutaneous administration and one with intravenous administration), and Study 4 was an international randomized trial (subcutaneous administration)
- Clinical Studies (14)]
- In Studies 1, 2 and 3, a total of 268 patients were exposed to azacitidine, including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately one year). Azacitidine was studied primarily in supportive-care controlled and uncontrolled trials (n=150 and n=118, respectively). The population in the subcutaneous studies (n=220) was 23 to 92 years old (mean 66.4 years), 68% male, and 94% white, and had MDS or AML. The population in the intravenous study (n=48) was 35 to 81 years old (mean 63.1 years), 65% male, and 100% white. Most patients received average daily doses between 50 and 100 mg/m
- In Study 4, a total of 175 patients with higher-risk MDS (primarily RAEB and RAEB-T subtypes) were exposed to azacitidine. Of these patients, 119 were exposed for 6 or more cycles, and 63 for at least 12 cycles. The mean age of this population was 68.1 years (ranging from 42 to 83 years), 74% were male, and 99% were white. Most patients received daily azacitidine doses of 75 mg/m
- Table 1 presents adverse reactions occurring in at least 5% of patients treated with azacitidine (subcutaneous) in Studies 1 and 2. It is important to note that duration of exposure was longer for the azacitidine-treated group than for the observation group: patients received azacitidine for injection for a mean of 11.4 months while mean time in the observation arm was 6.1 months.Table 1: Most Frequently Observed Adverse Reactions (≥ 5.0% in All Subcutaneous Azacitidine Treated Patients; Studies 1 and 2)Number (%) of PatientsSystem Organ ClassPreferred TermMultiple terms of the same preferred terms for a patient are only counted once within each treatment group.All Azacitidine for InjectionIncludes adverse reactions from all patients exposed to azacitidine, including patients after crossing over from observations.(N=220)ObservationIncludes adverse reactions from observation period only; excludes any adverse events after crossover to azacitidine.(N=92)Blood and lymphatic system disorders Anemia153 (70)59 (64) Anemia aggravated12 (6)5 (5) Febrile neutropenia36 (16)4 (4) Leukopenia106 (48)27 (29) Neutropenia71 (32)10 (11) Thrombocytopenia144 (66)42 (46) Gastrointestinal disorders Abdominal tenderness26 (12)1 (1) Constipation74 (34)6 (7) Diarrhea80 (36)13 (14) Gingival bleeding21 (10)4 (4) Loose stools12 (6)0 Mouth hemorrhage11 (5)1 (1) Nausea155 (71)16 (17) Stomatitis17 (8)0 Vomiting119 (54)5 (5) General disorders and administration site conditions Chest pain36 (16)5 (5) Injection site bruising31 (14)0 Injection site erythema77 (35)0 Injection site granuloma11 (5)0 Injection site pain50 (23)0 Injection site pigmentation changes11 (5)0 Injection site pruritus15 (7)0 Injection site reaction30 (14)0 Injection site swelling11 (5)0 Lethargy17 (8)2 (2) Malaise24 (11)1 (1) Pyrexia114 (52)28 (30) Infections and infestations Nasopharyngitis32 (15)3 (3) Pneumonia24 (11)5 (5) Upper respiratory tract infection28 (13)4 (4) Injury, poisoning, and procedural complications Post procedural hemorrhage13 (6)1 (1) Metabolism and nutrition disorders Anorexia45 (21)6 (7) Musculoskeletal and connective tissue disorders Arthralgia49 (22)3 (3) Chest wall pain11 (5)0 Myalgia35 (16)2 (2) Nervous system disorders Dizziness41 (19)5 (5) Headache48 (22)10 (11) Psychiatric disorders Anxiety29 (13)3 (3) Insomnia24 (11)4 (4) Respiratory, thoracic and mediastinal disorders Dyspnea64 (29)11 (12) Skin and subcutaneous tissue disorders Dry skin11 (5)1 (1) Ecchymosis67 (31)14 (15) Erythema37 (17)4 (4) Rash31 (14)9 (10) Skin nodule11 (5)1 (1) Urticaria13 (6)1 (1) Vascular disorders Hematoma19 (9)0 Hypotension15 (7)2 (2) Petechiae52 (24)8 (9)Table 2 presents adverse reactions occurring in at least 5% of patients treated with azacitidine in Study 4. Similar to Studies 1 and 2 described above, duration of exposure to treatment with azacitidine was longer (mean 12.2 months) compared with best supportive care (mean 7.5 months). Table 2: Most Frequently Observed Adverse Reactions (≥ 5.0% in the Azacitidine Treated Patients and the Percentage with NCI CTC Grade 3/4 Reactions; Study 4)Number (%) of PatientsAny GradeGrade 3/4System Organ ClassPreferred TermMultiple reports of the same preferred term from a patient were only counted once within each treatment.Azacitidine for Injection(N=175)Best Supportive Care Only(N=102)Azacitidine for Injection(N=175)Best Supportive Care Only(N=102)Blood and lymphatic system disorders Anemia90 (51)45 (44)24 (14)9 (9) Febrile neutropenia24 (14)10 (10)22 (13)7 (7) Leukopenia32 (18)2 (2)26 (15)1 (1) Neutropenia115 (66)29 (28)107 (61)22 (22) Thrombocytopenia122 (70)35 (34)102 (58)29 (28)Gastrointestinal disordersAbdominal pain22 (13)7 (7)7 (4)0Constipation88 (50)8 (8)2 (1)0Dyspepsia10 (6)2 (2)00Nausea84 (48)12 (12)3 (2)0Vomiting47 (27)7 (7)00General disorders and administration site conditionsFatigue42 (24)12 (12)6 (3)2 (2)Injection site bruising9 (5)000Injection site erythema75 (43)000Injection site hematoma11 (6)000Injection site induration9 (5)000Injection site pain33 (19)000Injection site rash10 (6)000Injection site reaction51 (29)01 (1)0Pyrexia53 (30)18 (18)8 (5)1 (1)Infections and infestationsRhinitis10 (6)1 (1)00 Upper respiratory tract infection16 (9)4 (4)3 (2)0 Urinary tract infection15 (9)3 (3)3 (2)0 Investigations Weight decreased14 (8)01 (1)0Metabolism and nutrition disorders Hypokalemia11 (6)3 (3)3 (2)3 (3) Nervous system disorders Lethargy13 (7)2 (2)01 (1) Psychiatric disorders Anxiety9 (5)1 (1)00 Insomnia15 (9)3 (3)00Renal and urinary disorders Hematuria11 (6)2 (2)4 (2)1 (1)Respiratory, thoracic and mediastinal disorders Dyspnea26 (15)5 (5)6 (3)2 (2) Dyspnea exertional9 (5)1 (1)00 Pharyngolaryngeal pain11 (6)3 (3)00Skin and subcutaneous tissue disorders Erythema13 (7)3 (3)00 Petechiae20 (11)4 (4)2 (1)0 Pruritus21 (12)2 (2)00 Rash18 (10)1 (1)00 Vascular disorders Hypertension15 (9)4 (4)2 (1)2 (2)In Studies 1, 2 and 4 with subcutaneous administration of azacitidine, adverse reactions of neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and injection site erythema/reaction tended to increase in incidence with higher doses of azacitidine for injection.Adverse reactions that tended to bemore pronounced during thefirst1to2 cycles of subcutaneous treatment compared with later cycles included thrombocytopenia, neutropenia, anemia, nausea, vomiting, injection site erythema/pain/bruising/reaction, constipation, petechiae, dizziness, anxiety, hypokalemia, and insomnia. There did not appear to be any adverse reactions that increased in frequency over the course of treatment.
- Overall, adverse reactions were qualitatively similar between the intravenous andsubcutaneousstudies.Adversereactionsthatappearedtobespecificallyassociated with the intravenous route of administration included infusion site reactions (e.g. erythema or pain) and catheter site reactions (e.g. infection, erythema, or hemorrhage).
- In clinical studies of either subcutaneous or intravenous azacitidine, the following serious adverse reactions occurring at a rate of < 5% (and not described in Tables 1 or 2) were reported:Blood and lymphatic system disorders: agranulocytosis, bone marrow failure, pancytopenia splenomegaly.
- Cardiac disorders:atrialfibrillation,cardiacfailure, cardiac failure congestive, cardio-respiratory arrest, congestive cardiomyopathy.
- Eye disorders: eye hemorrhage
- Gastrointestinal disorders: diverticulitis, gastrointestinal hemorrhage, melena, perirectal abscess.
- General disorders and administration site conditions: catheter site hemorrhage, general physical healthdeterioration, systemicinflammatory response syndrome.
- Hepatobiliary disorders: cholecystitis.
- Immune system disorders: anaphylactic shock, hypersensitivity.
- Infections and infestations: abscess limb, bacterial infection, cellulitis, blastomycosis, injection site infection, Klebsiella sepsis, neutropenic sepsis, pharyngitis streptococcal, pneumonia Klebsiella, sepsis, septic shock, Staphylococcal bacteremia, Staphylococcal infection, toxoplasmosis.
- Metabolism and nutrition disorders: dehydration.
- Musculoskeletal and connective tissue disorders: bone pain aggravated, muscle weakness, neck pain.
- Neoplasms benign, malignant and unspecified: leukemia cutis.
- Nervous system disorders: cerebral hemorrhage, convulsions, intracranial hemorrhage.
- Renal and urinary disorders: loin pain, renal failure.
- Respiratory, thoracic and mediastinal disorders:hemoptysis,lung infiltration, pneumonitis, respiratory distress.
- Skin and subcutaneous tissue disorders: pyoderma gangrenosum, rash pruritic, skin induration.
- Surgical and medical procedures: cholecystectomy.
- Vascular disorders: orthostatic hypotension.
6.2 Postmarketing Experience
- Thefollowingadversereactions have been identified duringpostmarketinguse of azacitidine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Interstitial lung disease
- Tumor lysis syndrome
- Injection site necrosis
- Sweet's syndrome (acute febrile neutrophilic dermatosis)
- Necrotizing fasciitis (including fatal cases)
- Differentiation syndrome
8.3 Females And Males Of Reproductive Potential
- Based on its mechanism of action and findings in animals,azacitidine for injection can cause fetal harm when administered to a pregnant woman
- Use in Specific Populations (8.1)]
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5 Geriatric Use
Of the total number of patients in Studies 1, 2 and 3, 62% were 65 years and older and 21% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In addition there were no relevant differences in the frequency of adverse reactions observed in patients 65 years and older compared to younger patients.Of the 179 patients randomized to azacitidine in Study 4, 68% were 65 years and older and 21% were 75 years and older. Survival data for patients 65 years and older were consistent with overall survival results. The majority of adverse reactions occurred at similar frequencies in patients < 65 years of age and patients 65 years of age and older.Elderly patients are more likely to have decreased renal function. Monitor renal function in these patients
Dosage and Administration (2.5) and
Warnings and Precautions (5.3)]
One case of overdose with azacitidine was reported during clinical trials. A patient experienced diarrhea, nausea, and vomiting after receiving a single intravenous dose of approximately 290 mg/m
2, almost 4 times the recommended starting dose. The events resolved without sequelae, and the correct dose was resumed the following day. In the event of overdosage, the patient should be monitored with appropriate blood counts and should receive supportive treatment, as necessary. There is no known specific antidote for azacitidine overdosage.
- Azacitidine for injection contains azacitidine, which is a pyrimidine nucleosideanalog of cytidine. Azacitidine is 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one. The structural formulaisas follows:
- The empirical formula is C
- 5. The molecular weight is 244. Azacitidine is a white to off-white solid. Azacitidine was found to be insoluble in acetone, ethanol,andmethyl ethylketone;slightlysolubleinethanol/water (50/50), propylene glycol, and polyethylene glycol; sparingly soluble inwater,water saturated octanol, 5% dextrose in water, N-methyl-2-pyrrolidone, normal saline and 5% Tween 80 in water; andsoluble indimethylsulfoxide (DMSO).
- Thefinishedproductissupplied in a sterile form for reconstitution as asuspension for subcutaneous injection or reconstitution as a solution with furtherdilution for intravenous infusion. Vials of azacitidine for injection contain 100 mg of azacitidine and 100 mg mannitol as a sterile lyophilized powder.
12.1 Mechanism Of Action
- Azacitidine for injection is a pyrimidine nucleoside analog of cytidine. Azacitidine for injection 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 ofDNAsynthesis.Hypomethylation may restore normal functiontogenesthat 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.
The pharmacokinetics of azacitidine were studied in 6 MDS patients following a single 75 mg/m
2 subcutaneous dose and a single 75 mg/m
2 intravenous dose.
13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility
- The potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine induced tumors of the hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m
- 2, approximately 8% the recommended human daily dose on a mg/m
- 2 basis) administered IP three times per week for 52 weeks. An increased incidence of tumors in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine IP at 2.0 mg/kg (6.0 mg/m
- 2, approximately 8% the recommended human daily dose on a mg/m
- 2 basis) once a week for 50 weeks. A tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m
- 2 (approximately 20%-80% the recommended human daily dose on a mg/m
- 2 basis) revealed an increased incidence of testicular tumors compared with controls.
- The mutagenic and clastogenic potential of azacitidine was tested in
- In vitro bacterial systems Salmonella typhimurium strains TA100 and several strains oftrpE8,EscherichiacolistrainsWP14Pro,WP3103P,WP3104P,andCC103;in
- In vitro forward gene mutation assay in mouse lymphoma cells andhumanlymphoblastcells; and inan
- In vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian hamster embryo cells. Azacitidine was mutagenic in bacterial and mammalian cell systems. The clastogenic effect of azacitidine was shown by the induction of micronuclei in L5178Y mouse cells and Syrian hamster embryo cells.
- Administration of azacitidine to male mice at 9.9 mg/m
- 2 (approximately 9% the recommended human daily dose on a mg/m
- 2 basis) daily for 3 days prior to mating with untreated female mice resulted in decreased fertility and loss of offspring during subsequent embryonic and postnatal development. Treatment of male rats 3 times per week for 11 or 16 weeks at doses of 15-30 mg/m
- 2 (approximately 20% - 40%, the recommended human daily dose on a mg/m
- 2 basis) resulted in decreased weight of the testes and epididymides, and decreased sperm counts accompanied by decreased pregnancy rates and increased loss of embryos in mated females. In a related study, male rats treated for 16 weeks at 24 mg/m
- 2 resulted in an increase in abnormal embryos in mated females when examined on day 2 of gestation.
- "OSHA Hazardous Drugs." OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html
Storage And Handling
- StorageStore unreconstituted vials at 25° C (77° F); excursions permittedto15°-30° C (59°-86° F) (See USP Controlled Room Temperature).
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