Vidaza Drug Information

Myelodysplastic Syndromes (MDS) VIDAZA ® is indicated for treatment of adult 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).

Juvenile Myelomonocytic Leukemia (JMML) VIDAZA is indicated for the treatment of pediatric patients aged one month and older with newly diagnosed JMML.

Important Administration Information

Do not substitute VIDAZA for oral azacitidine. The indications and dosing regimen for VIDAZA differ from that of oral azacitidine.

First Treatment Cycle for Adults

The recommended starting dose for the first treatment 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.

Subsequent Treatment Cycles for Adults

Repeat cycles every 4 weeks. The dose may be increased to 100 mg/m 2 if no beneficial effect is seen after 2 treatment cycles and if no toxicity other than nausea and vomiting has occurred. It is recommended that patients be treated for a minimum of 4 to 6 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, and delay or reduce dosage if necessary.

Pediatric Patients with JMML Table 1: Dosage and Administration for Pediatric Patients (JMML) The recommended dosage for pediatric patients with JMML is provided in Table 1. VIDAZA is administered as an intravenous infusion daily for 7 days in a 28-day cycle. Patients should be treated for a minimum of 3 cycles and maximum of 6 cycles.

A delay in dose not exceeding 14 days can be considered for non-hematologic toxicities.

Dosage Adjustment Based on Hematology Laboratory Values •

For adult patients with baseline (start of treatment) WBC greater than or equal to 3 x10 9 /L, ANC greater than or equal to 1.5 x10 9 /L, and platelets greater than or equal to 75 x10 9 /L, adjust the dose as follows, based on nadir counts for any given cycle: • For adult patients whose baseline counts are WBC less than 3 x10 9 /L, ANC less than 1.5 x10 9 /L, or platelets less than 75 x10 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. If a nadir as defined in the table above has occurred, give the next course 28 days after the start of the preceding course, provided that both the WBC and the platelet counts 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%. Pediatric Patients with JMML As hematological toxicity will be difficult to assess and to differentiate from the natural course of the underlying disorder, dose reductions are not recommended due to hematological toxicity within the first 3 cycles. 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.

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.

Preparation of VIDAZA VIDAZA is a hazardous drug

Follow applicable special handling and disposal procedures. The VIDAZA vial is single-dose and does not contain any preservatives. Discard unused portions of each vial properly.

Do not save any unused portions for later administration.

Instructions for Subcutaneous Administration Reconstitute

VIDAZA aseptically with 4 mL Sterile Water for Injection, USP to obtain a concentration of 25 mg/mL. Inject the diluent slowly into the vial. Vigorously shake or roll the vial until a uniform suspension is achieved.

The suspension will be cloudy. Do not filter the suspension after reconstitution. Doing so could remove the active substance.

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.

The product must be refrigerated immediately. See Table 2 for suspension stability storage timelines based on the temperature of the diluent for delayed subcutaneous administration. After removal from refrigerated conditions, the suspension may be allowed to equilibrate to room temperature for up to 30 minutes prior to administration.

Subcutaneous Administration To 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. VIDAZA 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.

Instructions for Intravenous Administration

Parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use the product if there is evidence of particulate matter or discoloration. Adult Patients with MDS Reconstitute the appropriate number of VIDAZA vials to achieve the desired dose.

Reconstitute each vial with 10 mL Sterile Water for Injection, USP. Vigorously shake or roll the vial until all solids are dissolved. The resulting solution will contain azacitidine 10 mg/mL.

The solution should be clear. Withdraw the required amount of VIDAZA solution to deliver the desired dose and inject into a 50 -100 mL infusion bag of either 0.9% Sodium Chloride Injection, USP or Lactated Ringer’s Injection, USP. Intravenous Solution Incompatibility VIDAZA is incompatible with 5% Dextrose Injection, USP solutions, Hespan, or solutions that contain bicarbonate.

These solutions have the potential to increase the rate of degradation of VIDAZA and should therefore be avoided. Intravenous Administration VIDAZA 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 VIDAZA vial. Solution Stability: VIDAZA reconstituted and diluted for intravenous administration may be stored at 25°C (77°F), but administration must be completed within 1 hour of reconstitution.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. MDS The data described below reflect exposure to VIDAZA in 443 patients with MDS 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).

VIDAZA was studied primarily in supportive-care controlled and uncontrolled trials (n=150 and n=118, respectively). Most patients received average daily doses between 50 and 100 mg/m 2. In Study 4, a total of 175 patients with higher-risk MDS (primarily RAEB and RAEB-T subtypes) were exposed to VIDAZA.

Most patients received daily VIDAZA doses of 75 mg/m 2. Most Commonly Occurring Adverse Reactions (Subcutaneous or Intravenous Route) in Adult Patients with MDS: 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) in Adult Patients with MDS: Discontinuation: leukopenia, thrombocytopenia, neutropenia. Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia. Dose Reduced: leukopenia, neutropenia, thrombocytopenia.

It is important to note that duration of exposure was longer for the VIDAZA-treated group than for the observation group: patients received VIDAZA for a mean of 11.4 months while mean time in the observation arm was 6.1 months. 52 8 Table 4 presents adverse reactions occurring in at least 5% of patients treated with VIDAZA in Study 4. Similar to Studies 1 and 2 described above, duration of exposure to treatment with VIDAZA was longer (mean 12.2 months) compared with best supportive care (mean 7.5 months). In Studies 1, 2 and 4 with subcutaneous administration of VIDAZA, adverse reactions of neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and injection site erythema/reaction tended to increase in incidence with higher doses of VIDAZA.

Adverse reactions that tended to be more pronounced during the first 1 to 2 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 and subcutaneous studies.

Adverse reactions that appeared to be specifically associated 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 VIDAZA, the following serious adverse reactions occurring at a rate of <5% (and not described in Tables 2 or 3) were reported: Blood and lymphatic system disorders: agranulocytosis, bone marrow failure, pancytopenia splenomegaly. Cardiac disorders: atrial fibrillation, cardiac failure, 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 health deterioration, systemic inflammatory 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. Juvenile Myelomonocytic Leukemia (JMML) The safety of VIDAZA was evaluated in pediatric patients with JMML (N=18; 0.2-6.9 years old) in Study AZA-JMML-001.

Patients received VIDAZA as intravenous infusion daily for 7 days in a 28-day cycle. Serious adverse reactions occurred in 67% of patients who received VIDAZA for JMML. Permanent discontinuation of VIDAZA due to an adverse reaction occurred in a single patient who had abdominal pain and acute respiratory distress syndrome.

The most common (≥30%) adverse reactions were pyrexia, rash, upper respiratory tract infection, and anemia. Table 5 summarizes the adverse reactions in pediatric JMML. 0 a Grouped term includes: face edema, generalized edema, edema peripheral. b Grouped term includes: rash, rash macular, dermatitis bullous, rash maculo-papular, rash papular, rash pruritic. c Grouped term includes: pruritis, pruritis generalized. d Grouped term includes: influenza, nasopharyngitis, Parainfluenzae virus infection, respiratory tract infection, rhinitis, upper respiratory tract infection, and viral upper respiratory tract infection e Grouped term includes: anal candidiasis, Candida infection, oral candidiasis. f Grouped term includes: lung infection, pneumonia respiratory syncytial viral. g Grouped term includes: abdominal pain, abdominal pain upper. h Grouped term includes: mouth hemorrhage, rectal hemorrhage. i Grouped term includes: back pain, musculoskeletal pain, non-cardiac chest pain, pain in extremity.

Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of VIDAZA. 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 ‑ Pericardial effusion ‑ Pericarditis ‑ Cutaneous vasculitis

Pregnancy Risk Summary Based on its mechanism of action and findings in animals, VIDAZA can cause fetal harm when administered to a pregnant woman. 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 (see Data).

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. 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. Fetal anomalies included: CNS anomalies (exencephaly/encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly), and others (micrognathia, gastroschisis, edema, and rib abnormalities).

Pediatric Use Safety and effectiveness of VIDAZA in pediatric patients with MDS have not been established. The safety and effectiveness of VIDAZA have been established in pediatric patients with newly diagnosed JMML aged 1 month and older and the information on this use is discussed throughout the labeling. The safety and effectiveness of VIDAZA have not been established in pediatric patients younger than 1 month old.

Advanced Malignant Hepatic Tumors VIDAZA is contraindicated in patients with advanced malignant hepatic tumors.

Hypersensitivity to Azacitidine or Mannitol VIDAZA is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol.

One case of overdose with VIDAZA 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 VIDAZA overdosage.