ACN_7.14_Full Issue digital | Page 17

respectively . Four patients ( 1 %) treated with PROMACTA and three patients in the placebo group ( 2 %)
discontinued treatment due to hepatobiliary laboratory abnormalities . Seventeen of the patients treated
with PROMACTA in the controlled trials with hepatobiliary laboratory abnormalities were re-exposed to
PROMACTA in the extension trial . Eight of these patients again experienced liver test abnormalities
( less than or equal to Grade 3 ) resulting in discontinuation of PROMACTA in one patient . In the extension
persistent or chronic ITP trial , six additional patients had PROMACTA discontinued due to liver
test abnormalities ( less than or equal to Grade 3 ).
In the three controlled persistent or chronic ITP trials , cataracts developed or worsened in 7 % of patients
treated with PROMACTA and 7 % of patients in the placebo group . All patients had documented , preexisting
risk factors for cataractogenesis , including cortico steroid use . In the extension trial , cataracts
developed or worsened in 11 % of patients who underwent ocular examination prior to therapy with
PROMACTA . Seventy-two percent of patients had preexisting risk factors , including corticosteroid use .
The safety of PROMACTA was also assessed in all patients treated in 7 adult persistent or chronic ITP
clinical trials ( N = 763 PROMACTA-treated patients and 179 placebo-treated patients ). Thromboembolic
events were reported in 6 % of PROMACTA-treated patients versus 0 % of placebo-treated patients and
thrombotic microangiopathy with acute renal failure was reported in < 1 % of PROMACTA-treated
patients versus 0 % of placebo-treated patients .
In a placebo-controlled trial of PROMACTA in patients with chronic liver disease and thrombocytopenia
not related to ITP , six patients treated with PROMACTA and one patient in the placebo group developed
portal vein thromboses [ see Warnings and Precautions ( 5.4 )].
Pediatric Patients : The data described below reflect median exposure to PROMACTA of 91 days for
107 pediatric patients ( aged 1 to 17 years ) with persistent or chronic ITP , of whom 53 % were female ,
across the randomized phase of two placebo-controlled trials .
Table 10 presents the most common adverse drug reactions ( experienced by greater than or equal to
3 % of pediatric patients 1 year and older receiving PROMACTA ) across the two placebo-controlled
trials , with a higher incidence for PROMACTA versus placebo .
Table 10 . Adverse Reactions ( ≥ 3 %) With a Higher Incidence for PROMACTA Versus Placebo From
Two Placebo-controlled Trials in Pediatric Patients 1 Year and Older With Persistent or Chronic
Immune Thrombocytopenia
PROMACTA
Placebo
n = 107
n = 50
Adverse Reaction
(%)
(%)
Upper respiratory tract infection
17
6
Nasopharyngitis
12
4
Cough
9
0
Diarrhea
9
2
Pyrexia
9
8
Abdominal pain
8
4
Oropharyngeal pain
8
2
Toothache
6
0
ALT increased a
6
0
Rash
5
2
AST increased
4
0
Rhinorrhea
4
0
Abbreviations : ALT , alanine aminotransferase ; AST , aspartate aminotransferase .
a
Includes adverse reactions or laboratory abnormalities > 3 x ULN .
In the two controlled clinical persistent or chronic ITP trials , cataracts developed or worsened in
2 ( 1 %) patients treated with PROMACTA . Both patients had received chronic oral corticosteroids , a
risk factor for cataractogenesis .
Chronic Hepatitis C-associated Thrombocytopenia : In the two placebo-controlled trials , 955 patients
with chronic hepatitis C-associated thrombocytopenia received PROMACTA . Table 11 presents the most
common adverse drug reactions ( experienced by greater than or equal to 10 % of patients receiving
PROMACTA compared with placebo ).
Table 11 . Adverse Reactions ( ≥ 10 % and Greater Than Placebo ) From Two Placebo-controlled Trials
in Adults With Chronic Hepatitis C
PROMACTA
Placebo
+ Peginterferon / Ribavirin
+ Peginterferon / Ribavirin
n = 955
n = 484
Adverse Reaction
(%)
(%)
Anemia
40
35
Pyrexia
30
24
Fatigue
28
23
Headache
21
20
Nausea
19
14
Diarrhea
19
11
Decreased appetite
18
14
Influenza-like illness
18
16
Insomnia a
16
15
Asthenia
16
13
Cough
15
12
Pruritus
15
13
Chills
14
9
Myalgia
12
10
Alopecia
10
6
Peripheral edema
10
5
a
Includes PTs of Insomnia , Initial insomnia , and Poor quality sleep .
Rash was reported in 9 % and 7 % of patients receiving PROMACTA and placebo , respectively .
In the two controlled clinical trials in patients with chronic hepatitis C , hyperbilirubinemia was reported
in 8 % of patients receiving PROMACTA compared with 3 % for placebo . Total bilirubin greater than
or equal to 1.5 x ULN was reported in 76 % and 50 % of patients receiving PROMACTA and placebo ,
respectively . ALT or AST greater than or equal to 3 x ULN was reported in 34 % and 38 % of patients
for PROMACTA and placebo , respectively .
In the two controlled clinical trials in patients with chronic hepatitis C , cataracts developed or worsened
in 8 % of patients treated with PROMACTA and 5 % of patients treated with placebo .
The safety of PROMACTA was also assessed in all patients treated with PROMACTA in the two controlled
trials , including patients who initially received PROMACTA in the pre-antiviral treatment phase of the
trial and were later randomized to the placebo arm ( N = 1520 PROMACTA-treated patients ). Hepatic
failure was reported in 0.8 % of PROMACTA-treated patients and 0.4 % of placebo-treated patients .
Severe Aplastic Anemia : 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 ) in the full prescribing information ]. 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
PROMACTA n = 92
Adverse Reaction (%)
ALT increased 29 AST increased 17 Blood bilirubin increased 17 Rash 8 Skin discoloration , including hyperpigmentation 5 Abbreviations : ALT , alanine aminotransferase ; AST , aspartate aminotransferase .
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 In the single-arm , open-label trial , 43 patients with refractory severe aplastic anemia received PROMACTA . Eleven patients ( 26 %) were treated for greater than 6 months and 7 patients ( 16 %) were treated for greater than 1 year . The most common adverse reactions ( greater than or equal to 20 %) were nausea , fatigue , cough , diarrhea , and headache .
Table 13 . Adverse Reactions ( ≥ 10 %) From One Open-label Trial in Adults With Refractory Severe Aplastic Anemia
PROMACTA n = 43
Adverse Reaction (%)
Nausea 33 Fatigue 28 Cough 23 Diarrhea 21 Headache 21 Pain in extremity 19 Pyrexia 14 Dizziness 14 Oropharyngeal pain 14 Abdominal pain 12 Muscle spasms 12 Transaminases increased 12 Arthralgia 12 Rhinorrhea 12
Rash and hyperbilirubinemia were reported in 7 % of patients ; cataract was reported in 2 % of patients .
In this trial , concurrent ALT or AST greater than 3 x ULN with total bilirubin greater than 1.5 x ULN were reported in 5 % of patients . Total bilirubin greater than 1.5 x ULN occurred in 14 % of patients .
In this trial , patients had bone marrow aspirates evaluated for cytogenetic abnormalities . Eight patients had a new cytogenetic abnormality reported on therapy , including 5 patients who had complex changes in chromosome 7 .
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of PROMACTA . Because these reactions are reported voluntarily from a population of uncertain size , it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure .
Skin and Subcutaneous Tissue Disorders : Skin discoloration , including hyperpigmentation and skin yellowing .