Azacytin Adverse Reactions

Overview: Adverse Reactions Described in Other Labeling Sections: anemia, neutropenia, thrombocytopenia, elevated serum creatinine, renal failure, renal tubular acidosis, hepatic coma.
Most Commonly Occurring Adverse Reactions (SC or IV Route): nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia, ecchymosis. The most common adverse reactions by IV route also included petechiae, rigors, weakness and hypokalemia.
Adverse Reactions Most Frequently (> 2%) Resulting in Clinical Intervention (SC or IV Route): Discontinuation: leukopenia, thrombocytopenia, neutropenia.
Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia.
Dose Reduced: leukopenia, neutropenia, and thrombocytopenia.
Adverse Reactions in clinical trials: The data described as follows reflect exposure to azacitidine in 443 MDS patients from 4 clinical studies. Study 1 was a supportive-care controlled trial (SC administration), Studies 2 and 3 were single arm studies (one with SC administration and one with IV administration), and Study 4 was an international randomized trial (SC administration).
In Studies 1, 2, 3, a total of 268 patients were exposed to azacitidine including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater that 12 cycles (approximately one year). Azacitidine was studied primarily in supportive-care-controlled and uncontrolled trials (n=150 and n=118, respectively). The population in the subcutaneous studies (n=220) was 23 to 92 years old (mean 66.4 years), 68% male, and 94% white, and had MDS or AML. The population in the IV study (n=48) was 35 to 81 years old (mean 63.1 years), 65% male, and 100% white. Most patients received average daily doses between 50 and 100 mg/m².
In Study 4, a total of 175 patients with higher-risk MDS (primarily RAEB and RAEB-T subtypes) were exposed to azacitidine. Of these patients, 119 were exposed for 6 or more cycles, and 63 for at least 12 cycles. The mean age 61 this population was 68.1 years (ranging from 42 to 83 years), 74% were male, and 99% were white. Most patients received daily azacitidine doses of 75 mg/m². Table 7 presents adverse reactions occurring in at least 5% of patients treated with azacitidine in studies 1 and 2. It is important to note that duration of exposure was longer for the azacitidine treated group than for the observation group: patients received azacitidine for a mean of 11.4 months while mean time in the observation arm was 6.1 months. (See Table 7.)

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Table 8 presents adverse reactions occurring in at least 5% of patients treated with azacitidine in Study 4. Similar to Studies 1 and 2 described previously, duration of exposure to treatment with azacitidine was longer (mean 12.2 months) compared with best supportive care (mean 7.5 months). (See Table 8.)

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In Studies 1, 2 and 4 with SC azacitidine administration, neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and injection site erythema / reaction tended to increase in incidence with increasing doses of azacitidine. Thrombocytopenia, neutropenia, anemia, nausea, vomiting, injection site erythema / pain / bruising / reaction, constipation, petechiae, dizziness, anxiety, hypokalemia and insomnia tended to be more pronounced during the first 1-2 cycles of SC azacitidine treatment compared with later cycles of treatment. There did not appear to be any adverse events that increased in frequency over the course of treatment.
Overall, adverse reactions were qualitatively similar between the IV and SC studies. Adverse reactions that appeared to be specifically associated with the IV route of administration included infusion site reactions (e.g., erythema or pain) and catheter site reactions (e.g., infection, erythema, or hemorrhage).
In clinical studies of either SC or IV azacitidine the following serious treatment-related adverse events occurring at a rate of <5% (not described in Table 7 or 8) were reported: Blood and lymphatic system disorders: agranulocytosis; bone marrow failure, pancytopenia, splenomegaly.
Cardiac disorders: atrial fibrillation, cardiac failure, cardiac failure congestive, cardio-respiratory arrest, congestive cardiomyopathy.
Eye disorders: eye hemorrhage.
Gastrointestinal disorders: diverticulitis, gastrointestinal hemorrhage, melena, perirectal abscess.
General disorders and administration site conditions: catheter site hemorrhage, general physical health deterioration, systemic inflammatory response syndrome.
Hepatobiliary disorders: cholecystitis.
Immune system disorders: anaphylactic shock, hypersensitivity.
Infections and Infestations: abscess limb, bacterial infection, cellulitis, blastomycosis, injection site infection, Klebsiella sepsis, neutropenic sepsis, pharyngitis streptococcal, pneumonia Klebsiella, sepsis, septic shock, Staphylococcal bacteremia, Staphylococcal infection, toxoplasmosis.
Metabolism and nutrition disorders: dehydration.
Musculoskeletal and connective tissue disorders: bone pain aggravated, muscle weakness, neck pain.
Neoplasms benign, malignant and unspecified: leukemia cutis.
Nervous system disorders: cerebral hemorrhage; convulsions, intracranial hemorrhage.
Renal and urinary disorders: loin pain, renal failure.
Respiratory, thoracic and mediastinal disorders: hemoptysis, lung infiltration, pneumonitis, respiratory distress.
Skin and subcutaneous tissue disorders: pyoderma gangrenosum, rash pruritic, skin induration.
Surgical and medical procedures: cholecystectomy.
Vascular disorders: orthostatic hypotension.
Post-marketing Experience: The following adverse reactions have been identified during post-marketing use of azacitidine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Interstitial lung disease; Tumor lysis syndrome; Injection site necrosis; Sweet's syndrome (acute febrile neutrophilic dermatosis).