ADVERSE REACTIONS
Overview
Adverse Reactions Described in Other Labeling Sections: anemia, neutropenia, thrombocytopenia, elevated serum creatinine, renal failure, renal tubular acidosis, hypokalemia, hepatic coma [see Warnings and Precautions (5.1, 5.2, 5.3)].
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, thrombocytopenia.
Adverse Reactions in Clinical Trials
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect exposure to VIDAZA 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) [see Clinical Studies].
In Studies 1, 2 and 3, a total of 268 patients were exposed to VIDAZA, including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately one year). VIDAZA 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 VIDAZA. 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 VIDAZA doses of 75 mg/m2.
Table 1 presents adverse reactions occurring in at least 5% of patients treated with VIDAZA (SC) in Studies 1 and 2. It is important to note that duration of exposure was longer for the VIDAZA-treated group than for the observation group: patients received VIDAZA for a mean of 11.4 months while mean time in the observation arm was 6.1 months.
Table 1: Most Frequently Observed Adverse Reactions (≥ 5.0% in All SC VIDAZA Treated Patients; Studies 1 and 2) | Number (%) of Patients |
|---|
System Organ Class
Preferred Term a | All VIDAZA b
(N=220) | Observation c
(N=92) |
|---|
|
a Multiple terms of the same preferred terms for a patient are only counted once within each treatment group.
|
|
b Includes adverse reactions from all patients exposed to VIDAZA, including patients after crossing over from observations.
|
|
c Includes adverse reactions from observation period only; excludes any adverse events after crossover to VIDAZA.
|
| Blood and lymphatic system disorders | | |
| Anemia | 153 (69.5) | 59 (64.1) |
| Anemia aggravated | 12 (5.5) | 5 (5.4) |
| Febrile neutropenia | 36 (16.4) | 4 (4.3) |
| Leukopenia | 106 (48.2) | 27 (29.3) |
| Neutropenia | 71 (32.3) | 10 (10.9) |
| Thrombocytopenia | 144 (65.5) | 42 (45.7) |
| Gastrointestinal disorders | | |
| Abdominal tenderness | 26 (11.8) | 1 (1.1) |
| Constipation | 74 (33.6) | 6 (6.5) |
| Diarrhea | 80 (36.4) | 13 (14.1) |
| Gingival bleeding | 21 (9.5) | 4 (4.3) |
| Loose stools | 12 (5.5) | 0 |
| Mouth hemorrhage | 11 (5.0) | 1 (1.1) |
| Nausea | 155 (70.5) | 16 (17.4) |
| Stomatitis | 17 (7.7) | 0 |
| Vomiting | 119 (54.1) | 5 (5.4) |
| General disorders and administration site conditions | |
| Chest pain | 36 (16.4) | 5 (5.4) |
| Injection site bruising | 31 (14.1) | 0 |
| Injection site erythema | 77 (35.0) | 0 |
| Injection site granuloma | 11 (5.0) | 0 |
| Injection site pain | 50 (22.7) | 0 |
| Injection site pigmentation changes | 11 (5.0) | 0 |
| Injection site pruritus | 15 (6.8) | 0 |
| Injection site reaction | 30 (13.6) | 0 |
| Injection site swelling | 11 (5.0) | 0 |
| Lethargy | 17 (7.7) | 2 (2.2) |
| Malaise | 24 (10.9) | 1 (1.1) |
| Pyrexia | 114 (51.8) | 28 (30.4) |
| Infections and infestations | | |
| Nasopharyngitis | 32 (14.5) | 3 (3.3) |
| Pneumonia | 24 (10.9) | 5 (5.4) |
| Upper respiratory tract infection | 28 (12.7) | 4 (4.3) |
| Injury, poisoning, and procedural complications | | |
| Post procedural hemorrhage | 13 (5.9) | 1 (1.1) |
| Metabolism and nutrition disorders | | |
| Anorexia | 45 (20.5) | 6 (6.5) |
| Musculoskeletal and connective tissue disorders | |
| Arthralgia | 49 (22.3) | 3 (3.3) |
| Chest wall pain | 11 (5.0) | 0 |
| Myalgia | 35 (15.9) | 2 (2.2) |
| Nervous system disorders | | |
| Dizziness | 41 (18.6) | 5 (5.4) |
| Headache | 48 (21.8) | 10 (10.9) |
| Psychiatric disorders | | |
| Anxiety | 29 (13.2) | 3 (3.3) |
| Insomnia | 24 (10.9) | 4 (4.3) |
| Respiratory, thoracic and mediastinal disorders | | |
| Dyspnea | 64 (29.1) | 11 (12.0) |
| Skin and subcutaneous tissue disorders | | |
| Dry skin | 11 (5.0) | 1 (1.1) |
| Ecchymosis | 67 (30.5) | 14 (15.2) |
| Erythema | 37 (16.8) | 4 (4.3) |
| Rash | 31 (14.1) | 9 (9.8) |
| Skin nodule | 11 (5.0) | 1 (1.1) |
| Urticaria | 13 (5.9) | 1 (1.1) |
| Vascular disorders | | |
| Hematoma | 19 (8.6) | 0 |
| Hypotension | 15 (6.8) | 2 (2.2) |
| Petechiae | 52 (23.6) | 8 (8.7) |
Table 2 presents adverse reactions occurring in at least 5% of patients treated with VIDAZA in Study 4. Similar to Studies 1 and 2 described above, duration of exposure to treatment with VIDAZA was longer (mean 12.2 months) compared with best supportive care (mean 7.5 months).
Table 2: Most Frequently Observed Adverse Reactions (≥ 5.0% in the VIDAZA Treated Patients and the Percentage with NCI CTC Grade 3/4 Reactions; Study 4) | Number (%) of Patients |
|---|
| Any Grade | Grade 3/4 |
|---|
System Organ Class
Preferred Term a | VIDAZA
(N=175) | Best Supportive Care Only
(N=102) | VIDAZA
(N=175) | Best Supportive Care Only
(N=102) |
|---|
|
a Multiple reports of the same preferred term from a patient were only counted once within each treatment.
|
| Blood and lymphatic system disorders | | | | |
| Anemia | 90 (51.4) | 45 (44.1) | 24 (13.7) | 9 (8.8) |
| Febrile neutropenia | 24 (13.7) | 10 (9.8) | 22 (12.6) | 7 (6.9) |
| Leukopenia | 32 (18.3) | 2 (2.0) | 26 (14.9) | 1 (1.0) |
| Neutropenia | 115 (65.7) | 29 (28.4) | 107 (61.1) | 22 (21.6) |
| Thrombocytopenia | 122 (69.7) | 35 (34.3) | 102 (58.3) | 29 (28.4) |
| Gastrointestinal disorders | | | | |
| Abdominal pain | 22 (12.6) | 7 (6.9) | 7 (4.0) | 0 |
| Constipation | 88 (50.3) | 8 (7.8) | 2 (1.1) | 0 |
| Dyspepsia | 10 (5.7) | 2 (2.0) | 0 | 0 |
| Nausea | 84 (48.0) | 12 (11.8) | 3 (1.7) | 0 |
| Vomiting | 47 (26.9) | 7 (6.9) | 0 | 0 |
| General disorders and administration site conditions | | | | |
| Fatigue | 42 (24.0) | 12 (11.8) | 6 (3.4) | 2 (2.0) |
| Injection site bruising | 9 (5.1) | 0 | 0 | 0 |
| Injection site erythema | 75 (42.9) | 0 | 0 | 0 |
| Injection site hematoma | 11 (6.3) | 0 | 0 | 0 |
| Injection site induration | 9 (5.1) | 0 | 0 | 0 |
| Injection site pain | 33 (18.9) | 0 | 0 | 0 |
| Injection site rash | 10 (5.7) | 0 | 0 | 0 |
| Injection site reaction | 51 (29.1) | 0 | 1 (0.6) | 0 |
| Pyrexia | 53 (30.3) | 18 (17.6) | 8 (4.6) | 1 (1.0) |
| Infections and infestations | | | | |
| Rhinitis | 10 (5.7) | 1 (1.0) | 0 | 0 |
| Upper respiratory tract infection | 16 (9.1) | 4 (3.9) | 3 (1.7) | 0 |
| Urinary tract infection | 15 (8.6) | 3 (2.9) | 3 (1.7) | 0 |
| Investigations | | | | |
| Weight decreased | 14 (8.0) | 0 | 1 (0.6) | 0 |
| Metabolism and nutrition disorders | | | | |
| Hypokalemia | 11 (6.3) | 3 (2.9) | 3 (1.7) | 3 (2.9) |
| Nervous system disorders | | | | |
| Lethargy | 13 (7.4) | 2 (2.0) | 0 | 1 (1.0) |
| Psychiatric disorders | | | | |
| Anxiety | 9 (5.1) | 1 (1.0) | 0 | 0 |
| Insomnia | 15 (8.6) | 3 (2.9) | 0 | 0 |
| Renal and urinary disorders | | | | |
| Hematuria | 11 (6.3) | 2 (2.0) | 4 (2.3) | 1 (1.0) |
| Respiratory, thoracic and mediastinal disorders | | | | |
| Dyspnea | 26 (14.9) | 5 (4.9) | 6 (3.4) | 2 (2.0) |
| Dyspnea exertional | 9 (5.1) | 1 (1.0) | 0 | 0 |
| Pharyngolaryngeal pain | 11 (6.3) | 3 (2.9) | 0 | 0 |
| Skin and subcutaneous tissue disorders | | | | |
| Erythema | 13 (7.4) | 3 (2.9) | 0 | 0 |
| Petechiae | 20 (11.4) | 4 (3.9) | 2 (1.1) | 0 |
| Pruritus | 21 (12.0) | 2 (2.0) | 0 | 0 |
| Rash | 18 (10.3) | 1 (1.0) | 0 | 0 |
| Vascular disorders | | | | |
| Hypertension | 15 (8.6) | 4 (3.9) | 2 (1.1) | 2 (2.0) |
In Studies 1, 2 and 4 with SC administration of VIDAZA, adverse reactions of neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and injection site erythema/reaction tended to increase in incidence with higher doses of VIDAZA. 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 VIDAZA, the following serious adverse reactions occurring at a rate of < 5% (and not described in Tables 1 or 2) 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.
Postmarketing Experience
Adverse reactions identified from spontaneous reports have been similar to those reported during clinical trials with VIDAZA.
|
