PROMACTA

Eltrombopag olamine is practically insoluble in aqueous buffer across a pH range of 1 to 7.4, and is sparingly soluble in water.

The inactive ingredients of PROMACTA are: Tablet Core: magnesium stearate, mannitol, microcrystalline cellulose, povidone, and sodium starch glycolate. Coating: hypromellose (12.5 mg, 25 mg, 50 mg, and 75 mg tablets) or polyvinyl alcohol and talc (100 mg tablet), polyethylene glycol 400, titanium dioxide, polysorbate 80 (12.5 mg tablet), FD&C Yellow No. 6 aluminum lake (25 mg tablet), FD&C Blue No. 2 aluminum lake (50 mg tablet), Iron Oxide Red and Iron Oxide Black (75 mg tablet), or Iron Oxide Yellow and Iron Oxide Black (100 mg tablet).

12 CLINICAL PHARMACOLOGY

12.1 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 of megakaryocytes from bone marrow progenitor cells.

12.3 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 AUC_0-∞ by approximately 59% and C_max by 65% and delayed t_max 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 (>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 ITP patients.

Drug Interactions: Polyvalent Cation-containing Antacids: In a clinical trial, co-administration 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 AUC_0-∞ and C_max 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, co-administration 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 AUC_0-∞ by 55% and C_max by 103%.
•   Protease Inhibitors: HIV Protease Inhibitors: In a clinical trial, co-administration 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 AUC_0-∞ by 17%.
•   HCV Protease Inhibitors: In a clinical trial, co-administration 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 AUC_0-∞ or C_max 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 ITP and chronic hepatitis C patients, East Asian (i.e., Japanese, Chinese, Taiwanese, and Korean) subjects exhibited 50 to 55% higher eltrombopag plasma concentrations compared to non-East Asian subjects [see Dosage and Administration (2.1, 2.2)].

•  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 to subjects with normal hepatic function. The degree of hepatic impairment was based on Child-Pugh score. Plasma eltrombopag AUC_0-∞ was 41% higher in patients with mild hepatic impairment (Child-Pugh Class A) compared to subjects with normal hepatic function. Plasma eltrombopag AUC_0-∞ 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 to 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 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 to 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 to subjects with normal renal function. Average total plasma eltrombopag AUC_0-∞ 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.

12.6 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 was 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Eltrombopag does not stimulate platelet production in rats, mice, or dogs because of unique TPO receptor specificity. Data from these animals do not fully model effects in humans.

Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 2 times the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day).

Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in 2 in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on C_max in ITP patients at 75 mg/day and 7 times the human clinical exposure based on C_max in chronic hepatitis C patients at 100 mg/day). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (<3-fold increase in mutation frequency).

Eltrombopag did not affect female fertility in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and similar to the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day). Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 2 times the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day).

13.2 Animal Pharmacology/Toxicology

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

Treatment-related cataracts were detected in rodents in a dose- and time-dependent manner. At ≥6 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 3 times the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At ≥4 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 2 times the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing [see Warnings and Precautions (5.4)].

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 ITP patients at 75 mg/day and 0.6 times the human clinical exposure based on AUC in chronic hepatitis C patients 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.

14 CLINICAL STUDIES

14.1 Chronic ITP

The efficacy and safety of PROMACTA in adult patients with chronic ITP were evaluated in 3 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 <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 primary efficacy endpoint was response rate, defined as a shift from a baseline platelet count of <30 x 10⁹/L to ≥50 x 10⁹/L at any time during the treatment period.

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.

Table 6 shows for each trial the primary efficacy outcomes for the placebo groups and the patient groups who received the 50 mg daily regimen of PROMACTA.

•   ^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 >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 primary endpoint was the odds of achieving a platelet count ≥50 x 10⁹/L and ≤400 x 10⁹/L for patients receiving PROMACTA relative to placebo and was based on patient response profiles throughout the 6-month treatment period.

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 15 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.

In 134 patients who completed 26 weeks of treatment, a sustained platelet response (platelet count ≥50 x 10⁹/L and ≤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 to 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 PROMACTA treatment group was between 37% and 56% compared to 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 to those patients treated with placebo.

Outcomes of treatment are presented in Table 7 for all patients enrolled in the trial.

Among 94 patients receiving other ITP therapy at baseline, 37 (59%) of 63 patients in the PROMACTA group 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.

14.2 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 2 randomized, double-blind, placebo-controlled 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 <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 > 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 5-6) at baseline. A similar proportion of patients (2%) in both treatment groups had baseline international normalized ratio (INR) > 1.7. Median baseline platelet counts (approximately 60 x 10⁹/L) were similar in both treatment groups. The trials consisted of two 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 ≥90 x 10⁹/L for Trial 1 and ≥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 pre-treatment 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 primary efficacy endpoint for both trials was 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 ≥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 8). The improvement in the proportion of patients who achieved SVR was consistent across subgroups based on baseline platelet count (<50 x 10⁹/L versus ≥50 x 10⁹/L). In patients with high baseline viral loads (≥800,000), the SVR rate was 18% (82/452) for PROMACTA versus 8% (20/239) for placebo.

^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 10 ⁹ /L for Trial 1 and ≥100 x 10 ⁹ /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 ≥50 x 10⁹/L compared to 19% for placebo. A greater proportion of patients on PROMACTA did not require any antiviral dose reduction as compared to placebo (45% versus 27%).

16 HOW SUPPLIED/STORAGE AND HANDLING

• •The 12.5 mg tablets are round, biconvex, white, film-coated tablets debossed with GS MZ1 and 12.5 on one side and are available in bottles of 30: NDC 0007-4643-13.
• •The 25 mg tablets are round, biconvex, orange, film-coated tablets debossed with GS NX3 and 25 on one side and are available in bottles of 30: NDC 0007-4640-13.
• •The 50 mg tablets are round, biconvex, blue, film-coated tablets debossed with GS UFU and 50 on one side and are available in bottles of 30: NDC 0007-4641-13.
• •The 75 mg tablets are round, biconvex, pink, film-coated tablets debossed with GS FFS and 75 on one side and are available in bottles of 30: NDC 0007-4642-13.
• •The 100 mg tablets are round, biconvex, green, film-coated tablets debossed with GS 1L5 and are available in bottles of 30: NDC 0007-4646-13. This product contains a desiccant.

Store at room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Do not remove desiccant if present. Dispense in original bottle.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide).

Prior to treatment, patients should fully understand and be informed of the following risks and considerations for PROMACTA:

• •For patients with chronic ITP, therapy with PROMACTA is administered to achieve and maintain a platelet count ≥50 x 10⁹/L as necessary to reduce the risk for bleeding.
• •For patients with chronic hepatitis C, therapy with PROMACTA is administered to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin.
• •Therapy with PROMACTA may be associated with hepatobiliary laboratory abnormalities.
• •Advise patients with chronic hepatitis C and cirrhosis that they may be at risk for hepatic decompensation when receiving alfa interferon therapy.
• •Advise patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away.
  • •yellowing of the skin or the whites of the eyes (jaundice)
  • •unusual darkening of the urine
  • •unusual tiredness
  • •right upper stomach area pain
  • •confusion
  • •swelling of the stomach area (abdomen)
• •Advise patients that thrombocytopenia and risk of bleeding may reoccur upon discontinuing PROMACTA, particularly if PROMACTA is discontinued while the patient is on anticoagulants or antiplatelet agents.
• •Advise patients that too much PROMACTA may result in excessive platelet counts and a risk for thrombotic/thromboembolic complications.
• •Advise patients that during therapy with PROMACTA, they should continue to avoid situations or medications that may increase the risk for bleeding.
• •Advise patients to have a baseline ocular examination prior to administration of PROMACTA and be monitored for signs and symptoms of cataracts during therapy.
• •Advise patients to keep at least a 4-hour interval between PROMACTA and foods, mineral supplements, and antacids which contain polyvalent cations such as iron, calcium, aluminum, magnesium, selenium, and zinc.

PROMACTA is a registered trademark of the GSK group of companies. The following are registered trademarks of their respective owners: PEGASYS/Hoffmann-La Roche Inc.; PEGINTRON/Schering Corporation.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2014, the GSK group of companies. All rights reserved.

PRM:7PI

MEDICATION GUIDE

PROMACTA^®(pro-MAC-ta)

(eltrombopag)

tablets

Read this Medication Guide before you start taking PROMACTA and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or treatment.

What is the most important information I should know about PROMACTA?

PROMACTA can cause serious side effects, including:

Liver problems. If you have chronic hepatitis C virus, and take PROMACTA with interferon and ribavirin treatment, PROMACTA may increase your risk of liver problems. Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems:

• •yellowing of the skin or the whites of the eyes (jaundice)
• •unusual darkening of the urine
• •unusual tiredness
• •right upper stomach area pain
• •confusion
• •swelling of the stomach area (abdomen)

See “What are the possible side effects of PROMACTA?” for other side effects of PROMACTA.

What is PROMACTA?

PROMACTA is a prescription medicine used to treat low blood platelet counts in people with:

• •chronic immune (idiopathic) thrombocytopenia (ITP), when other medicines to treat your ITP or surgery to remove the spleen have not worked well enough
• •chronic hepatitis C virus (HCV) infection before and during treatment with interferon

PROMACTA is used to try to raise your platelet count in order to lower your risk for bleeding.

PROMACTA is not used to make your platelet count normal.

PROMACTA is for treatment of certain people with low platelet counts caused by chronic ITP or chronic HCV, not low platelet counts caused by other conditions or diseases.

It is not known if PROMACTA is safe and effective when used with other antiviral medicines that are approved to treat chronic hepatitis C.

It is not known if PROMACTA is safe and effective in children.

What should I tell my healthcare provider before taking PROMACTA?

Before you take PROMACTA, tell your healthcare provider if you:

• •have liver or kidney problems
• •have or had a blood clot
• •have a history of cataracts
• •have had surgery to remove your spleen (splenectomy)
• •have bleeding problems
• •are Asian and you are of Chinese, Japanese, Taiwanese, or Korean ancestry. You may need a lower dose of PROMACTA.
• •have any other medical conditions
• •are pregnant or plan to become pregnant. It is not known if PROMACTA will harm an unborn baby.
  Pregnancy Registry: There is a registry for women who become pregnant during treatment with PROMACTA. If you become pregnant, consider this registry. The purpose of the registry is to collect safety information about the health of you and your baby. Contact the registry as soon as you become aware of the pregnancy, or ask your healthcare provider to contact the registry for you. You and your healthcare provider can get information and enroll in the registry by calling 1-888-825-5249.
• •are breastfeeding or plan to breastfeed. It is not known if PROMACTA passes into your breast milk. You and your healthcare provider should decide whether you will take PROMACTA or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. PROMACTA may affect the way certain medicines work. Certain other medicines may affect the way PROMACTA works.

Especially tell your healthcare provider if you take:

• •certain medicines used to treat high cholesterol, called “statins”
• •a blood thinner medicine

Certain medicines may keep PROMACTA from working correctly. Take PROMACTA at least 4 hours before or 4 hours after taking these products:

• •antacids used to treat stomach ulcers or heartburn
• •multivitamins or products that contain iron, calcium, aluminum, magnesium, selenium, and zinc which may be found in mineral supplements

Ask your healthcare provider if you are not sure if your medicine is one that is listed above.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take PROMACTA?

• •Take PROMACTA exactly as your healthcare provider tells you to take it. Do not stop taking PROMACTA without talking with your healthcare provider first. Do not change your dose or schedule for taking PROMACTA unless your healthcare provider tells you to change it.
• •Take PROMACTA on an empty stomach, either 1 hour before or 2 hours after eating food.
• •Take PROMACTA at least 4 hours before or 4 hours after eating dairy products and calcium fortified juices.
• •If you miss a dose of PROMACTA, wait and take your next scheduled dose. Do not take more than one dose of PROMACTA in one day.
• •If you take too much PROMACTA, you may have a higher risk of serious side effects. Call your healthcare provider right away.
• •Your healthcare provider will check your platelet count during your treatment with PROMACTA and change your dose of PROMACTA as needed.
• •Tell your healthcare provider about any bruising or bleeding that happens while you take and after you stop taking PROMACTA.

What should I avoid while taking PROMACTA?

Avoid situations and medicines that may increase your risk of bleeding.

What are the possible side effects of PROMACTA?

PROMACTA may cause serious side effects, including:

• •See “What is the most important information I should know about PROMACTA?”
• • Abnormal liver function tests. Your healthcare provider will order blood tests to check your liver before you start taking PROMACTA and during your treatment. In some cases treatment with PROMACTA may need to be stopped due to changes in your liver function tests.
• • High platelet counts and higher risk for blood clots. Your risk of getting a blood clot is increased if your platelet count is too high during treatment with PROMACTA. Your risk of getting a blood clot may also be increased during treatment with PROMACTA if you have normal or low platelet counts. You may have severe problems or die from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes. Your healthcare provider will check your blood platelet counts, and change your dose or stop PROMACTA if your platelet counts get too high. Tell your healthcare provider right away if you have signs and symptoms of a blood clot in the leg, such as swelling, pain, or tenderness in your leg.
  People with chronic liver disease may be at risk for a type of blood clot in the stomach area. Tell your healthcare provider right away if you have stomach area pain that may be a symptom of this type of blood clot.
• • New or worsened cataracts (a clouding of the lens in the eye). New or worsened cataracts have happened in people taking PROMACTA. Your healthcare provider will check your eyes before and during your treatment with PROMACTA. Tell your healthcare provider about any changes in your eyesight while taking PROMACTA.

The most common side effects of PROMACTA when used to treat chronic ITP are:

• •nausea
• •diarrhea
• •upper respiratory tract infection. Symptoms may include runny nose, stuffy nose, and sneezing
• •vomiting
• •muscle aches
• •urinary tract infection. Symptoms may include frequent or urgent need to urinate, low fever in some people, pain or burning with urination.
• •pain or swelling (inflammation) in your throat or mouth (oropharyngeal pain and pharyngitis)
• •abnormal liver function tests
• •back pain
• •“flu” like symptoms (influenza) including fever, headache, tiredness, cough, sore throat, and body aches
• •skin tingling, itching, or burning
• •rash

The most common side effects when PROMACTA is used in combination with other medicines to treat chronic HCV are:

• •low red blood cell count (anemia)
• •fever
• •tiredness
• •headache
• •nausea
• •diarrhea
• •decreased appetite
• •“flu” like symptoms (influenza) including fever, headache, tiredness, cough, sore throat, and body aches
• •feeling weak
• •trouble sleeping
• •cough
• •itching
• •chills
• •muscle aches
• •hair loss
• •swelling in your ankles, feet, and legs

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of PROMACTA. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store PROMACTA tablets?

• •Store PROMACTA at room temperature between 68^oF to 77^oF (20^oC to 25^oC).
• •Keep PROMACTA tightly closed in the bottle given to you.
• •The PROMACTA bottle may contain a desiccant pack to help keep your medicine dry. Do not remove the desiccant pack from the bottle.

Keep PROMACTA and all medicines out of the reach of children.

General information about the safe and effective use of PROMACTA

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PROMACTA for a condition for which it was not prescribed. Do not give PROMACTA to other people even, if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about PROMACTA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about PROMACTA that is written for health professionals.

For more information about PROMACTA, go to www.PROMACTA.com or call 1-888-825-5249.

What are the ingredients in PROMACTA?

Active ingredient: eltrombopag olamine.

Inactive ingredients:

• • Tablet Core: magnesium stearate, mannitol, microcrystalline cellulose, povidone, and sodium starch glycolate.
• • Coating: hypromellose (12.5 mg, 25 mg, 50 mg, and 75 mg tablets) or polyvinyl alcohol and talc (100 mg tablet), polyethylene glycol 400, titanium dioxide, polysorbate 80 (12.5 mg tablet), and FD&C Yellow No. 6 aluminum lake (25 mg tablet), FD&C Blue No. 2 aluminum lake (50 mg tablet), Iron Oxide Red and Iron Oxide Black (75 mg tablet), or Iron Oxide Yellow and Iron Oxide Black (100 mg tablet).

This Medication Guide has been approved by the U.S. Food and Drug Administration.

PROMACTA is a registered trademark of the GSK group of companies.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2014, the GSK group of companies. All rights reserved.

Revised: February 2014

PRM:7MG

PRINCIPAL DISPLAY PANEL

NDC 0007-4643-13

PROMACTA^®

(eltrombopag) Tablets

12.5 mg*

30 Tablets

R_x only

*Each tablet contains eltrombopag olamine equivalent to 12.5 mg of eltrombopag free acid.

Federal Law requires dispensing of PROMACTA^® with the Medication Guide provided with this bottle.

Store between 20^o and 25^oC (68^o to 77^oF); excursions permitted to 15^o to 30^oC (59^o to 86^oF).

Do not use if printed safety seal under cap is broken or missing.

Dosage: See accompanying prescribing information.

Important: Use safety closures when dispensing this product unless otherwise directed by physicians or requested by purchaser.

GlaxoSmithKline, RTP, NC 27709

Made in Ireland

10000000123247 Rev. 1/14