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

It is used to treat the following subtypes of MDS (Myelodysplastic Syndromes) as per the FAB classification:

• 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.

As an off-label medicine, it may be used to treat AML in frail patients who can not tolerate conventional chemotherapy and those requiring low-intensity treatment.

Azacitidine (Vidaza) Dose in Adults:

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

• 75 mg/m² /day administered intravenously or subQ for 7 days.
• The same dose is then repeated after every 4 weeks for 7 days.
• The dose may be increased to 100 mg/m²/day after 2 cycles if the response is minimal and the patient is tolerating it.
• A minimum treatment of 4 to 6 cycles is given. The further decision to continue the treatment is based on the response and side effects.

Off-label schedules :

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

or

• 50 mg/m²/day for 5 days (from Mon-Fri),
• Then 2 days rest (Sat and Sun),
• Then 50 mg/m² /day for 5 days (Mon-Fri)
• Repeat the cycle every 28 days

or

• 75 mg/m² /day for 5 days (Mon-Fri),
•  Then repeat the cycle every 28 days

Off-Lable Dosage used in the treatment of Acute myeloid leukemia:

• 75 mg/m² /day sub Q 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 falls to less than <20 mEq/L then reduce the dose by 50% for the next treatment course.

Azacitidine Dose in Children

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

• Children ≥2 years and Adolescents:

  • 75 mg/m² /dose sub Q once daily for 1 week

Dosing adjustment for toxicity:

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

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

  • Administer half the 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 the 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 decreased by 50% to 75% from standard and bone marrow biopsy cellularity of 30% to 60%:
  • Administer full dose during the next treatment course
• WBC or platelet decreased by 50% to 75% from standard and bone marrow biopsy cellularity of 15% to 30%:
  • Administer half the dose during the next treatment course
• WBC or platelet decreased more than 75% from baseline and bone marrow biopsy cellularity of 30% to 60%:
  • Administer 2/3rd of the dose during the next treatment course
• WBC or platelet decreased more than 75% from baseline and bone marrow biopsy cellularity 15% to 30%:
  • Administer half the dose during the next treatment

• WBC or platelet decreased by more than 75% from baseline and bone marrow biopsy cellularity less than 15%:

  • Administer 1/3rd of the dose during the next treatment course

Withhold the next course of chemotherapy. May administer the next dose after 4 weeks of the last dose and when the number of WBCs and platelets exceeds by 25%.

If the rise in counts is less than 25%, may wait for one more week. However, if by day 42 since the last dose, the counts are still low (not risen by 25%, administer half the recommended dose.

Electrolyte disturbances:

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

Azacitidine (Vidaza) pregnancy Risk factor: D

• Azacitidine can harm the fetus if administered to pregnant women. A pregnancy test is recommended before treatment initiation in women of childbearing age.
• Both men and women should be advised on effective contraception during the treatment.

Use of Azacitidine (Vidaza), during breastfeeding

• The manufacturer does not recommend breastfeeding due to the potential for serious adverse reactions in breastfed infants. However, it is not known if the drug enters human breast milk or not.

Azacitidine (Vidaza) dose in Renal disease:

Renal impairment at baseline:

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

  • No dosage adjustment is required.

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

  • Monitor for toxicity. However, no dosage adjustment is required for cycle 1

Renal toxicity during treatment:

• Unexplained increases in BUN or serum creatinine:

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

Vidaza (Azacitidine) dose in Liver disease:

• No dosage adjustment is given in the manufacturer’s labeling.
• It 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 the 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 reactions at the injection sites:

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

• 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

Contraindications to Vidaza (Azacitidine) Include:

• Allergic reactions to azacitidine, mannitol, or any other component of the formulation.
• Advanced liver 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 the 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 and hence those with impaired renal functions should be closely monitored.
• Tumor lysis syndrome
  • It can lead to serious or fatal tumor lysis syndrome (TLS).
  • TLS has been reported despite 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
• serum electrolytes (bicarbonate)
• CBC with differential and platelets
• renal function (BUN and serum creatinine) at baseline, before each cycle, and more frequently if indicated.
• hematologic response to treatment
• side effects such as 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 infusing between 10 and 40 minutes
• Infusion must be completed within 60 mins of 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 is used as an anticancer drug because of its ability to promote the hypomethylation of DNA.
• 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:

• It does not cross the blood-brain barrier

Metabolism:

• Via liver by 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:

• 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 are available in Pakistan.