azacitidine

a-za-SYE-ti-deen

Therapeutic Classification: antineoplastics

Pharmacologic Classification: nucleoside analogues

High Alert

IV: SC: Myelodysplastic syndromes including:
- Some refractory anemias,
- Chronic myelomonocytic leukemia.
IV: Newly diagnosed juvenile myelomonocytic leukemia.
PO: Continued treatment of patients with acute myeloid leukemia who achieved first complete remission or complete remission with incomplete blood count recovery following intensive induction chemotherapy and are not able to complete intensive curative therapy.

Inhibits DNA synthesis.

Therapeutic effects:

Death of rapidly replicating cells, particularly malignant ones.

Absorption: IV administration results in complete bioavailability; 89% absorbed following SUBQ administration; bioavailability of oral administration 11% relative to SUBQ administration.

Distribution: Widely distributed to extravascular tissues.

Metabolism/Excretion: 85% excreted in urine; some hepatic metabolism may occur. Less than 1% fecal elimination.

Half-Life: IV or SUBQ: 4 hr; Oral: 30 min.

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
SUBQ/IV	unknown	30 min	unknown
PO	unknown	1 hr	unknown

Contraindicated in:

Hypersensitivity;
Advanced malignant hepatic tumors (IV or SUBQ only);
Myelodysplastic syndromes (oral only) (↑ risk of mortality);
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Renal impairment;
Hepatic impairment;
Rep: Women of reproductive potential and men with female partners of reproductive potential;
Pedi: Safety and effectiveness not established in children 18 yr (PO or SUBQ) or 1 mo (IV);
Geri: risk of toxicity in older adults due to age-related in renal function.

Derm: acute febrile neutrophilic dermatosis, ecchymosis

F and E: hypokalemia

GI: abdominal pain, constipation, ↓appetite, diarrhea, nausea, vomiting, HEPATOTOXICITY

GU: ↓fertility, NEPHROTOXICITY, renal tubular acidosis

Hemat: anemia, neutropenia, thrombocytopenia

Local: injection site erythema

MS: arthralgia

Neuro: dizziness, fatigue

Misc: fever, HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS), TUMOR LYSIS SYNDROME

Drug-drug:

Additive bone marrow depression may occur with other antineoplastics.

Do NOT interchange/substitute parenteral product with oral formulation.

Myelodysplastic Syndromes

SC IV (Adults ): 75 mg/m²once daily on Days 1–7 of each 28-day cycle; if no beneficial effect occurs after two cycles and if no toxicity other than nausea or vomiting has occurred, may ↑ to 100 mg/m² once daily on Days 1–7 of each 28-day cycle. Continue for as long as patient benefits (minimum of 4–6 cycles recommended).

Juvenile Myelomonocytic Leukemia

IV (Children ≥1 yr and ≥10 kg): 75 mg/m²once daily on Days 1–7 of each 28-day cycle. Continue for at least 3 cycles and a maximum of 6 cycles (as long as patient continues to benefit).
IV (Children ≥1 mo–<1 yr or <10 kg): 2.5 mg/kg once daily on Days 1–7 of each 28-day cycle. Continue for at least 3 cycles and a maximum of 6 cycles (as long as patient continues to benefit).

Acute Myeloid Leukemia

PO (Adults ): 300 mg once daily on Days 1–14 of each 28-day cycle; continue until disease progression or unacceptable toxicity.

(Generic available)

Lyophilized powder for injection: 100 mg/vial
Tablets (Onureg): 200 mg; 300 mg

Monitor for bone marrow depression. Assess for bleeding (bleeding gums, bruising, petechiae, stools, urine, emesis) and avoid IM injections and taking rectal temperatures if platelet count is low. Apply pressure to venipuncture sites for 10 min. Assess for signs of infection during neutropenia. Anemia may occur. Monitor for increased fatigue, dyspnea, and orthostatic hypotension.
Assess patient for nausea and vomiting during therapy. Premedicate patient before each dose. For PO doses: If Grade 3 or 4 nausea or vomiting of diarrhea occurs: Hold dose until nausea and vomiting has resolved to ≤Grade 1. If symptoms reoccur, hold dose until resolved to ≤Grade 1. Resume at reduced dose of 200 mg. If a symptoms continue after dose reduction, reduce the treatment duration by 7 days. If the symptoms continue or reoccur after dose and schedule reduction, discontinue azacitidine.
Monitor for signs of anaphylaxis (facial edema, wheezing, dizziness, fainting, tachycardia, hypotension). Discontinue medication immediately and report symptoms. Epinephrine and resuscitation equipment should be readily available.

Lab Test Considerations:

Verify negative pregnancy status prior to starting therapy.
Monitor CBC with differential and platelet count prior to each dosing cycle. For PO doses: If ANC <0.5 x 10⁹/L on Day 1 of a cycle, do not administer azacitidine until ANC ≥0.5 x 10⁹/L. If neutrophils <1 x 10⁹/L and 1st occurrence, hold therapy until neutrophils ≥1 x 10⁹/L. If occurs in 2 consecutive cycles, hold therapy until neutrophils ≥1 x 10⁹/L, then resume at reduced dose of 200 mg. If febrile neutropenia continues after dose reduction, reduce treatment duration by 7 days. If febrile neutropenia reoccurs after dose and schedule reduction, discontinue azacitidine. If platelets <50 x 10⁹/L and 1st occurrence, hold therapy until platelets ≥50 x 10⁹/L. If occurs in 2 consecutive cycles,hold therapy until platelets ≥50 x 10⁹/L, then resume at reduced dose of 200 mg. If thrombocytopenia with bleeding continues after dose reduction, reduce the treatment duration by 7 days. If thrombocytopenia with bleeding reoccurs after dose and schedule reduction, discontinue azacitidine. For IV or SUBQ doses:If baseline WBC ≥3 x 10⁹/L, ANC ≥1.5 x 10⁹/L, and platelets ≥75 x 10⁹/L, then dose is adjusted based on nadir counts for each cycle. If ANC <0.5 x 10⁹ and platelets <25 x 10⁹, then ↓ dose by 50%. If ANC is 0.5–1.5 x 10⁹ and platelets are 25–50 x 10⁹, then ↓ dose to 67% in next course. If ANC >1.5 x 10⁹ and platelets >50 x 10⁹, then 100% of dose can be given in subsequent cycle. If baseline WBC <3 x 10⁹/L, ANC <1.5 x 10⁹/L, or platelets <75 x 10⁹/L, adjust dose based on nadir counts and bone marrow biopsy cellularity at time of nadir for each cycle. If WBC or platelet nadir decrease 50–75% in counts from baseline and bone marrow biopsy cellularity is 30–60% at time of nadir, give 100% of dose next course. If WBC or platelet nadir decrease 50–75% in counts from baseline and bone marrow biopsy cellularity is 15–30% at time of nadir, give 50% of dose next course. If WBC or platelet nadir decrease 50–75% in counts from baseline and bone marrow biopsy cellularity is <15% at time of nadir, give 33% of dose next course. If WBC or platelet nadir decrease >75% in counts from baseline and bone marrow biopsy cellularity is 30–60% at time of nadir, give 75% of dose next course. If WBC or platelet nadir decrease >75% in counts from baseline and bone marrow biopsy cellularity is 15–30% at time of nadir, give 50% of dose next course. If WBC or platelet nadir decrease >75% in counts from baseline and bone marrow biopsy cellularity is <15% at time of nadir, give 33% of dose next course. Administer next course 28 days after start of preceding course, if both WBC and platelet counts are >25% above nadir and rising. If >25% ↑ above nadir is not seen by Day 28, reassess counts every 7 days. If a 25% increase is not seen by Day 42, reduce scheduled dose by 50%.
- Obtain liver chemistries prior to initiation of therapy and before each cycle.
- Monitor renal function with serum creatinine and electrolytes prior to starting therapy and before each cycle. If serum bicarbonate <20 mEq/L,↓ dose by 50% in next course. If unexplained ↑ in BUN or serum creatinine occur, delay next cycle until values return to normal or baseline and ↓ dose by 50% in next course.
- May cause hypokalemia.

Premedicate for nausea and vomiting before each dose. For PO doses, administer antiemetic 30 min before each cycle for first 2 cycles; may be omitted if no nausea and vomiting occurs.
Do not confuse azacitidine with azathioprine.
Do not substitute PO form for IV or SUBQ azacitidine; may result in fatal adverse reactions.
PO: Administer once daily at the same time each day without regard to food on Days 1–14 of each 28-day cycle. DNC: Swallow tablet whole; do not crush, break, or chew.
Solution should be prepared in a biologic cabinet. Wear gloves, gown, and mask while handling medication. If powder or solution comes in contact with skin or mucosa, wash thoroughly with soap and water. Discard equipment in specially designated containers.
SC: Reconstitution: Reconstitute by adding 4 mL of sterile water for injection slowly into the azacitidine vial. Concentration: 25 mg/mL. Vigorously shake or roll until suspension is uniform. Suspension will be cloudy. For Immediate SUBQ Administration:Retention in needle and vial may limit drawing all suspension from vial. Stable for up to 1 hr at room temperature; must be administered within 1 hr of reconstitution. For Delayed SUBQ Administration: Reconstituted solution may be kept in vial or syringe. Retention in needle and vial may limit drawing all suspension from vial. Refrigerate immediately. If prepared with room temperature water for injection, may refrigerate for up to 8 hr. If prepared with refrigerated water for injection, may refrigerate for up to 22 hr. Allow suspension to come to room temperature for 30 min before administration.
- Divide doses greater than 4 mL equally into 2 syringes and administer into separate sites. Rotate sites (thigh, abdomen, upper arm) with new injections at least one inch from old site. Do not use site that is bruised, tender, red, or hard. Invert syringe 2–3 times and roll syringe gently between palms immediately prior to administration to mix suspension. Discard unused portion.

IV Administration:

Intermittent Infusion: Reconstitution: Reconstitute each vial with 10 mL sterile water for injection. Shake vigorously or roll vial until all solids are dissolved. Solution should be clear; do not administer solutions that are not clear or contain particulate matter. Concentration: 10 mg/mL.Diluent: Withdraw solution from required number of vials and inject into 50–100 mL of 0.9% NaCl or LR. Solution is stable for 1 hr at room temperature.
Rate: Infuse over 10–40 min. Infusion must be completed within 1 hr of reconstitution. Discard unused portions.

Instruct patient to notify health care professional promptly if fever; chills; cough; body aches; unusual headaches; hoarseness; sore throat; signs of infection; lower back or side pain; painful or difficult urination; bleeding gums; bruising; petechiae; blood in stools, urine, or emesis; increased fatigue or weakness; dyspnea; or orthostatic hypotension occurs. Caution patient to avoid crowds and persons with known infections. Instruct patient to use soft toothbrush and electric razor and to avoid falls. Caution patient not to drink alcoholic beverages or take medication containing aspirin or NSAIDs; may precipitate gastric bleeding.
May cause dizziness. Caution patient to avoid driving or other activities requiring alertness until response to medication is known.
Advise patient to notify health care professional if they have underlying liver or renal disease.
Rep: May cause fetal harm. Advise females of reproductive potential to use effective contraception during and for at least 6 mo after last dose and to avoid breastfeeding during and for 1 wk after last dose. Advise males with female partners of reproductive potential to use effective contraception during and for at least 3 mo after last dose. May impair male and female fertility. Advise female patient to notify health care professional promptly if pregnancy is planned or suspected.
PO: Instruct patient to take azacitidine as directed at the same time each day. Take missed doses as soon as remembered in same day; do not take 2 doses in dame day. Advise patient to read Patient Information before starting therapy and with each Rx refill in case of changes.

Improved bone marrow and blood counts.

Onureg

Vidaza

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