Safety
Warnings and precautions
Risks of substitution with other azacitidine products1
- Due to substantial differences in the pharmacokinetic parameters, the recommended dose and schedule for ONUREG® are different from those for the intravenous or subcutaneous azacitidine products
- Treatment of patients using intravenous or subcutaneous azacitidine at the recommended dosage of ONUREG® may result in a fatal adverse reaction
- Treatment of patients using ONUREG® at the doses recommended for intravenous or subcutaneous azacitidine may not be effective
- Do not substitute ONUREG® for intravenous or subcutaneous azacitidine
Myelosuppression1
- New or worsening Grade 3 or 4 neutropenia and thrombocytopenia occurred in 49% and 22% of patients who received ONUREG®, respectively
- Febrile neutropenia occurred in 12%
- A dose reduction was required for 7% and 2% of patients due to neutropenia and thrombocytopenia, respectively
- <1% of patients discontinued ONUREG® due to either neutropenia or thrombocytopenia
- Monitor complete blood counts and modify the dosage as recommended
- Provide standard supportive care, including hematopoietic growth factors, if myelosuppression occurs
Increased early mortality in patients with myelodysplastic syndromes1
- In AZA-MDS-003 (NCT01566695), 216 patients with red blood cell transfusion-dependent anemia and thrombocytopenia due to myelodysplastic syndromes were randomized to ONUREG® or placebo
- 107 patients received a median of 5 cycles of ONUREG® 300 mg daily for 21 days of a 28-day cycle
- Enrollment was discontinued early due to a higher incidence of early fatal and/or serious adverse reactions in patients who received ONUREG® compared with placebo
- The most frequent fatal adverse reaction was sepsis
- The safety and effectiveness of ONUREG® for treatment of myelodysplastic syndromes have not been established
- Treatment of patients with myelodysplastic syndromes with ONUREG® is not recommended outside of controlled trials
Embryo-fetal toxicity1
- Based on the mechanism of action and findings in animals, ONUREG® can cause fetal harm when administered to a pregnant woman
- Azacitidine administered to pregnant rats via a single intraperitoneal dose less than the recommended human daily dose of oral azacitidine on a mg/m2 basis caused fetal death and anomalies
- Advise pregnant women of the potential risk to a fetus
- Advise females of reproductive potential to use effective contraception during treatment with ONUREG® and for at least 6 months after the last dose
- Advise males with female partners of reproductive potential to use effective contraception during treatment with ONUREG® and for at least 3 months after the last dose
ONUREG® safety was assessed in the QUAZAR® AML-001 trial1
- 1 fatal AR (sepsis) occurred in a patient who received ONUREG®1
- Serious ARs occurred in 15% of patients receiving ONUREG®1
- Serious ARs in ≥2% of patients who received ONUREG® were pneumonia (8%) and febrile neutropenia (7%)
The majority of adverse reactions (ARs) were mild to moderate (Grade 1 or 2) with ONUREG®1
ARs (≥5%) in patients with AML who received ONUREG® with a difference between arms of >2% compared with placebo in QUAZAR® AML-0011
AR |
ONUREG®(n=236) |
Placebo(n=233) |
||
|---|---|---|---|---|
All Grades
|
Grade 3 or 4
|
All Grades
|
Grade 3 or 4
|
|
|
Gastrointestinal (GI) disorders |
||||
|
Nausea |
65 |
3 |
24 |
<1 |
|
Vomiting |
60 |
3 |
10 |
0 |
|
Diarrhea |
50 |
5 |
21 |
1 |
|
Constipation |
39 |
1 |
24 |
0 |
|
Abdominal paina |
22 |
2 |
13 |
<1 |
|
General disorders and administration site conditions |
||||
|
Fatigue/astheniab |
44 |
4 |
25 |
1 |
|
Infections |
||||
|
Pneumoniac |
27 |
9 |
17 |
5 |
|
Musculoskeletal and connective tissue disorders |
||||
|
Arthralgia |
14 |
1 |
10 |
<1 |
|
Pain in extremity |
11 |
<1 |
5 |
0 |
|
Metabolism and nutrition disorders |
||||
|
Decreased appetite |
13 |
1 |
6 |
1 |
|
Blood and lymphatic disorders |
||||
|
Febrile neutropenia |
12 |
11 |
8 |
8 |
|
Nervous system disorders |
||||
|
Dizziness |
11 |
0 |
9 |
0 |
aGrouped term includes abdominal pain, abdominal pain upper, abdominal discomfort, and GI pain.
bGrouped term includes fatigue and asthenia.
cBroad scope term includes influenza, pneumonia, respiratory tract infection, respiratory tract infection viral, bronchopulmonary aspergillosis, lung infection, Staphylococcal infection, atypical pneumonia, lower respiratory tract infection, lung abscess, Pneumocystis jirovecii pneumonia, pneumonia bacterial, pneumonia fungal, Pseudomonas infection, hemoptysis, productive cough, pleural effusion, atelectasis, pleuritic pain, rales, Enterobacter test positive, and Haemophilus test positive.
Selected hematological laboratory abnormalities that worsened from baseline in patients who received ONUREG® in QUAZAR® AML-0011
Laboratory
|
ONUREG® |
Placebo |
||
|---|---|---|---|---|
Baseline
|
Post-baseline
|
Baseline
|
Post-baseline
|
|
|
Neutropenia |
223 |
109 (49) |
217 |
50 (23) |
|
Thrombocytopenia |
222 |
46 (21) |
212 |
22 (10) |
|
Anemia |
229 |
10 (4) |
223 |
7 (3) |
Treatment duration for ONUREG®1,2
*1 cycle=28 days (median).
Continue ONUREG® until disease progression or unacceptable toxicity
For ONUREG®-treated patients, GI ARs were highest during the first 2 cycles of treatment and then subsequently decreased3
Select treatment-emergent adverse events (TEAEs) of GI disorders by cycle of onset (cycles 1-24)3
Most common
occurrence of GI ARs
TEAEs include adverse events that started between first dose date and the date 28 days after the last dose date of study treatment.
Percentage is based on the number of subjects who are exposed to investigational product at the beginning of each cycle category for the treatment group. A subject with multiple occurrences of a TEAE is counted only once in each cycle category.
Discontinuations and dose modifications in the QUAZAR® AML‑001 trial with ONUREG®1
Permanent discontinuation due to an AR occurred in 8% of patients1
ARs which resulted in permanent discontinuation in >1% of patients included:
Nausea
Diarrhea
Vomiting
Treatment interruptions due to an AR occurred in 35% of patients1
ARs requiring treatment interruption in >5% of patients included:
Neutropenia
Thrombocytopenia
Nausea
Dose reductions due to an AR occurred in 14% of patients1
ARs requiring dose reduction in >1% of patients included: