Vidaza (Azacitidine) promotes hypomethylation of the DNA, resulting in the restoration of normal DNA and gene differentiation.

It is used to treat the following conditions:

• It is used in the treatment of myelodysplastic syndromes (MDS) in patients with French-American-British (FAB) classification subtypes as follows:

  • Refractory anemia

  • Refractory anemia with ringed sideroblasts (if coexisting with neutropenia or thrombocytopenia or requiring  transfusions)

  • Refractory anemia with excess blasts,

  • Refractory anemia with excess blasts in transformation

  • Chronic myelomonocytic leukemia.

Off Label Usage of Azacitidine (vidaza) in Adults:

• Acute myeloid leukemia (AML) in patients requiring low-intensity traetment

Azacitidine Dose in Adults

Vidaza dosage in the treatment of Myelodysplastic syndromes (MDS):

• In initial cycle , 75 mg/m² /day IV or subQis given for 7 days.
• Then in subsequent cycles, 75 mg/m²/day for 7 days every 4 weeks
• The dose can be increased to 100 mg/m /day if no favorable results after 2 cycles and no toxicity other than nausea and vomiting have occurred.
• Patients should be given treatment for a minimum of 4 to 6 cycles then it may be continued as long as the patient continues to benefit.

Off-label schedules :

• Subcutaneous: 75 mg/m² /day for 5 days (Mon-Fri),
• Followed by 2 days rest (Sat, Sun),
• Then 75 mg/m² /day for 2 days (Mon, Tues);
• Repeat cycle every 28 days
•                                          or
• 50 mg/m /day for 5 days (Mon-Fri),
• Then 2 days rest (Sat, Sun),
• Then 50 mg/m² /day for 5 days (Mon-Fri)
• Repeat cycle every 28 days
•                                          or
• 75 mg/m² /day for 5 days (Mon-Fri),
•  Then repeat cycle every 28 days

Off label Dosage used in the treatment of Acute myeloid leukemia:

• • 75 mg/m² /day subQ for 7 days every 4 weeks for at least 6 cycles
  • Then treatment may be continued as long as the patient continues to improve or until disease progression or unwanted toxicity
  • Dose reductions and/or interruptions in therapy may be required for hematologic toxicity.

• Dosage adjustment according to serum electrolytes:

  • If serum bicarbonate becomes less than <20 mEq/L then reduce dose by 50% for next treatment course.

Azacitidine Dose in Childrens

Vidaza dose in the treatment of Acute myeloid leukemia (AML): 

• Children ≥2 years and Adolescents:

  • 75 mg/m² /dose subQ once daily for 1 week

• Dosing Choices variable:

  • Children and Adolescents:
    • 300 mg/m² /dose I/V OD daily for 2 consecutive days is widely used for induction and intensive consolidation therapy in various combinations in newly diagnosed patients.

• Dosing adjustment for toxicity:

  • The presented dosing adjustments are based on practice in adult patients.

  • Hematologic toxicity:

    • Adult:

    • For baseline WBC ≥3,000/mm , ANC ≥1,500/mm , and platelets ≥75,000/mm³:

      • If ANC is less than 500/mm³ or platelets less than 25,000/mm³:

        • Administer half dose during the next treatment course

      • If ANC is 500/mm³- 1,500/mm³ or platelets 25,000 - 50,000/mm³:

        • Administer 2/3 rd of dose during the next treatment course

      • If ANC is greater than 1,500/mm³ or platelets  more than 50,000/mm³:

        • Administer full dose during next treatment course

      • For baseline WBC <3,000/mm³ , ANC <1,500/mm³ , or platelets <75,000/mm³:

        • Adjust dose according to nadir counts and bone marrow biopsy cellularity at the time of nadir, unless a significant improvement in differentiation at the time of the next treatment cycle
      • WBC or platelet nadir decreased 50% to 75% from standard and bone marrow biopsy cellularity at time of nadir 30% to 60%:
        • Administer full dose during the next treatment course
      • WBC or platelet nadir decreased 50% to 75% from standard and bone marrow biopsy cellularity at time of nadir 15% to 30%:
        • Administer half dose during the next treatment course
      • WBC or platelet nadir decreased more than 75% from baseline and bone marrow biopsy cellularity at time of nadir 30% to 60%:
        • Administer 2/3rd of dose during the next treatment course
      • WBC or platelet nadir decreased more than 75% from baseline and bone marrow biopsy cellularity at time of nadir 15% to 30%:
        • Administer half dose during the next treatment

      • WBC or platelet nadir decreased more than 75% from baseline and bone marrow biopsy cellularity at time of nadir less than 15%:

        • Administer 1/3rd of dose during the next treatment course
• If a nadir defined above happens, give the next course of therapy 4 weeks after the beginning of the previous course as long as the number of WBCs and platelets is greater than 25% above the nadir and increasing.
• If day 28 does not see a rise of more than 25 percent above the nadir, reassess counts every 1 week.
• If day 42 does not see an increase of 25 percent, give half a scheduled dose.

Electrolyte disturbances:

• • If serum bicarbonate decreases to less than 20 mEq/L then reduce dose by 50% for next scheduled course.

Dose in  pregnancy and lectation :

Azacitidine (Vidaza) pregnancy Risk factor: D

• In animal reproduction studies, adverse events were observed.
• Azacitidine's mechanism of action can cause fetal harm when administered during pregnancy.
• Women with childbearing potential need to be advised to not get pregnant during treatment and to verify their pregnancy status before starting therapy.
• A male should also be warned not to father a child while receiving azacitidine therapy.
• Effective contraception should be used by males during therapy.

Use of Azacitidine (Vidaza), during breastfeeding

• It is not known if azacitidine can be found in breast milk.
• The manufacturer does not recommend breastfeeding due to the potential for serious adverse reactions in breastfed infants.

Azacitidine (Vidaza) dose in Renal disease:

Renal impairment at baseline:

• Mild to moderate impairment (CrCl ≥30 mL/minute):

  • No dosage adjustment required.

• Severe impairment (CrCl <30 mL/minute):

  • No dosage adjustment required for cycle 1
  • azacitidine and its metabolites are excreted renally
  • Look closely for toxicity.

Renal toxicity during treatment:

• Unexplained increases in BUN or serum creatinine:

  • Postpone next cycle until values reach baseline or normal, then reduce dose by half for next treatment course.

Vidaza (Azacitidine) dose in Liver disease:

• No dosage adjustment is given in the manufacturer’s labeling.
• Its use is contraindicated in patients with advanced malignant hepatic tumors.

Common Side Effects of Vidaza (Azacitidine) Include:

• Cardiovascular:

  • Peripheral Edema
  • Chest Pain

• Central Nervous System:

  • Fatigue
  • Rigors
  • Headache
  • Dizziness
  • Anxiety
  • Depression
  • Malaise
  • Pain
  • Insomnia

• Dermatologic:

  • Erythema
  • Pallor
  • Skin Lesion
  • Skin Rash
  • Pruritus
  • Diaphoresis

• Endocrine & Metabolic:

  • Weight Loss
  • Pitting Edema
  • Hypokalemia

• Gastrointestinal:

  • Nausea
  • Vomiting
  • Constipation
  • Diarrhea
  • Anorexia
  • Abdominal Pain
  • Abdominal Tenderness

• Hematologic & Oncologic:

  • Thrombocytopenia
  • Anemia
  • Neutropenia
  • Leukopenia
  • Bruise
  • Petechia
  • Febrile Neutropenia
  • Bone Marrow Depression

• Local:

  • Injection Site Reactions :
  • Erythema
  • Pain
  • Bruising

• Neuromuscular & Skeletal:

  • Weakness
  • Arthralgia
  • Limb Pain
  • Back Pain
  • Myalgia

• Respiratory:

  • Cough
  • Dyspnea
  • Pharyngitis
  • Epistaxis
  • Nasopharyngitis
  • Upper Respiratory Infection
  • Pneumonia
  • Rales

• Miscellaneous:

  • Fever

Less Common Side Effects of Vidaza (Azacitidine) Include:

• Cardiovascular:

  • Heart Murmur
  • Tachycardia
  • Hypertension
  • Hypotension
  • Syncope
  • Chest Wall Pain

• Central Nervous System:

  • Lethargy
  • Hypoesthesia
  • Postoperative Pain

• Dermatologic:

  • Night Sweats
  • Cellulitis
  • Rash At Injection Site
  • Urticaria
  • Skin Nodules
  • Xeroderma

• Gastrointestinal:

  • Gingival Hemorrhage
  • Stomatitis
  • Hemorrhoids
  • Dyspepsia
  • Abdominal Distention
  • Loose Stools
  • Dysphagia
  • Tongue Ulcer

• Genitourinary:

  • Urinary Tract Infection
  • Dysuria
  • Hematuria

• Hematologic & Oncologic:

  • Lymphadenopathy
  • Hematoma
  • Oral Mucosal Petechiae
  • Postprocedural Hemorrhage
  • Oral Hemorrhage

• Hypersensitivity:

  • Transfusion Reaction

• Infection:

  • Herpes Simplex Infection

• Local:

  • Itching At Injection Site
  • Hematoma At Injection Site
  • Induration At Injection Site
  • Injection Site Granuloma
  • Skin Discoloration At Injection Site
  • Swelling At Injection Site

• Neuromuscular & Skeletal:

  • Muscle Cramps

• Respiratory:

  • Rhinorrhea
  • Wheezing
  • Abnormal Breath Sounds
  • Nasal Congestion
  • Pharyngolaryngeal Pain
  • Pleural Effusion
  • Post-Nasal Drip
  • Rhinitis
  • Rhonchi
  • Atelectasis
  • Sinusitis

• Miscellaneous:

  • Lymphadenopathy
  • Herpes Simplex
  • Night Sweats
  • Transfusion Reaction
  • Mouth Hemorrhage

Contraindication to Vidaza (Azacitidine) Include:

• Hypersensitivity to azacitidine or mannitol, and any component of the formulation.
• Advanced malignant hepatic cancers

Warnings and precautions

• Suppression of bone marrow
  • Anemia, thrombocytopenia and neutropenia are all very common
  • It can cause treatment delays or dosage reductions.
  • At a minimum, monitor blood counts prior to each cycle and when clinically indicated.
  • Based on the hematologic response and nadir counts, adjust dose for the next cycle.
• Hepatotoxicity
  • Patients with preexisting hepatic impairments can be exposed to it.
  • Patients with metastatic disease and extensive tumor burden have been known to experience coma.
  • Patients with advanced malignant liver tumors are not advised to use this medication.
  • Before each cycle begins, monitor liver function.
• Gastrointestinal toxicities:
  • Azacitidine has moderate emetic properties.
  • Antiemetics can be used to prevent nausea or vomiting.
• Reactions at the injection site:
  • Subcutaneous administration can often cause injection site reactions.
• Nephrotoxicity
  • When intravenous Azacitidine is used with other chemotherapy agents, it has been associated with renal toxicities such as serum creatinine and renal tubular acidosis.
  • Before each cycle, and prior to therapy initiation, test serum creatinine.
  • Reduce or withhold the dose if there are unexplained drops in serum bicarbonate 20 mg/L, or if there are elevations in serum creatinine or BUN.
  • Patients with kidney impairment are more at risk of renal toxicity.
  • Patients with severe renal dysfunction should be monitored for toxicities (azacitidine or metabolites excreted renally).
• Tumor lysis syndrome
  • It can lead to serious or fatal tumor lysis syndrome (TLS).
  • TLS has been reported in patients who have received anti-hyperuricemic therapy (eg allopurinol).
  • TLS risk assessment at baseline. Monitor for symptoms of TLS and treat accordingly.

Azacitidine: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitor:

• liver function tests
• electrolytes
• CBC with differential and platelets
• renal function (BUN and serum creatinine) at baseline, before each cycle, and more frequently if indicated.
• hematologic response
• nausea/vomiting
• injection site reactions.

How to administer Azacitidine (Vidaza)?

• Azacitidine has a moderate emetic potency.
• To prevent nausea and vomiting, antiemetics should be used.

Intravenous:

• Allow to infuse for between 10 and 40 minutes
• Infusion must be completed within 60 mins of (vial), reconstitution.

Administration of SubQ:

• According to the manufacturer, it is recommended that you divide doses that require more than one vial into two syringes so that they can be injected into two different sites.
• Rotate injection sites (thighs, abdomen, and upper arms)
• Next injections should be at least 1 inch away from the previous injection sites
• Do not inject into areas that are tender, bruised or red.
• Before administering, allow refrigerated suspensions (up to 30 min) to reach room temperature.
• Continue to roll the syringe between your palms, until it becomes cloudy.
• Wash your skin immediately if azacitidine suspension comes into contact with it.
• Flush it with water if it comes in contact with mucous membranes

Mechanism of action of Azacitidine (Vidaza):

• Azacitidine's ability promote hypomethylation of DNA can lead to antineoplastic effects.
• This allows normal gene differentiation and proliferation to be restored.
• Azacitidine can also cause direct toxicity to abnormal hematopoietic bone marrow cells.

Absorption: SubQ:

• It is rapid and complete

Distribution: V :

• IV: 76 ± 26 L
• It does not cross the blood-brain barrier

Metabolism:

• Hepatic; hydrolysis to several metabolites

Bioavailability: SubQ:

• Almost 89%

Half-life elimination: Intravenous, SubQ:

• almost 4 hours

Time to peak plasma concentration after SubQ administration:

• 30 minutes

Excretion: By  Urine (50% to 85%) & feces (<1%)  

International Brands of Azacitidine:

• Azadine
• Celazadine
• NAT-AzaCITIDine
• REDDY-Azacitidine
• Vidaza
• Xpreza 100

Azacitidine Brands in Pakistan:

No Brands available in Pakistan