Azacitidine

Name: Azacitidine

Description

VIDAZA (azacitidine for injection) contains azacitidine, which is a pyrimidine nucleoside analog of cytidine. Azacitidine is 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one. The structural formula is as follows:

The empirical formula is C8H12N4O5. The molecular weight is 244. Azacitidine is a white to off-white solid. Azacitidine was found to be insoluble in acetone, ethanol, and methyl ethyl ketone; slightly soluble in ethanol/water (50/50), propylene glycol, and polyethylene glycol; sparingly soluble in water, water saturated octanol, 5% dextrose in water, N-methyl-2-pyrrolidone, normal saline and 5% Tween 80 in water; and soluble in dimethylsulfoxide (DMSO).

The finished product is supplied in a sterile form for reconstitution as a suspension for subcutaneous injection or reconstitution as a solution with further dilution for intravenous infusion. Vials of VIDAZA contain 100 mg of azacitidine and 100 mg mannitol as a sterile lyophilized powder.

Indications

Myelodysplastic Syndromes (MDS)

VIDAZA® 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).

Inform MD

Before taking azacitidine, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

  • are allergic to azacitidine or to any of its ingredients
  • are allergic to mannitol
  • have advanced malignant liver tumors
  • have liver problems
  • have kidney problems
  • are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Azacitidine Usage

Take azacitidine exactly as prescribed.

This medication is available in an injectable form to be given directly under the skin (subQ) or into the vein (IV) by a healthcare professional.

If you miss a dose, be sure to make a follow up appointment.

How is azacitidine given?

Azacitidine is injected under the skin, or into a vein through an IV. A healthcare provider will give you this injection.

This medicine is usually given for 7 days in a row every 4 weeks for at least 4 treatment cycles. Your treatment schedule may be different. Follow your doctor's instructions.

You may also be given medications to reduce nausea and vomiting while you are receiving azacitidine.

Tell your caregiver right away if azacitidine accidentally gets on your skin. Wash the area thoroughly with soap and warm water.

Azacitidine can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often. Your cancer treatments may be delayed based on the results of these tests.

Azacitidine dosing information

Usual Adult Dose for Myelodysplastic Syndrome:

-First Treatment Cycle: 75 mg/m2/day via subcutaneous injection or IV infusion for 7 days; repeat cycles every 4 weeks.
-Subsequent Cycles: After 2 treatment cycles, may increase dose to 100 mg/m2 if no beneficial effect is seen and if no toxicity other than nausea and vomiting has occurred.
-Duration of Therapy: Minimum of 4 to 6 cycles; may continue treatment as long as the patient continues to benefit.

Comments: Premedicate patients for nausea and vomiting.

Use: Treatment of patients with the following French-American-British (FAB) myelodysplastic syndrome (MDS) subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) 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).

Introduction

Antineoplastic agent;1 2 3 4 6 7 a synthetic pyrimidine nucleoside analog of cytidine.1 7

Cautions for Azacitidine

Contraindications

  • Known hypersensitivity to azacitidine or mannitol.1

  • Advanced malignant hepatic tumors.1

Warnings/Precautions

Hematologic Effects.

Possible neutropenia, thrombocytopenia, or anemia.1

Perform CBC and platelet counts prior to each treatment cycle and periodically thereafter as needed.1

After administration of the recommended dosage for the first cycle, reduce or delay dosage for subsequent cycles based on nadir blood cell counts and hematologic response.1 (See Dosage under Dosage and Administration.)

Hepatotoxicity

Progressive hepatic coma and death reported rarely in patients with extensive tumor burden secondary to metastatic disease, particularly in those with baseline serum albumin concentrations of <3 g/dL.1

Contraindicated in patients with advanced malignant hepatic tumors.1

Perform liver function tests prior to initiation of therapy.1

Renal Toxicity

Renal abnormalities (e.g., elevated Scr, renal tubular acidosis), renal failure, and death reported rarely in patients treated with IV azacitidine in combination with other antineoplastic agents (e.g., etoposide) for conditions other than MDS (e.g., chronic myelogenous leukemia).1

Determine Scr prior to initiation of therapy.1

If unexplained reductions in serum bicarbonate concentrations to <20 mEq/L or elevations of BUN or Scr occur, reduce the dosage or withhold therapy with the drug.1 (See Dosage under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.1 Avoid pregnancy during therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Advise male patients to not father a child while receiving azacitidine.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether azacitidine or its metabolites are distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in children <16 years of age.13

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.1

Assess renal function periodically, since azacitidine and its metabolites are substantially eliminated by the kidneys and geriatric patients are more likely to have decreased renal function.1

Hepatic Impairment

Potentially hepatotoxic in patients with severe preexisting hepatic impairment; use with caution in patients with liver disease.1 (See Hepatotoxicity under Cautions.)

Safety and efficacy not established in patients with MDS and hepatic impairment.1

Renal Impairment

Close monitoring for toxicity is recommended.1 Azacitidine and its metabolites are substantially eliminated by the kidneys.1

Safety and efficacy not established in patients with MDS and renal impairment.1

Common Adverse Effects

Sub-Q or IV administration: Nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, fatigue, injection site erythema, constipation, neutropenia, ecchymosis.1 With IV administration, petechiae, rigors, weakness, and hypokalemia also occur commonly.1

What are some things I need to know or do while I take Azacitidine?

  • Tell all of your health care providers that you take azacitidine. This includes your doctors, nurses, pharmacists, and dentists.
  • This medicine may have unsafe effects on the bone marrow. The bone marrow may not be able to make cells found in the blood as well as it used to for a few weeks. This may raise the chance of bleeding or infection. Talk with the doctor.
  • You may have more chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu.
  • You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
  • If you have upset stomach, throwing up, loose stools (diarrhea), or are not hungry, talk with your doctor. There may be ways to lower these side effects.
  • Talk with your doctor before getting any vaccines. Use with this medicine may either raise the chance of an infection or make the vaccine not work as well.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • Very bad and sometimes deadly kidney problems have happened in people getting azacitidine along with other cancer drugs for other health problems. Talk with the doctor.
  • This medicine may cause a bad and sometimes deadly health problem called tumor lysis syndrome (TLS). Call your doctor right away if you have a fast heartbeat or a heartbeat that does not feel normal; any passing out; trouble passing urine; muscle weakness or cramps; upset stomach, throwing up, loose stools or not able to eat; or feel sluggish.
  • If you are 65 or older, use this medicine with care. You could have more side effects.
  • This medicine may affect fertility. Fertility problems may lead to not being able to get pregnant or father a child. Talk with the doctor.
  • If you are a man and have sex with a female who could get pregnant, protect her from pregnancy. Use birth control that you can trust.
  • If you are a man and your sex partner is pregnant or gets pregnant at any time while you are being treated, talk with your doctor.
  • This medicine may cause harm to the unborn baby if you take it while you are pregnant.
  • If you are able to get pregnant, a pregnancy test will be done to show that you are NOT pregnant before starting azacitidine. Talk with your doctor.
  • Use birth control that you can trust to prevent pregnancy while taking this medicine.
  • If you are pregnant or you get pregnant while taking azacitidine, call your doctor right away.

How is this medicine (Azacitidine) best taken?

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • It is given as a shot into the fatty part of the skin.
  • It is given as an infusion into a vein over a period of time.
  • Other drugs may be given before azacitidine to help avoid side effects.

What do I do if I miss a dose?

  • Call your doctor to find out what to do.

Index Terms

  • 5-Azacytidine
  • 5-AZC
  • AZA-CR
  • Azacytidine
  • Ladakamycin

Special Populations Renal Function Impairment

The AUC was increased by 70% after a single subcutaneous dose and by 41% after multiple subcutaneous doses in patients with severe renal impairment (CrCl <30 mL/minute), compared to patients with normal renal function. This increase in exposure did not correlate with increased adverse effects.

Reconstitution

If reconstituted solution comes in contact with skin, wash immediately and thoroughly with soap and water; if comes in contact with mucous membranes, flush thoroughly with water.

IV: Reconstitute vial with 10 mL SWFI to form a 10 mg/mL solution; vigorously shake or roll vial until solution is dissolved and clear. Mix in 50 to 100 mL of NS or lactated Ringer's injection for infusion.

SubQ: Slowly add 4 mL SWFI to each vial, resulting in a concentration of 25 mg/mL. Vigorously shake or roll vial until a suspension is formed (suspension will be cloudy). The manufacturer recommends dividing doses >4 mL equally into 2 syringes. Do not filter after reconstitution (may remove active drug). Resuspend contents of syringe by vigorously rolling between palms immediately prior to administration.

Discard unused portion (does not contain preservatives); do not save unused portions for later administration.

Administration

Azacitidine is associated with a moderate emetic potential (Basch 2011; Dupuis 2011; Roila 2010); antiemetics are recommended to prevent nausea and vomiting.

SubQ: The manufacturer recommends equally dividing volumes >4 mL into 2 syringes and injecting into 2 separate sites; however, policies for maximum SubQ administration volume may vary by institution; interpatient variations may also apply. Rotate sites for each injection (thigh, abdomen, or upper arm). Administer subsequent injections at least 1 inch from previous injection sites; do not inject into tender, bruised, red, or hard areas. Allow refrigerated suspensions to come to room temperature (up to 30 minutes) prior to administration. Resuspend by inverting the syringe 2 to 3 times and then rolling the syringe between the palms for 30 seconds.

IV: Infuse over 10 to 40 minutes; infusion must be completed within 1 hour of (vial) reconstitution.

If azacitidine suspension comes in contact with the skin, immediately wash with soap and water. If it comes into contact with mucous membranes, flush thoroughly with water.

For the Consumer

Applies to azacitidine: injection powder for suspension

Along with its needed effects, azacitidine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking azacitidine:

More common
  • Black, tarry stools
  • bladder pain
  • bleeding gums
  • blood in the urine or stools
  • cloudy urine
  • body aches or pain
  • burning or stinging of the skin
  • chest pain
  • chills
  • congestion
  • cough
  • difficult breathing
  • difficulty swallowing
  • dizziness
  • ear congestion
  • fast heartbeat
  • fever
  • frequent urge to urinate
  • headache
  • hives, itching, or skin rash
  • hoarseness
  • loss of voice
  • lower back or side pain
  • muscle aches
  • nasal congestion
  • nausea
  • pain or tenderness around the eyes and cheekbones
  • painful cold sores or blisters on the lips, nose, eyes, or genitals
  • painful or difficult urination
  • pain, redness, swelling, tenderness, warmth on the skin
  • pale skin
  • pinpoint red spots on the skin
  • puffiness or swelling of the eyelids or around the eyes, face, lips or tongue
  • rapid heartbeat
  • runny nose
  • sneezing
  • sore throat
  • sores, ulcers, or white spots on lips or in mouth
  • stuffy nose
  • swollen glands
  • tender, swollen glands in the neck
  • tightness in the chest
  • troubled breathing with exertion
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • voice changes
  • vomiting
Less common
  • Change in consciousness
  • convulsions
  • decreased urine
  • drowsiness
  • dry mouth
  • increased thirst
  • irregular heartbeat
  • loss of appetite
  • mood changes
  • muscle pain or cramps
  • numbness or tingling in the hands, feet, or lips
  • loss of consciousness

Get emergency help immediately if any of the following symptoms of overdose occur while taking azacitidine:

Symptoms of overdose
  • Diarrhea
  • nausea
  • vomiting

Some side effects of azacitidine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Acid or sour stomach
  • appetite decreased
  • belching
  • bleeding after defecation
  • bloody nose
  • blurred vision
  • bruise
  • bumps on the skin
  • burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
  • burning while urinating
  • diarrhea
  • difficulty having a bowel movement (stool)
  • difficulty with moving
  • discouragement
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
  • dry skin
  • fainting
  • fear
  • feeling of discomfort or illness
  • feeling of sluggishness
  • feeling sad or empty
  • feeling unusually cold
  • flushing
  • full or bloated feeling or pressure in the stomach
  • heartburn
  • heart murmur
  • indigestion
  • inflamed tissue from infection at the injection site
  • injection site bruising
  • irritability
  • itching at injection site
  • joint pain
  • lack of appetite
  • large, flat, blue or purplish patches in the skin
  • loss of interest or pleasure
  • mouth hemorrhage
  • muscle stiffness
  • nervousness
  • night sweats
  • pain in the joints
  • postnasal drip
  • post procedural hemorrhage
  • redness of the skin
  • shivering
  • small clicking, bubbling, or rattling sounds in the lung when listening with a stethoscope
  • small lumps under the skin
  • small red or purple spots in the mouth
  • soreness or discomfort to touch or pressure on the stomach
  • stomach discomfort upset or pain
  • sweating
  • swelling of abdominal or stomach area
  • swelling of the hands, ankles, feet, or lower legs
  • swelling or inflammation of the mouth
  • swelling with pits or depressions visible on the skin
  • swollen joints
  • tongue ulceration
  • trouble concentrating
  • trouble sleeping
  • uncomfortable swelling around the anus
  • unusual drowsiness
  • unusually warm skin
  • upper abdominal or stomach pain
  • weight loss

Other Comments

Administration Advice:
-Subcutaneous administration: Divide doses greater than 4 mL equally into 2 syringes and inject into 2 separate sites. Rotate sites (thigh, abdomen, upper arm) for each injection; give new injections at least 1 inch/2.5 cm from the previous site and avoid areas that are tender, bruised, red, or hardened.
-IV administration: Administer the total dose over a period of 10 to 40 minutes; complete the administration within 45 to 60 minutes of reconstitution.

Storage Requirements:
-Consult the manufacturer product information.

Reconstitution/Preparation Techniques:
-Consult the manufacturer product information.

IV Compatibility:
-Consult the manufacturer product information.

General:
-Overdosage: There is no known specific antidote.

Monitoring:
-Hematologic: Complete blood counts (prior to treatment initiation and with each cycle); signs and symptoms of bleeding (during treatment)
-Hepatic: Liver chemistries (prior to treatment initiation and with each cycle)
-Metabolic: Signs and symptoms of tumor lysis syndrome (during treatment)
-Renal: Serum creatinine, serum bicarbonate, and electrolytes (prior to treatment initiation and with each cycle)

Patient Advice:
-Avoid potentially dangerous activities such as driving and operating machinery until you know how this drug affects you.

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