PROMACTA SIDE EFFECTS

Last updated on MDtodate: 10/10/2022

SIDE EFFECTS

The following clinically significant adverse reactions associated with PROMACTA are described in other sections.

• Hepatic Decompensation in Patients with Chronic Hepatitis C
• Hepatotoxicity
• Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia
• Thrombotic/Thromboembolic Complications
• Cataracts

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Persistent Or Chronic Immune Thrombocytopenia

Adults

In clinical trials, hemorrhage was the most common serious adverse reaction and most hemorrhagic reactions followed discontinuation of PROMACTA. Other serious adverse reactions included thrombotic/thromboembolic complications. The data described below reflect exposure of PROMACTA to patients with persistent or chronic ITP aged 18 to 85 years, of whom 66% were female, in three placebo-controlled trials and one open-label extension trial. PROMACTA was administered to 330 patients for at least 6 months and 218 patients for at least 1 year.

Table 8 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of patients receiving PROMACTA) from the three placebo-controlled trials, with a higher incidence in PROMACTA versus placebo.

Table 1. Adverse Reactions (≥ 3%) From Three Placebo-controlled Trials in Adults With Persistent or Chronic Immune Thrombocytopenia

Adverse Reaction	PROMACTA 50 mg n = 241 (%)	Placebo n = 128 (%)
Nausea	9	3
Diarrhea	9	7
Upper respiratory tract infection	7	6
Vomiting	6	<1
Urinary tract infectiona	5	4
Increased ALT	5	3
Myalgia	5	2
Oropharyngeal pain	4	3
Increased AST	4	2
Pharyngitis	4	2
Back pain	3	2
Influenza	3	2
Paresthesia	3	2
Rash	3	2
a Includes PTs of Urinary tract infection, Cystitis, Urinary tract infection bacterial, and Bacteriuria.

 

In the three controlled clinical persistent or chronic ITP trials, alopecia, musculoskeletal pain, blood alkaline phosphatase increased, and dry mouth were the adverse reactions reported in 2% of patients treated with PROMACTA and in no patients who received placebo.

Among 302 patients with persistent or chronic ITP who received PROMACTA in the single-arm extension trial, the adverse reactions occurred in a pattern similar to that seen in the placebo-controlled trials. Table 2 presents the most common treatment-related adverse reactions (experienced by greater than or equal to 3% of patients receiving PROMACTA) from the extension trial.

Table 2. Treatment-related Adverse Reactions (≥ 3%) From Extension Trial in Adults With Persistent or Chronic Immune Thrombocytopenia

Adverse Reaction	PROMACTA 50 mg n = 302 (%)
Headache	10
ALT increased	5
AST increased	5
Cataract	5
Fatigue	5
Blood bilirubin increased	4
Nausea	4
Hyperbilirubinemia	3
Diarrhea	3

 

In the three controlled persistent or chronic ITP trials, serum liver test abnormalities (predominantly Grade 2 or less in severity) were reported in 11% and 7% of patients for PROMACTA and placebo, 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 corticosteroid 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.

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 3 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 3. 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

Adverse Reaction	PROMACTA n = 107 (%)	Placebo n = 50 (%)
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 increaseda	6	0
Rash	5	2
AST increased	4	0
Rhinorrhea	4	0
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 4 presents the most common adverse drug reactions (experienced by greater than or equal to 10% of patients receiving PROMACTA compared with placebo).

Table 4. Adverse Reactions (≥ 10% and Greater Than Placebo) From Two Placebo-controlled Trials in Adults With Chronic Hepatitis C

Adverse Reaction	PROMACTA + Peginterferon/Ribavirin n = 955 (%)	Placebo + Peginterferon/Ribavirin n = 484 (%)
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
Insomniaa	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. 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 5 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 5. Adverse Reactions (≥ 5%) From One Open-label Trial in First-Line Treatment of Patients With Severe Aplastic Anemia

Adverse Reaction	PROMACTA n = 92 (%)
ALT increased	29
AST increased	17
Blood bilirubin increased	17
Rash	8
Skin discoloration, including hyperpigmentation	5

 

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 6. Adverse Reactions (≥ 10%) From One Open-label Trial in Adults With Refractory Severe Aplastic Anemia

Adverse Reaction	PROMACTA n = 43 (%)
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.

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.