Vidaza

Contraindications

Hypersensitivity to azacitidine or mannitol

Advanced malignant hepatic tumors

Pregnancy/lactation

Cautions

Should not get pregnant/father children while on this drug

Renal tubular acidosis, and renal failure reported

Thrombocytopenia, neutropenia, and anemia are common occurrence

Hepatotoxicity reported

Thoroughly monitor hematologic responses

Females with reproductive potential should avoid pregnancy during treatment; men should be advised to not father a child while receiving therapy

Monitor liver chemistries prior to initiation of therapy and with each cycle

Monitor serum creatinine and electrolytes prior to initiation of therapy and with each cycle

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

Serious side effects have been reported with Vidaza including the following:

• lowered blood counts. This is medically known as bone marrow suppression. Your doctor may monitor for bone marrow suppression, as it can lead to thrombocytopenia, anemia, and neutropenia.
  • thrombocytopenia. This is a condition in which your blood has a lower than normal number of blood cell fragments called platelets. Tell your healthcare provider right away if you have the following signs and symptoms of thrombocytopenia:
    • mild to serious bleeding
    • purple, brown, and red bruises (purpura)
    • small red or purple dots on your skin (petechiae)
    • prolonged bleeding, even from minor cuts
    • bleeding or oozing from the mouth or nose, especially nosebleeds or bleeding from brushing your teeth
    • abnormal vaginal bleeding (especially heavy menstrual flow)
    • blood in the urine or stool or bleeding from the rectum. Blood in the stool can appear as red blood or as a dark, tarry color. Taking iron supplements also can cause dark, tarry stools.
    • headaches and other neurological symptoms. These problems are very rare, but you should discuss them with your doctor.
  • anemia. This is a condition in which your blood has a lower than normal number of red blood cells. Tell your healthcare provider right away if you have the following signs and symptoms of anemia:
    • shortness of breath
    • dizziness
    • headache
    • coldness in the hands and feet
    • pale skin
    • chest pain
  • neutropenia. This is when there is an abnormally low number of white blood cells. These cells, which are called neutrophils, help the body fight infection. Those who develop neutropenia are more likely to have fevers and infections.
• a decline in kidney function. Toxicity from Vidaza may occur resulting in kidney dysfunction. Your doctor may want to monitor your kidney functions with certain blood tests. Tell your healthcare provider right away right away if you have any of the following symptoms of kidney dysfunction:
  • swelling of face, ankles, hands, or feet
  • fatigue
  • paleness of skin
  • decreased urination
  • shortness of breath
  • change in blood pressures
  • side effects as mentioned in this section or in the “Side Effects” section of this medication page

Do not take Vidaza if you:

• are allergic to Vidaza or to any of its ingredients
• are allergic to mannitol
• have advanced malignant liver tumors

Call your doctor for instructions if you miss an appointment for your azacitidine injection.

• Exerts antineoplastic effect by inhibiting DNA methyltransferase, thereby causing hypomethylation of DNA,6 7 and by direct cytotoxic effect on abnormal hematopoietic cells in the bone marrow.1 9

Azacitidine injection is used to treat patients with French-American-British (FAB) myelodysplastic syndrome subtypes, including refractory anemia or chronic leukemia.

Azacitidine belongs to the group of medicines called metabolites. It interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by azacitidine, other effects will also occur. Some of these may be serious and must be reported to your doctor. Some effects may not occur for months or years after the medicine is used.

This medicine is to be given only by or under the direct supervision of your doctor.

A nurse or other trained health professional will give you this medicine. You may also be taught how to give your medicine at home. This medicine is given as a shot under your skin or into a vein.

This medicine is given once a day, for 7 days (1 treatment cycle). Then, you may receive this medicine every 4 weeks. You may also receive medicines to help prevent nausea and vomiting.

Cancer medicines can cause nausea or vomiting in most people, sometimes even after receiving medicines to prevent it. Ask your doctor or nurse about other ways to control these side effects.

Missed Dose

This medicine needs to be given on a fixed schedule. If you miss a dose, call your doctor, home health caregiver, or treatment clinic for instructions.

• If you need to store Vidaza (azacitidine) at home, talk with your doctor, nurse, or pharmacist about how to store it.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Vidaza or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Vidaza. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

First Treatment Cycle

The recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology laboratory values, is 75 mg/m2 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

Repeat cycles every 4 weeks. The dose may be increased to 100 mg/m2 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 [see Warnings and Precautions (5.3)], and delay or reduce dosage if necessary as described below.

Dosage Adjustment Based on Hematology Laboratory Values

• For patients with baseline (start of treatment) WBC ≥3.0 x109/L, ANC ≥1.5 x109/L, and platelets ≥75.0 x109/L, adjust the dose as follows, based on nadir counts for any given cycle:

• For patients whose baseline counts are WBC <3.0 x109/L, ANC<1.5 x109/L, or platelets <75.0 x109/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 >25% above the nadir and rising. If a >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%.

Dosage Adjustment Based on Serum Electrolytes and Renal Toxicity

If unexplained reductions in serum bicarbonate levels to <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 [see Warnings and Precautions (5.3)].

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 [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5)].

Preparation of Vidaza

Vidaza is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1

The Vidaza vial is single-dose and does not contain any preservatives. Discard unused portions of each vial properly [see How Supplied/Storage and Handling (16)]. Do not save any unused portions for later administration.

Instructions for Subcutaneous Administration

Reconstitute Vidaza aseptically with 4 mL sterile water for injection. Inject the diluent slowly into the vial. Vigorously shake or roll the vial until a uniform suspension is achieved. The suspension will be cloudy. The resulting suspension will contain azacitidine 25 mg/mL. Do not filter the suspension after reconstitution. Doing so could remove the active substance.

Preparation for Immediate Subcutaneous Administration: Doses greater than 4 mL should be divided equally into 2 syringes. 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. Doses greater than 4 mL should be divided equally into 2 syringes. The product must be refrigerated immediately. When Vidaza is reconstituted using water for injection that has not been refrigerated, the reconstituted product may be held under refrigerated conditions (2ºC - 8ºC, 36ºF - 46ºF) for up to 8 hours. When Vidaza is reconstituted using refrigerated (2ºC - 8ºC, 36ºF - 46ºF) water for injection, the reconstituted product may be stored under refrigerated conditions (2ºC - 8ºC, 36ºF - 46ºF) 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 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. Doses greater than 4 mL should be divided equally into 2 syringes and injected into 2 separate sites. 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: Vidaza reconstituted with non-refrigerated water for injection for subcutaneous administration may be stored for up to 1 hour at 25°C (77°F) or for up to 8 hours between 2°C and 8°C (36°F and 46°F); when reconstituted with refrigerated (2ºC - 8ºC, 36ºF - 46ºF) water for injection, it may be stored for 22 hours between 2°C and 8°C (36°F and 46°F).

Instructions for Intravenous Administration

Reconstitute the appropriate number of Vidaza vials to achieve the desired dose. Reconstitute each vial with 10 mL sterile water for injection. 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. Parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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 or Lactated Ringer's Injection.

Intravenous Solution Incompatibility

Vidaza is incompatible with 5% Dextrose 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 for intravenous administration may be stored at 25°C (77°F), but administration must be completed within 1 hour of reconstitution.

Vidaza (azacitidine for injection) is supplied as lyophilized powder in 100 mg single-dose vials.

The following adverse reactions are described in other labeling sections:

• Anemia, Neutropenia and Thrombocytopenia [see Warnings and Precautions (5.1)]
• Hepatotoxicity in Patients with Severe Pre-existing Hepatic Impairment [see Warnings and Precautions (5.2)]
• Renal Toxicity [see Warnings and Precautions (5.3)]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.4)]
• Embryo-Fetal Risk [see Warnings and Precautions (5.5)]

Most Commonly Occurring Adverse Reactions (SC or IV Route): nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia, ecchymosis. The most common adverse reactions by IV route also included petechiae, rigors, weakness and hypokalemia.

Adverse Reactions Most Frequently (>2%) Resulting in Clinical Intervention (SC or IV Route):
Discontinuation: leukopenia, thrombocytopenia, neutropenia.
Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia.
Dose Reduced: leukopenia, neutropenia, thrombocytopenia.

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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to Vidaza in 443 MDS patients from 4 clinical studies. Study 1 was a supportive-care controlled trial (SC administration), Studies 2 and 3 were single arm studies (one with SC administration and one with IV administration), and Study 4 was an international randomized trial (SC administration) [see Clinical Studies (14)].

In Studies 1, 2 and 3, a total of 268 patients were exposed to Vidaza, including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately one year). Vidaza 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 IV 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/m2.

In Study 4, a total of 175 patients with higher-risk MDS (primarily RAEB and RAEB-T subtypes) were exposed to Vidaza. 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 Vidaza doses of 75 mg/m2.

Table 1 presents adverse reactions occurring in at least 5% of patients treated with Vidaza (SC) in Studies 1 and 2. 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.

Table 2 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 SC 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 SC 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 IV and SC studies. Adverse reactions that appeared to be specifically associated with the IV 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 SC or IV Vidaza, 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: 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.

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.

1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

You should not receive Vidaza if you have liver cancer.

Vidaza can lower blood cells that help your body fight infections and help your blood to clot. You may get an infection or bleed more easily. Call your doctor if you have unusual bruising or bleeding, or signs of infection (fever, chills, body aches).

You should not receive Vidaza if you are allergic to azacitidine or mannitol, or if you have:

• liver cancer.

To make sure Vidaza is safe for you, tell your doctor if you have:

• kidney disease; or

• a history of liver disease.

Do not use Vidaza if you are pregnant. It could harm the unborn baby.

Use birth control to prevent pregnancy while you are receiving Vidaza, whether you are a man or a woman. If a man fathers a baby while using Vidaza, the baby may have birth defects. Use a condom to prevent pregnancy during your treatment, and for at least 4 weeks after your treatment ends.

It is not known whether azacitidine passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.