Page 1013 - Hematology_ Basic Principles and Practice ( PDFDrive )

896 Part VII Hematologic Malignancies

inactive ingredients corn and potato starch, lactose, magnesium SC administration may be stored for up to 1 hour at 25°C (77°F) or
stearate, and stearic acid. An IV preparation containing 500 mg of for up to 8 hours between 2°C and 8°C (36°F and 46°F).To provide
6-MP per vial is available for investigational use. a homogeneous suspension, the contents of the dosing syringe must
be resuspended immediately before administration. To resuspend,
Toxic Effects: The major dose-limiting toxicity of 6-MP is myelo- vigorously roll the syringe between the palms until a uniform, cloudy
suppression. This is dose related and is manifested by leukopenia, suspension is achieved. When given IV, reconstitute each vial with
thrombocytopenia, and anemia. The hematologic effects of 6-MP 10 mL of sterile water for injection. Vigorously shake or roll the vial
may be delayed, so it is important to withdraw the medication until all solids are dissolved. Withdraw the required amount of solu-
temporarily at the first sign of unusual hematologic toxicity. Individu- tion to deliver the desired dose and inject into a 50–100-mL infusion
als with an inherited disorder of thiopurine methyltransferase bag of either 0.9% sodium chloride injection or lactated Ringer
deficiency may be particularly susceptible to 6-MP–mediated hema- solution.
topoietic suppression. Other toxicities include hepatotoxicity (elevated
liver function test results, cholestasis, hepatic necrosis, ascites), Toxic Effects: The major toxicity of 5′-azacitidine has been leu-
nausea, vomiting, mucositis, fever, rash, and diarrhea. The hepato- kopenia and, to a lesser extent, thrombocytopenia. Nausea and
toxicity, which occurs in 10%–40% of patients, requires close moni- vomiting, which are often refractory to standard antiemetic therapy,
toring and discontinuation of therapy until recovery occurs. Patients have also been encountered, most frequently in patients receiving
receiving 6-MP uniformly experience immunosuppression. bolus infusions. Gastrointestinal toxicity is ameliorated by adminis-
tering 5′-azacitidine as a continuous infusion. Other potential side
Potential Drug Interactions: Allopurinol, an inhibitor of xan- effects include diarrhea, fever, hepatotoxicity (most frequently in
thine oxidase, significantly reduces the catabolism of 6-MP when the patients with preexisting hepatic disease), neuromuscular toxicity,
latter is given orally, leading to major increases in plasma concentra- rash, and hypotension.
tions. Allopurinol does not alter the pharmacokinetics of IV 6-MP,
presumably because of the absence of first-pass metabolism of 6-MP Drug Interactions: None reported.
when administered by this route. When administered in conjunction
with allopurinol, the dose of 6-MP should be reduced by one-third Therapeutic Indications in Hematology: 5′-Azacitidine is
to one-fourth. Increased toxicity has been reported in patients receiv- primarily used in the treatment of refractory AML, with response
ing concurrent 6-MP and trimethoprim–sulfamethoxazole. 6-MP rates ranging from 17% to 30% when used as a single agent.
may also modify the effects of warfarin. 5′-Azacitidine has also yielded clinical responses in a subset of patients
with the MDS when administered as a low-dose continuous infusion.
Therapeutic Indications in Hematology: The major use for In early trials, low-dose 5′-azacytidine increased fetal hemoglobin
6-MP is in the maintenance phase of treatment for ALL. 6-MP has levels in some patients with sickle cell anemia and thalassemia;
also been used in the treatment of patients with immune thrombo- however, its mutagenic potential has limited the use of this agent in
cytopenia purpura or autoimmune hemolytic anemia refractory to all nonmalignant conditions.
other forms of therapy.
Decitabine
5′-Azacitidine
Chemistry and Mechanism of Action: Decitabine is a synthetic
Chemistry and Mechanism of Action: 5′-Azacitidine is an nucleoside analog of 2′-deoxycytidine, a cytotoxic S-phase pyrimidine
analog of the nucleoside cytidine, differing from the parent com- analogue that induces hypomethylation of DNA at concentrations
pound by virtue of the presence of nitrogen at the 5′ position of the that do not cause major suppression of DNA synthesis. It also causes
heterocyclic ring. 5′-Azacytidine is transported across the cell mem- cellular differentiation or apoptosis. This is accomplished by intracel-
brane by facilitated nucleoside diffusion and is converted to its lular phosphorylation of decitabine to its triphosphate form, which
nucleotide monophosphate form, 5′-aza-CMP, by the pyrimidine is incorporated into DNA and blocks methylation of newly synthe-
salvage pathway enzyme uridine–cytidine kinase. 5′-Azacytidine is sized DNA by binding to DNA methyltransferase. Nonproliferating
also a substrate for the degradative enzyme CDD. It is ultimately cells seem relatively insensitive to decitabine.
converted to its lethal derivative, 5′-aza-CTP, which is incorporated
into RNA, and to a lesser extent, DNA. The lethal actions of Absorption, Fate, and Excretion: Decitabine is widely distrib-
5′-azacytidine are believed to result from its ability to interfere with uted with less than 1% protein binding and is tolerated after SC
protein synthesis through disruption of RNA processing. The chemi- injection. There is some CNS penetration after subcutaneous injec-
cal instability of the 5′-azacitidine ring structure is also believed to tion with cerebrospinal fluid concentrations in patients with menin-
contribute to the cytotoxicity of this compound. geal leukemia that were approximately 20% of corresponding
steady-state plasma levels. The mean half-life is 0.5–0.6 hours. The
Absorption, Fate, and Excretion: The drug distributes into a route of metabolism appears to be deamination by CDD, principally
volume corresponding to the total body water after IV administration found in the liver but also in granulocytes, the intestinal epithelium,
and is also well absorbed after SC injection. and whole blood.
It is extensively deaminated in the plasma and liver and displays
minimal plasma binding. Peak plasma concentrations after IV injec- Preparation and Administration: Decitabine is available in
tion approximate 1.0 mM. The initial half-life of 5′-azacitidine (or 50-mg vials, which are reconstituted with 10 mL of sterile water for
its metabolites) is approximately 4 hours, although the drug is rapidly injection (USP); upon reconstitution, each milliliter contains
converted to various derivatives within minutes of administration. approximately 5.0 mg of decitabine at a pH of 6.7–7.3. Immediately
There is minimal cerebrospinal fluid penetrance. after reconstitution, the solution should be further diluted with 0.9%
sodium chloride injection, 5% dextrose injection, or lactated Ringer
Preparation and Administration: Azacitidine is available in solution injection to a final drug concentration of 0.1–1.0 mg/mL.
100-mg vials and can be administered both IV and SC. When given Unless used within 15 minutes of reconstitution, the diluted solution
SC, it should be reconstituted with 4 mL of sterile water for injection. must be prepared using cold (2°–8°C) infusion fluids and stored at
The diluents should be injected slowly into the vial. Vigorously shake 2°–8°C (36°–46°F) for up to a maximum of 7 hours until
or roll the vial until a uniform suspension is achieved. The suspension administration.
will be cloudy. The resulting suspension will contain azacitidine
25 mg/mL. Do not filter the suspension after reconstitution. Doing Toxic Effects: The major toxicity of decitabine has been bone
so could remove the active substance. Azacitidine reconstituted for marrow suppression, including leukopenia, thrombocytopenia, and