July 29, 2015
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Promacta

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Promacta




CLINICAL PHARMACOLOGY

Mechanism Of Action

Eltrombopag is an orally bioavailable, small-molecule TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor and initiates signaling cascades that induce proliferation and differentiation from bone marrow progenitor cells.

Pharmacokinetics

Absorption

Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Based on urinary excretion and biotransformation products eliminated in feces, the oral absorption of drug-related material following administration of a single 75-mg solution dose was estimated to be at least 52%.

An open-label, randomized, crossover trial was conducted to assess the effect of food on the bioavailability of eltrombopag. A standard high-fat breakfast significantly decreased plasma eltrombopag AUC0-∞ by approximately 59% and Cmax by 65% and delayed Tmax by 1 hour. The calcium content of this meal may have also contributed to this decrease in exposure.

Distribution

The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1.

Metabolism

Absorbed eltrombopag is extensively metabolized, predominantly through pathways including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag.

Elimination

The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in patients with ITP.

Drug Interactions

Polyvalent Cation-containing Antacids: In a clinical trial, coadministration of 75 mg of PROMACTA with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) to 26 healthy adult subjects decreased plasma eltrombopag AUC0-∞ and Cmax by approximately 70%. The contribution of sodium alginate to this interaction is not known.

Cytochrome P450 Enzymes (CYPs): In a clinical trial, PROMACTA 75 mg once daily was administered for 7 days to 24 healthy male subjects did not show inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans. Probe substrates for CYP2C8 were not evaluated in this trial.

Rosuvastatin: In a clinical trial, coadministration of 75 mg of PROMACTA once daily for 5 days with a single 10-mg dose of the OATP1B1 and BCRP substrate, rosuvastatin to 39 healthy adult subjects increased plasma rosuvastatin AUC0-∞ by 55% and Cmax by 103%.

Protease Inhibitors: HIV Protease Inhibitors: In a clinical trial, coadministration of repeat-dose lopinavir 400 mg/ritonavir 100 mg twice daily with a single dose of PROMACTA 100 mg to 40 healthy adult subjects decreased plasma eltrombopag AUC0-∞ by 17%.

HCV Protease Inhibitors: In a clinical trial, coadministration of repeat-dose telaprevir 750 mg every 8 hours or boceprevir 800 mg every 8 hours with a single dose of PROMACTA 200 mg to healthy adult subjects did not alter plasma telaprevir, boceprevir, or eltrombopag AUC0-∞ or Cmax to a significant extent.

Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin: The pharmacokinetics of eltrombopag in both the presence and absence of pegylated interferon alfa-2a and 2b therapy were evaluated using a population pharmacokinetic analysis in 635 patients with chronic hepatitis C. The population PK model estimates of clearance indicate no significant difference in eltrombopag clearance in the presence of pegylated interferon alfa plus ribavirin therapy.

In vitro Studies: Eltrombopag is an inhibitor of CYP2C8 and CYP2C9 in vitro. Eltrombopag is an inhibitor of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 in vitro. Eltrombopag is an inhibitor of the organic anion transporting polypeptide OATP1B1 and BCRP in vitro.

Specific Populations

Ethnicity: Based on two population PK analyses of eltrombopag concentrations in patients with ITP or chronic hepatitis C, East Asian (i.e., Japanese, Chinese, Taiwanese, Korean) subjects exhibited 50% to 55% higher eltrombopag plasma concentrations compared with non-East Asian subjects [see DOSAGE AND ADMINISTRATION].

An approximately 40% higher systemic eltrombopag exposure in healthy African- American subjects was noted in at least one clinical pharmacology trial. The effect of African- American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established.

Hepatic Impairment: In a pharmacokinetic trial, the disposition of a single 50-mg dose of PROMACTA in patients with mild, moderate, and severe hepatic impairment was compared with subjects with normal hepatic function. The degree of hepatic impairment was based on Child-Pugh score. Plasma eltrombopag AUC0-∞ was 41% higher in patients with mild hepatic impairment (Child-Pugh Class A) compared with subjects with normal hepatic function. Plasma eltrombopag AUC0-∞ was approximately 2-fold higher in patients with moderate (Child-Pugh Class B) and severe hepatic impairment (Child-Pugh Class C). The half-life of eltrombopag was prolonged 2-fold in these patients. This clinical trial did not evaluate protein-binding effects.

Chronic Liver Disease: A population PK analysis in thrombocytopenic patients with chronic liver disease following repeat doses of eltrombopag demonstrated that mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC(0-τ) and patients with moderate hepatic impairment had approximately 141% to 240% higher plasma eltrombopag AUC(0-τ) values compared with patients with normal hepatic function. The half-life of eltrombopag was prolonged 3-fold in patients with mild hepatic impairment and 4-fold in patients with moderate hepatic impairment. This clinical trial did not evaluate protein-binding effects.

Chronic Hepatitis C: A population PK analysis in 28 healthy adults and 635 patients with chronic hepatitis C demonstrated that patients with chronic hepatitis C treated with PROMACTA had higher plasma AUC(0-τ) values as compared with healthy subjects, and AUC(0- τ) increased with increasing Child-Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC(0-τ) compared with healthy subjects. This clinical trial did not evaluate protein-binding effects.

Renal Impairment: The disposition of a single 50-mg dose of PROMACTA in patients with mild (creatinine clearance [CrCl] of 50 to 80 mL/min), moderate (CrCl of 30 to 49 mL/min), and severe (CrCl less than 30 mL/min) renal impairment was compared with subjects with normal renal function. Average total plasma eltrombopag AUC0-∞ was 32% to 36% lower in subjects with mild to moderate renal impairment and 60% lower in subjects with severe renal impairment compared with healthy subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed.

Pediatric Patients: The pharmacokinetics of eltrombopag have been evaluated in 130 pediatric patients 6 years and older with ITP dosed once daily in two trials. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. East Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC(0-τ) values as compared with non-East Asian patients.

Plasma eltrombopag AUC(0-τ) and Cmax in pediatric patients aged 12 to 17 years was similar to that observed in adults. The pharmacokinetic parameters of eltrombopag in pediatric patients with ITP are shown in Table 9.

Table 9: Geometric Mean (95% CI) Steady-state Plasma Eltrombopag Pharmacokinetic Parametersa in Patients with ITP (Normalized to a 50-mg Dose Once-daily)

Age C maxb (mcg/mL) AUC(0-τ)b (mcg•h/mL)
Adults (n = 108) 7.03 (6.44, 7.68) 101 (91.4, 113)
12 to 17 years (n = 62) 6.80 (6.17, 7.50) 103 (91.1, 116)
6 to 11 years (n = 68) 10.3 (9.42, 11.2) 153 (137, 170)
a PK parameters presented as geometric mean (95% CI).
b Based on population PK post-hoc estimates.

Assessment Of Risk Of QT/QTc Prolongation

There is no indication of a QT/QTc prolonging effect of PROMACTA at doses up to 150 mg daily for 5 days. The effects of PROMACTA at doses up to 150 mg daily for 5 days (supratherapeutic doses) on the QT/QTc interval were evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg, single oral dose) crossover trial in healthy adult subjects. Assay sensitivity was confirmed by significant QTc prolongation by moxifloxacin.

Animal Pharmacology And/Or Toxicology

Eltrombopag is phototoxic in vitro. There was no evidence of n vivo cutaneous or ocular phototoxicity in rodents.

Treatment-related cataracts were detected in rodents in a dose- and time-dependent manner. At greater than or equal to 6 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 3 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At greater than or equal to 4 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 2 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing [see WARNINGS AND PRECAUTIONS].

Renal tubular toxicity was observed in studies up to 14 days in duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75, and 150 mg/kg/day. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in patients with ITP at 75 mg/day and 0.6 times the human clinical exposure based on AUC in patients with chronic hepatitis C at 100 mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2-year study, suggesting that this effect is both dose- and time-dependent.

Clinical Studies

Chronic ITP

Adults

The efficacy and safety of PROMACTA in adult patients with chronic ITP were evaluated in three randomized, double-blind, placebo-controlled trials and in an open-label extension trial.

Trials 1 and 2: In trials 1 and 2, patients who had completed at least one prior ITP therapy and who had a platelet count less than 30 x 109/L were randomized to receive either PROMACTA or placebo daily for up to 6 weeks, followed by 6 weeks off therapy. During the trials, PROMACTA or placebo was discontinued if the platelet count exceeded 200 x 109/L.

The median age of the patients was 50 years and 60% were female. Approximately 70% of the patients had received at least 2 prior ITP therapies (predominantly corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol, and azathioprine) and 40% of the patients had undergone splenectomy. The median baseline platelet counts (approximately 18 x 109/L) were similar among all treatment groups.

Trial 1 randomized 114 patients (2:1) to PROMACTA 50 mg or placebo. Trial 2 randomized 117 patients (1:1:1:1) among placebo or 1 of 3 dose regimens of PROMACTA, 30 mg, 50 mg, or 75 mg each administered daily.

The efficacy of PROMACTA in this trial was evaluated by response rate, defined as a shift from a baseline platelet count of less than 30 x 109/L to greater than or equal to 50 x 109/L at any time during the treatment period (Table 10).

Table 10: Trials 1 and 2 Platelet Count Response ( ≥ 50 x 109/L) Rates in Adults with Chronic Immune (Idiopathic) Thrombocytopenia

Trial PROMACTA 50 mg Daily Placebo
1 43/73 (59%)a 6/37 (16%)
2 19/27 (70%)a 3/27 (11%)
a P value < 0.001 for PROMACTA versus placebo.

The platelet count response to PROMACTA was similar among patients who had or had not undergone splenectomy. In general, increases in platelet counts were detected 1 week following initiation of PROMACTA and the maximum response was observed after 2 weeks of therapy. In the placebo and 50-mg-dose groups of PROMACTA, the trial drug was discontinued due to an increase in platelet counts to greater than 200 x 109/L in 3% and 27% of the patients, respectively. The median duration of treatment with the 50-mg dose of PROMACTA was 42 days in Trial 1 and 43 days in Trial 2.

Of 7 patients who underwent hemostatic challenges, additional ITP medications were required in 3 of 3 placebo group patients and 0 of 4 patients treated with PROMACTA. Surgical procedures accounted for most of the hemostatic challenges. Hemorrhage requiring transfusion occurred in one placebo group patient and no patients treated with PROMACTA.

Trial 3: In this trial, 197 patients were randomized (2:1) to receive either PROMACTA 50 mg once daily (n = 135) or placebo (n = 62) for 6 months, during which time the dose of PROMACTA could be adjusted based on individual platelet counts. Patients were allowed to taper or discontinue concomitant ITP medications after being treated with PROMACTA for 6 weeks. Patients were permitted to receive rescue treatments at any time during the trial as clinically indicated.

The median age of the patients treated with PROMACTA and placebo was 47 years and 52.5 years, respectively. Approximately half of the patients treated with PROMACTA and placebo (47% and 50%, respectively) were receiving concomitant ITP medication (predominantly corticosteroids) at randomization and had baseline platelet counts less than or equal to15 x 109/L (50% and 48%, respectively). A similar percentage of patients treated with PROMACTA and placebo (37% and 34%, respectively) had a prior splenectomy.

The efficacy of PROMACTA in this trial was evaluated by the odds of achieving a platelet count greater than or equal to 50 x 109/L and less than or equal to 400 x 109/L for patients receiving PROMACTA relative to placebo and was based on patient response profiles throughout the 6-month treatment period. In 134 patients who completed 26 weeks of treatment, a sustained platelet response (platelet count greater than or equal to 50 x 109/L and less than or equal to 400 x 109/L for 6 out of the last 8 weeks of the 26-week treatment period in the absence of rescue medication at any time) was achieved by 60% of patients treated with PROMACTA, compared with 10% of patients treated with placebo (splenectomized patients: PROMACTA 51%, placebo 8%; non-splenectomized patients: PROMACTA 66%, placebo 11%). The proportion of responders in the group of patients treated with PROMACTA was between 37% and 56% compared with 7% and 19% in the placebo treatment group for all on-therapy visits. Patients treated with PROMACTA were significantly more likely to achieve a platelet count between 50 x 109/L and 400 x 109/L during the entire 6-month treatment period compared with those patients treated with placebo.

Outcomes of treatment are presented in Table 11 for all patients enrolled in the trial.

Table 11: Outcomes of Treatment from Trial 3 in Adults with Chronic Immune (Idiopathic) Thrombocytopenia

Outcome PROMACTA
N = 135
Placebo
N = 62
Mean number of weeks with platelet counts ≥ 50 x 109/L 11.3 2.4
Requiring rescue therapy, n (%) 24 (18) 25 (40)

Among 94 patients receiving other ITP therapy at baseline, 37 (59%) of 63 patients treated with PROMACTA and 10 (32%) of 31 patients in the placebo group discontinued concomitant therapy at some time during the trial.

Extension Trial: Patients who completed any prior clinical trial with PROMACTA were enrolled in an open-label, single-arm trial in which attempts were made to decrease the dose or eliminate the need for any concomitant ITP medications. PROMACTA was administered to 299 patients; 249 completed 6 months, 210 patients completed 12 months, and 138 patients completed 24 months of therapy. The median baseline platelet count was 19 x 109/L prior to administration of PROMACTA.

Pediatric Patients

The efficacy and safety of PROMACTA in pediatric patients 6 years and older with chronic ITP were evaluated in two double-blind, placebo-controlled trials. The trials differed in time since ITP diagnosis: at least 6 months versus at least 12 months. During the trials, doses could be increased every 2 weeks to a maximum of 75 mg once daily. The dose of PROMACTA was reduced if the platelet count exceeded 200 x 109/L and interrupted and reduced if it exceeded 400 x 109/L.

Trial 4: Patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 109/L (n = 72) were stratified by age and randomized (2:1) to PROMACTA (n = 49) or placebo (n = 23). The starting dose for patients aged 6 to 17 years was 50 mg once daily for those at least 27 kg and 37.5 mg once daily for those less than 27 kg, administered as oral tablets. A reduced dose of 25 mg once daily was used for East Asian patients aged 6 to 17 years regardless of weight.

The 13-week, randomized, double-blind period was followed by a 24-week, open-label period where patients from both arms were eligible to receive PROMACTA.

The median age of the patients was 11 years and 44% were female. Approximately 63% of patients had a baseline platelet count less than or equal to 15 x 109/L, a characteristic that was similar between treatment arms. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 73% in the group treated with PROMACTA and 91% in the group treated with placebo. Three patients in the group treated with PROMACTA had undergone splenectomy.

The efficacy of PROMACTA in this trial was evaluated by the proportion of subjects on PROMACTA achieving platelet counts ≥ 50 x 109/L (in the absence of rescue therapy) for at least 6 out of 8 weeks between Weeks 5 to 12 of the randomized, double-blind period (Table 12).

Table 12: Trial 4 Platelet Response ( ≥ 50 x 109/L without Rescue) for 6 out of 8 Weeks (between Weeks 5 to 12) Overall and by Age Cohort in Pediatric Patients 6 Years and

Age Cohort PROMACTA Placebo
Overall 21/49 (43%)a 1/23 (4%)
  12 to 17 years 10/24 (42%) 1/10 (10%)
  6 to 11 years 11/25 (44%) 0/13 (0%)
a P value = 0.0011 for PROMACTA versus placebo.

More pediatric patients treated with PROMACTA (76%) compared with placebo (26%) had at least one platelet count greater than or equal to 50 x 109/L during the first 12 weeks of randomized treatment in absence of rescue therapy. Fewer pediatric patients treated with PROMACTA required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (18% [9/49] versus 22% [5/23]). In the patients who achieved a platelet response ( ≥ 50 x 109/L without rescue) for 6 out of 8 weeks (between weeks 5 to 12), 71% (15/21) had an initial response in the first 2 weeks after starting PROMACTA.

Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 10 patients receiving other ITP therapy at baseline, 50% (5/10) reduced (n = 1) or discontinued (n = 4) concomitant therapy, mainly corticosteroids, without needing rescue therapy.

Trial 5: Patients refractory or relapsed to at least one prior ITP therapy with a platelet count less than 30 x 109/L (n = 52) were stratified by age and randomized (2:1) to PROMACTA (n = 35) or placebo (n = 17). The starting dose for patients aged 12 to 17 years was 37.5 mg once daily regardless of weight or race. The starting dose for patients aged 6 to 11 years was 50 mg once daily for those greater than or equal to 27 kg and 25 mg once daily for those less than 27 kg, administered as oral tablets. Reduced doses of 25 mg (for those greater than or equal to 27 kg) and 12.5 mg (for those less than 27 kg), each once daily, were used for East Asian patients in this age range.

The 7-week, randomized, double-blind period was followed by an open-label period of up to 24 weeks where patients from both arms were eligible to receive PROMACTA.

The median age of the patients was 11 years and 63% were female. Approximately 54% of patients had a baseline platelet count less than or equal to 15 x 109/L. The percentage of patients with at least 2 prior ITP therapies (predominantly corticosteroids and immunoglobulins) was 89% in the group treated with PROMACTA and 82% in the group treated with placebo. Five patients in the group treated with PROMACTA had undergone splenectomy.

The efficacy of PROMACTA in this trial was evaluated by the proportion of patients achieving platelet counts greater than or equal to 50 x 109/L (in absence of rescue therapy) at least once between Weeks 1 and 6 of the randomized, double-blind period (Table 13). Platelet response to PROMACTA was consistent across the age cohorts.

Table 13: Trial 5 Platelet Count Response ( ≥ 50 x 109/L without Rescue) Rates in Pediatric Patients 6 Years and Older with Chronic Immune (Idiopathic) Thrombocytopenia

  PROMACTA Placebo
Overall 22/35 (63%)a 3/17 (18%)
  12 to 17 years 10/16 (62%) 0/8 (0%)
  6 to 11 years 12/19 (63%) 3/9 (33%)
a P value = 0.0043 for PROMACTA versus placebo.

Fewer pediatric patients treated with PROMACTA required rescue treatment during the randomized, double-blind period compared with placebo-treated patients (14% [5/35] versus 59% [10/17]).

Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the trial. Among 11 patients receiving other ITP therapy at baseline, 36% (4/11) reduced (n = 2) or discontinued (n = 2) concomitant therapy, mainly corticosteroids, without needing rescue therapy.

Chronic Hepatitis C-associated Thrombocytopenia

The efficacy and safety of PROMACTA for the treatment of thrombocytopenia in adult patients with chronic hepatitis C were evaluated in two randomized, double-blind, placebocontrolled trials. Trial 1 utilized peginterferon alfa-2a (PEGASYS®) plus ribavirin for antiviral treatment and Trial 2 utilized peginterferon alfa-2b (PEGINTRON®) plus ribavirin. In both trials, patients with a platelet count of less than 75 x 109/L were enrolled and stratified by platelet count, screening HCV RNA, and HCV genotype. Patients were excluded if they had evidence of decompensated liver disease with Child-Pugh score greater than 6 (class B and C), history of ascites, or hepatic encephalopathy. The median age of the patients in both trials was 52 years, 63% were male, and 74% were Caucasian. Sixty-nine percent of patients had HCV genotypes 1, 4, 6, with the remainder genotypes 2 and 3. Approximately 30% of patients had been previously treated with interferon and ribavirin. The majority of patients (90%) had bridging fibrosis and cirrhosis, as indicated by noninvasive testing. A similar proportion (95%) of patients in both treatment groups had Child-Pugh level A (score 5 to 6) at baseline. A similar proportion of patients (2%) in both treatment groups had baseline international normalized ratio (INR) greater than 1.7. Median baseline platelet counts (approximately 60 x 109/L) were similar in both treatment groups. The trials consisted of 2 phases - a pre-antiviral treatment phase and an antiviral treatment phase. In the pre-antiviral treatment phase, patients received open-label PROMACTA to increase the platelet count to a threshold of greater than or equal to 90 x 109/L for Trial 1 and greater than or equal to 100 x 109/L for Trial 2. PROMACTA was administered at an initial dose of 25 mg once daily for 2 weeks and increased in 25-mg increments over 2- to 3- week periods to achieve the optimal platelet count to initiate antiviral therapy. The maximal time patients could receive open-label PROMACTA was 9 weeks. If threshold platelet counts were achieved, patients were randomized (2:1) to the same dose of PROMACTA at the end of the pretreatment phase or to placebo. PROMACTA was administered in combination with pegylated interferon and ribavirin per their respective prescribing information for up to 48 weeks.

The efficacy of PROMACTA for both trials was evaluated by sustained virologic response (SVR) defined as the percentage of patients with undetectable HCV-RNA at 24 weeks after completion of antiviral treatment. The median time to achieve the target platelet count greater than or equal to 90 x 109/L was approximately 2 weeks. Ninety-five percent of patients were able to initiate antiviral therapy.

In both trials, a significantly greater proportion of patients treated with PROMACTA achieved SVR (see Table 14). The improvement in the proportion of patients who achieved SVR was consistent across subgroups based on baseline platelet count (less than 50 x 109/L versus greater than or equal to 50 x 109/L). In patients with high baseline viral loads (greater than or equal to 800,000), the SVR rate was 18% (82/452) for PROMACTA versus 8% (20/239) for placebo.

Table 14: Trials 1 and 2 Sustained Virologic Response in Adults with Chronic Hepatitis C

Pre-antiviral Treatment Phase Trial 1a
N = 715
Trial 2b
N = 805
% Patients who achieved target platelet counts and initiated antiviral therapyc 95% 94%
  PROMACTA
N = 450
Placebo
N = 232
PROMACTA
N = 506
Placebo
N = 253
Antiviral Treatment Phase % % % %
Overall SVRd 23 14 19 13
HCV Genotype 2,3 35 24 34 25
HCV Genotype 1,4,6 18 10 13 7
a PROMACTA given in combination with peginterferon alfa-2a (180 mcg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,200 mg daily in 2 divided doses orally).
b PROMACTA given in combination with peginterferon alfa-2b (1.5 mcg/kg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,400 mg daily in 2 divided doses orally).
c Target platelet count was ≥ 90 x 109/L for Trial 1 and ≥ 100 x 109/L for Trial 2.
d P value < 0.05 for PROMACTA versus placebo.

The majority of patients treated with PROMACTA (76%) maintained a platelet count greater than or equal to 50 x 109/L compared with 19% for placebo. A greater proportion of patients on PROMACTA did not require any antiviral dose reduction as compared with placebo (45% versus 27%).

Severe Aplastic Anemia

PROMACTA was studied in a single-arm, single-center, open-label trial in 43 patients with severe aplastic anemia who had an insufficient response to at least one prior immunosuppressive therapy and who had a platelet count less than or equal to 30 x 109/L. PROMACTA was administered at an initial dose of 50 mg once daily for 2 weeks and increased over 2-week periods up to a maximum dose of 150 mg once daily. The efficacy of PROMACTA in the study was evaluated by the hematologic response assessed after 12 weeks of treatment. Hematologic response was defined as meeting 1 or more of the following criteria: 1) platelet count increases to 20 x 109/L above baseline, or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) hemoglobin increase by greater than 1.5 g/dL, or a reduction in greater than or equal to 4 units of RBC transfusions for 8 consecutive weeks; 3) ANC increase of 100% or an ANC increase greater than 0.5 x 109/L. PROMACTA was discontinued after 16 weeks if no hematologic response was observed. Patients who responded continued therapy in an extension phase of the trial.

The treated population had median age of 45 years (range: 17 to 77 years) and 56% were male. At baseline, the median platelet count was 20 x 109/L, hemoglobin was 8.4 g/dL, ANC was 0.58 x 109/L, and absolute reticulocyte count was 24.3 x 109/L. Eighty-six percent of patients were RBC transfusion dependent and 91% were platelet transfusion dependent. The majority of patients (84%) received at least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline.

Table 15 presents the efficacy results.

Table 15:Hematologic Response in Patients with Severe Aplastic Anemia

Outcome PROMACTA
N = 43
Response ratea, n (%) 17 (40)
  95% CI (%) (25, 56)
Median of duration of response in months (95%CI) NRb (3.0, NRb)
a Includes single-and multi-lineage.
b NR = Not reached due to few events (relapsed).

In the 17 responders, the platelet transfusion-free period ranged from 8 to 1,096 days with a median of 200 days, and the RBC transfusion-free period ranged from 15 to 1,082 days with a median of 208 days.

In the extension phase, 8 patients achieved a multi-lineage response; 4 of these patients subsequently tapered off treatment with PROMACTA and maintained the response (median follow up: 8.1 months, range: 7.2 to 10.6 months).

Last reviewed on RxList: 7/7/2015
This monograph has been modified to include the generic and brand name in many instances.

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