Additions and/or revisions underlined:
PROMACTA may
increase the risk of severe and potentially life-threatening hepatotoxicity. One
patient (< 1%) with chronic ITP treated with PROMACTA in clinical trials
experienced drug-induced liver injury. Eleven patients (1%) with chronic
hepatitis C treated with PROMACTA in clinical trials experienced drug-induced
liver injury.
Treatment of ITP, Chronic Hepatitis
C-associated Thrombocytopenia, and Refractory Severe Aplastic Anemia
Measure serum
ALT, AST, and bilirubin prior to initiation of PROMACTA …
Newly added information to the end of the subsection:
First-Line Treatment of Severe Aplastic Anemia
Measure ALT, AST, and bilirubin prior to
initiation of PROMACTA, every other day while hospitalized for h- ATG therapy,
and then every 2 weeks during treatment. During treatment, manage increases in
ALT or AST levels as recommended in Table 6.
Severe Aplastic Anemia:
Newly added information:
First-Line Treatment of Severe Aplastic
Anemia
The safety of PROMACTA was established based
upon a single-arm trial of 153 patients with severe aplastic anemia who had not
received prior definitive immunosuppressive therapy. In this trial, PROMACTA
was administered in combination with horse antithymocyte globulin (h-ATG) and
cyclosporine [see Clinical Studies
(14.3)]. Among the 153 patients who were dosed in this trial, 92 patients
were evaluable for safety of the concurrent use of PROMACTA, h-ATG, and
cyclosporine at the recommended dose and schedule.
In this cohort, PROMACTA was administered at
up to 150 mg once daily on Day 1 to Month 6 (D1-M6) in combination with h-ATG
on Days 1 to 4 and cyclosporine for 6 months, followed by low dose of
cyclosporine (maintenance dose) for an additional 18 months for patients who
achieved a hematologic response at 6 months. The median duration of exposure to
PROMACTA in this cohort was 183 days with 70% of patients exposed for > 24
weeks. Table 12 presents the most common adverse reactions (experienced by
greater than or equal to 5% of patients) associated with PROMACTA in the D1-M6
cohort.
Table 12. Adverse Reactions (? 5%) from One Open-label Trial in First-line
Treatment of Patients with Severe Aplastic Anemia Please see label for table complete information.
In the PROMACTA D1-M6 cohort, ALT increased
(29%), AST increased (17%), and blood bilirubin increased (17%) were reported
more frequently than in patients with refractory severe aplastic anemia (see
Table 13).
New or worsening liver function laboratory
abnormalities (CTCAE Grade 3 and Grade 4) in the Promacta D1- M6 cohort were
15% and 2% for AST, 26% and 4% for ALT, and 12% and 1% for bilirubin,
respectively.
In this single-arm open-label clinical trial,
ALT or AST > 3 x ULN with total bilirubin > 1.5 x ULN and ALT or AST >
3 x ULN with total bilirubin > 2 x ULN were reported in 44% and 32% of
patients, respectively, in the PROMACTA D1-M6 cohort.
Pediatric Patients
A total of 34 pediatric patients (2 patients
2 to 5 years of age, 12 patients 6 to 11 years of age, and 20 patients 12 to 16
years of age) were enrolled in this single-arm trial of which 26 pediatric
patients were enrolled in the PROMACTA D1-M6 cohort. In this cohort, the most
frequent serious adverse reactions (experienced by ? 10% of patients) were upper respiratory
tract infection (12% in patients age 2 to 16 years compared to 5% in patients
17 years of age and older, respectively) and rash (12% compared to 2%). The
most common adverse reactions (experienced by ? 10% of patients) associated with PROMACTA were ALT
increased (23% in patients age 2 to 16 years compared to 32% in patients 17
years of age and older, respectively), blood bilirubin increased (12% compared
to 20%), AST increased (12% compared to 20%), and rash (12% compared to 6%).
Cytogenetic Abnormalities
In this trial, patients had bone marrow
aspirates evaluated for cytogenetic abnormalities. Seven patients in the
PROMACTA D1-M6 cohort had a new cytogenetic abnormality reported of which 4 had
the loss of chromosome 7; these 4 occurred within 6.1 months. Across all
cohorts, clonal cytogenetic evolution occurred in 15 out of 153 (10%) patients.
Of the 15 patients who experienced a cytogenetic abnormality: 7 patients had
the loss of chromosome 7, 6 of which occurred within 6.1 months; 4 patients had
chromosomal aberrations which were of unclear significance; 3 patients had a
deletion of chromosome 13; and 1 patient had a follow-up bone marrow assessment
at 5 years with features of dysplasia with hypercellularity concerning for
potential development of MDS. It is unclear whether these findings occurred due
to the underlying disease, the immunosuppressive therapy, and/or treatment with
PROMACTA.
Refractory Severe Aplastic Anemia
Additions and/or revisions underlined:
In the single-arm, open-label trial, 43
patients with refractory severe aplastic anemia
Table 13. Adverse Reactions (? 10%) from One Open-label Trial in Adults
with Refractory Severe Aplastic Anemia Table number
changed from Table 8 to Table 13 and the word Refractory added.
8.4 Pediatric Use
Addition of the following to the beginning of the
subsection:
The safety and efficacy of PROMACTA have been
established in pediatric patients 1 year and older with chronic ITP and in
pediatric patients 2 years and older with definitive immunosuppressive therapy
(IST)-naïve severe aplastic anemia (in combination
with horse antithymocyte globulin [h-ATG] and cyclosporine). Safety and
efficacy in pediatric patients below the age of 1 year with ITP have not been
established. Safety and efficacy in pediatric patients with thrombocytopenia
associated with chronic hepatitis C and refractory severe aplastic anemia have
not been established.
Addition of the following to the end of the subsection:
The safety and efficacy of PROMACTA in
combination with h-ATG and cyclosporine for the first-line treatment of severe
aplastic anemia in pediatric patients 2 years and older were evaluated in a
single-arm, open- label trial. A total of 26 pediatric patients (ages 2 to <
17 years) were evaluated; 12 children (aged 2 to < 12 years) and 14
adolescents (aged 12 to < 17). See Dosage
and Administration (2.3) for dosing recommendations for pediatric patients
2 years and older. The safety and efficacy of PROMACTA in combination with
h-ATG and cyclosporine in pediatric patients younger than 2 years for the
first-line treatment of severe aplastic anemia have not yet been established.
In patients 2 to 16 years of age, 69% of patients experienced serious adverse
events compared to 42% in patients 17 years and older. Among the 12 patients
who were 2 to 11 years of age in the PROMACTA D1-M6 cohort and reached the
6-month assessment or withdrew earlier, the complete response rate at Month 6
was 8% versus 46% in patients age 12 to 16 years and 50% in patients 17 years
of age and older.
8.5 Geriatric Use
Additions and/or revisions underlined:
Of the 196 patients who received
PROMACTA for the treatment of severe aplastic anemia, 18% were 65
years of age and over, while 3% were 75 years of age and over. No
overall differences …
8.6 Hepatic Impairment
Additions and/or revisions underlined:
Patients with Chronic ITP and Severe Aplastic Anemia
Reduce the initial dose of PROMACTA in
patients with chronic ITP (adult and pediatric patients 6 years and older only)
or refractory severe aplastic anemia …
In a clinical trial in patients with severe
aplastic anemia who had not received prior definitive immunosuppressive
therapy, patients with baseline ALT or AST > 5 x ULN were ineligible to
participate. If a patient with hepatic impairment (Child-Pugh Class A, B, C)
initiates therapy with PROMACTA for the first- line treatment of severe
aplastic anemia, reduce the initial dose.
Patients with Chronic Hepatitis C
No dosage adjustment is recommended …
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