Azacitidine – Uses, Dosage, Side Effects, Interactions

Azacitidine is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine. Upon uptake into cells, azacitidine is phosphorylated to the 5-azacytidine monophosphate by uridine–cytidine kinase, then to diphosphate by pyrimidine monophosphate kinases and triphosphate by diphosphate kinases. 5-Azacitidine triphosphate is incorporated into RNA, leading to the disruption of nuclear and cytoplasmic RNA metabolism and inhibition of protein synthesis. 5-Azacytidine diphosphate is reduced to 5-aza-deoxycytidine diphosphate by ribonucleotide reductase. The resultant metabolite is phosphorylated to 5-aza deoxycytidine triphosphate by nucleoside diphosphate kinases. 5-aza deoxycytidine triphosphate is then incorporated into DNA, leading to the inhibition of DNA synthesis. Azacitidine is most toxic during the S-phase of the cell cycle.

Use in Cancer

Azacitidine is approved to treat:

• Acute myeloid leukemia in adults who had a first complete remission? after intensive induction therapy and who are not able to finish intensive curative therapy. This use is approved for the Onureg brand of azacitidine.
• Myelodysplastic syndromes (MDS).
  • It is used in adults with certain types of myelodysplastic syndromes, including chronic? myelomonocytic leukemia.
  • It is used in children aged 1 month and older with newly diagnosed juvenile myelomonocytic leukemia.

  This use is approved for the Vidaza brand of azacitidine.

Azacitidine is also being studied in the treatment of other conditions and types of cancer.

Contraindications

The following conditions are contraindicated with this drug. Check with your physician if you have any of the following:

• anemia?
• decreased blood platelets
• low levels of a type of white blood cell called neutrophils
• severe liver disease
• decreased kidney function
• abnormal liver function tests
• pregnancy
• a patient who is producing milk and breastfeeding
• advanced liver cancer
• Hypersensitivity to the active component or any of the ingredients
• Hypersensitivity to mannitol
• Advanced malignant? hepatic tumors

Dosage

Strengths: 100 mg; 200 mg; 300 mg

Myelodysplastic Syndrome

• FIRST TREATMENT CYCLE: 75 mg/m2 IV or subcutaneously daily for 7 days; repeat cycles every 4 weeks
• SUBSEQUENT CYCLES: After 2 cycles, may increase the 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 if the patient continues to benefit

Acute Myeloid Leukemia

• FIRST TREATMENT CYCLE: 75 mg/m2 IV or subcutaneously daily for 7 days; repeat cycles every 4 weeks
• SUBSEQUENT CYCLES: After 2 cycles, may increase the 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 if the patient continues to benefit

Renal Dose Adjustments

• Unexplained reductions in serum bicarbonate levels to less than 20 mEq/L: Reduce dose by 50% for the next course.
• Unexplained elevations of BUN or serum creatinine: Delay the next cycle until values return to normal or baseline and reduce the dose by 50% for the next course.

Dose Adjustments

Baseline WBC 3 x 10(9)/L or greater, absolute neutrophil count (ANC) 1.5 x 10(9)/L or greater, AND platelets 75 x 10(9)/L or greater:

• ANC less than 0.5 x 10(9)/L and platelets less than 25 x 10(9)/L: Administer 50% of the dose in the next course.
• ANC 0.5 to 1.5 x 10(9)/L and platelets 25 to 50 x 10(9)/L: Administer 67% of the dose in the next course.
• ANC greater than 1.5 x 10(9)/l and platelets greater than 50 x 10(9)/L: Administer 100% of the dose in the next course.

Baseline WBC less than 3 x 10(9)/L, ANC less than 1.5 x 10(9)/L, OR platelets less than 75 x 10(9)/L, base dose adjustments on nadir counts and bone marrow biopsy cellularity at the time of the nadir unless there is a clear improvement in differentiation (percentage of mature granulocytes is higher and ANC is higher than at the onset of that course) at the time of the next cycle, in which case continue the current dose:

• Bone marrow biopsy cellularity (BMBC) of 30% to 60% at the time of nadir: Administer 100% of the dose in the next course.
• BMBC of 15% to 30% at the time of nadir: Administer 50% of the dose in the next course.
• BMBC Less Than 15% at the time of nadir: Administer 33% of the dose in the next course.

BASELINE WBC less than 3 x 10(9)/L, ANC less than 1.5 x 10(9)/L, OR platelets less than 75 x 10(9)/L AND WBC or platelet nadir 50% to 75% decrease in counts from baseline:

• BMBC of 30% to 60% at nadir time: Administer 100% of the dose in the next course.
• BMBC of 15% to 30% at nadir time: Administer 50% of the dose in the next course.
• BMBC Less Than 15% at nadir time: Administer 33% of the dose in the next course.

BASELINE WBC less than 3 x 10(9)/L, ANC less than 1.5 x 10(9)/L, OR platelets less than 75 x 10(9)/L AND WBC or platelet nadir greater than 75% decrease in counts from baseline:

• BMBC of 30% to 60% at nadir time: Administer 75% of the dose in the next course.
• BMBC of 15% to 30% at nadir time: Administer 50% of the dose in the next course.
• BMBC Less Than 15% at nadir time: Administer 33% of the dose in the next course.
• Give the next course 28 days after the start of the preceding course provided that both the WBC and platelet counts are greater than 25% above the nadir and rising.
• At the time of the next cycle, continue the current dose if there is a clear improvement in differentiation (i.e., the percentage of mature granulocytes and ANC is higher than at the onset of that course).
• If a greater than 25% increase above the nadir is not seen by Day 28: Reassess counts every 7 days.
• If 25% increase is not seen by Day 42: Reduce the scheduled dose by 50%.

Side Effects

The Most Common

• nausea
• vomiting
• diarrhea
• constipation
• sores on the mouth or tongue
• hemorrhoids
• stomach pain or tenderness
• heartburn
• loss of appetite
• weight loss
• headache
• dizziness
• weakness
• excessive tiredness
• difficulty falling asleep or staying asleep
• depression
• anxiety
• back, muscle, or joint pain
• muscle cramps
• sweating
• night sweats
• difficulty urinating or pain when urinating
• swelling of the hands, feet, ankles, or lower legs
• dry skin
• redness, pain, bruising, swelling, itching, lump, or change in the skin color in the place where the medication was injected
• severe ongoing nausea, vomiting, or diarrhea;
• redness, swelling, warmth, oozing, or other signs of skin infection;
• low blood cell counts–fever, chills, tiredness, mouth sores, skin sores, easy bruising, unusual bleeding, pale skin, cold hands, and feet, feeling light-headed or short of breath;
• signs of a lung infection–fever, cough with mucus, chest pain, feeling short of breath;
• kidney problems–pain in your lower back, blood in your urine, little or no urination, swelling in your feet or ankles;
• liver problems–upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
• low potassium level–leg cramps, constipation, irregular heartbeats, fluttering in your chest, increased thirst or urination, numbness or tingling, muscle weakness or limp feeling; or
• signs of tumor cell breakdown–tiredness, weakness, muscle cramps, nausea, vomiting, diarrhea, fast or slow heart rate, tingling in your hands and feet or around your mouth.

More Common

• pale skin
• shortness of breath
• fast heartbeat
• chest pain
• cough
• unusual bruising or bleeding
• nosebleeds
• bleeding gums
• small red or purple dots on the skin
• sore throat, fever, chills, or other signs of infection
• hives
• rash
• itching
• difficulty breathing or swallowing

Rare

• constipation
• decreased appetite
• diarrhea
• dizziness
• gas
• joint, back, arm, or leg pain
• nausea
• stomach pain
• tiredness
• vomiting
• weakness
• anxiety
• fainting
• increased frequency of infection symptoms (symptoms may include fever or chills, severe diarrhea, shortness of breath, prolonged dizziness, headache, stiff neck, weight loss, or listlessness)
• signs of anemia (low red blood cells; e.g., dizziness, pale skin, unusual tiredness or weakness, shortness of breath)
• signs of clotting problems (e.g., unusual nosebleeds, bruising, blood in urine, coughing blood, bleeding gums, cuts that don’t stop bleeding)
• symptoms of an upper respiratory tract infection (colds or cases of flu; runny or stuffy nose, sore throat, cough, nasal congestion, body aches, headache, sneezing, fever, general feeling of being unwell)
• symptoms of a urinary tract infection (e.g. pain when urinating, urinating more often than usual, low back or flank pain)
• symptoms of a lung infection (e.g., chest pain when you breathe or cough, confusion, cough producing phlegm, nausea, shortness of breath)

Drug Interactions

Pregnancy and Lactation

Pregnancy Category D

Pregnancy

Azacitidine may cause harm to the developing baby if it is taken by the mother during pregnancy or it is taken by either the man or the woman at the time of conception. If you or your partner become pregnant while taking this medication, contact your doctor immediately. Effective birth control should be practiced by both men and women while using this medication and for at least 6 months after taking the last dose.

Lactation

Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy. It might be possible to breastfeed safely during intermittent azacitidine therapy with an appropriate period of breastfeeding abstinence; the manufacturer recommends an abstinence period of 1 week after the last dose. Avoid breastfeeding while taking azacitidine and for at least 1 week after taking your last dose of azacitidine. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breast milk. Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant.

References