Xpreza 100 Adverse Reactions

Overview: Adverse Reactions Described in Other Monograph 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, diarrhoea, 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 and 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 and 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 than 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 of 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 represents adverse reactions occurring in at least 5% of patients treated with azacitidine (SC) 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 administration of AZACITIDINE, adverse reactions of neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhoea, constipation, and injection site erythema/reaction tended to increase in incidence with higher doses of AZACITIDINE. Adverse reactions that tended to be more pronounced during the first 1 to 2 cycles of SC treatment compared with later cycles included thrombocytopenia, neutropenia, anemia, nausea, vomiting, injection site erythema/pain/bruising/reaction, constipation, petechiae, dizziness, anxiety, hypokalemia, and insomnia. There did not appear to be any adverse reactions 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 adverse reactions occurring at a rate of <5% (and not described in Tables 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, cardiorespiratory 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: haemoptysis, 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.
Adult population aged 65 years or older with AML with >30% marrow blasts: The most common serious adverse reactions (≥10%) noted from AML >30% within the azacitidine treatment arm included febrile neutropenia (25.0%), pneumonia (20.3%), and pyrexia (10.6%). Other less frequently reported serious adverse reactions in the azacitidine treatment arm included sepsis (5.1%), anaemia (4.2%), neutropenic sepsis (3.0%), urinary tract infection (3.0%), thrombocytopenia (2.5%), neutropenia (2.1%), cellulitis (2.1%), dizziness (2.1%) and dyspnoea (2.1%).
The most commonly reported (≥30%) adverse reactions with azacitidine treatment were gastrointestinal events, including constipation (41.9%), nausea (39.8%) and diarrhea (36.9%) (usually Grade 1-2), general disorders and administration site conditions including pyrexia (37.7%; usually Grade 1-2) and haematological events, including febrile neutropenia (32.2%) and neutropenia (30.1%), (usually grade 3-4).
Table 9 as follows contains adverse reactions associated with azacitidine treatment obtained from the main clinical studies in MDS and AML and post marketing surveillance.
Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to < 1/1000; very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Adverse reactions are presented in the table as follows according to the highest frequency observed in any of the main clinical studies. (See Table 9.)

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