Revolade

Eltrombopag olamine.

Each 25- and 50-mg tablet contains eltrombopag olamine equivalent to eltrombopag 25 and 50 mg as eltrombopag free acid, respectively.

Pharmacology: Pharmacodynamics: Mechanism of Action: Thrombopoietin (TPO) is the main cytokine involved in regulation of megakaryopoiesis and platelet production, and is the endogenous ligand for the thrombopoietin-receptor (TPO-R). Eltrombopag interacts with the transmembrane domain of the human TPO-R and initiates signaling cascades similar but not identical to that of endogenous TPO inducing proliferation and differentiation of megakaryocytes from bone marrow progenitor cells.
Effects: Revolade differs from TPO with respect to the effects on platelet aggregation. Unlike TPO, Revolade treatment of normal human platelets does not enhance adenosine diphosphate (ADP)-induced aggregation or induce P-selectin expression. Revolade does not antagonize platelet aggregation induced by ADP or collagen.
Pharmacokinetics: The pharmacokinetic parameters of eltrombopag after administration of Revolade to patients with idiopathic thrombocytopenic purpura (ITP) are shown in table 1.

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Absorption and Bioavailability: Eltrombopag is absorbed with a peak concentration occurring 2-6 hrs after oral administration. Administration of Revolade concomitantly with antacids and other products containing polyvalent cations eg, dairy products and mineral supplements significantly reduces eltrombopag exposure (see Dosage & Administration and Interactions). The absolute oral bioavailability of eltrombopag after administration to humans has not been established. Based on urinary excretion and metabolites eliminated in feces, the oral absorption of drug-related material following administration of a single dose of eltrombopag 75 mg solution was estimated to be at least 52%.
Distribution: Eltrombopag is highly bound to human plasma proteins (>99.9%). Eltrombopag is a substrate for breast cancer resistance protein (BCRP), but is not a substrate for P-glycoprotein or organic anion transporter polypeptide (OATP1B1).
Metabolism: Eltrombopag is primarily metabolized through cleavage, oxidation and conjugation with glucuronic acid, glutathione or cysteine. In a human radiolabel study, eltrombopag accounted for approximately 64% of plasma radiocarbon AUC_0-∞. Minor metabolites, each accounting for <10% of the plasma radioactivity, arising from glucuronidation and oxidation were also detected. Based on a human study with radiolabel eltrombopag, it is estimated that approximately 20% of a dose is metabolized by oxidation. In vitro studies identified CYP1A2 and CYP2C8 as the isoenzymes responsible for oxidative metabolism, uridine diphosphoglucuronyl transferase UGT1A1 and UGT1A3 as the isozymes responsible for glucuronidation, and that bacteria in the lower gastrointestinal tract may be responsible for the cleavage pathways.
Elimination: Absorbed eltrombopag is extensively metabolized. The predominant route of eltrombopag excretion is via feces (59%) with 31% of the dose found in the urine as metabolites. Unchanged parent compound (eltrombopag) is not detected in urine. Unchanged eltrombopag excreted in feces accounts for approximately 20% of the dose. The plasma elimination t_½ of eltrombopag is approximately 21-32 hrs.
Interactions: Based on a human study with radiolabelled eltrombopag, glucuronidation plays a minor role in the metabolism of eltrombopag. Human liver microsome studies identified UGT1A1 and UGT1A3 as the enzymes responsible for eltrombopag glucuronidation. Eltrombopag was an inhibitor of a number of UGT enzymes in vitro. Clinically significant drug interactions involving glucuronidation are not anticipated due to limited contribution of individual UGT enzymes in the glucuronidation of eltrombopag and potential co-medications.
Based on a human study with radiolabelled eltrombopag, approximately 21% of an eltrombopag dose could undergo oxidative metabolism. Human liver microsome studies identified CYP1A2 and CYP2C8 as the enzymes responsible for eltrombopag oxidation. In studies utilizing human liver microsomes, eltrombopag (up to 100 microM) showed no in vitro inhibition of the CYP450 enzymes 1A2, 2A6, 2C19, 2D6, 2E1, 3A4/5 and 4A9/11 and was an inhibitor of CYP2C8 and CYP2C9 as measured using paclitaxel and diclofenac as the probe substrates, with IC₅₀ values of 24.8 microM (11 mcg/mL) and 20.2 microM (8.9 mcg/mL), respectively. Administration of Revolade 75 mg once daily for 7 days to 24 healthy male subjects did not inhibit or induce the metabolism of probe substrates for 1A2 (caffeine), 2C19 (omeprazole), 2C9 (flurbiprofen) or 3A4 (midazolam) in humans. No clinically significant interactions are expected when Revolade and CYP450 substrates, inducers or inhibitors are co-administered.
In vitro studies demonstrate that eltrombopag is an inhibitor of the OATP1B1 transporter, with an IC₅₀ value of 2.7 microM (1.2 mcg/mL) and an inhibitor of the BCRP transporter, with an IC₅₀ value of 2.7 microM (1.2 mcg/mL). Administration of Revolade 75 mg 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 rosuvastastin C_max 103% (90% CI: 82%, 126%) and AUC_0-∞ 55% (90% CI: 42%, 69%) (see Interactions).
Administration of a single dose of Revolade 75 mg with a polyvalent cation-containing antacid (aluminium hydroxide 1524 mg and magnesium carbonate 1425 mg) decreased plasma eltrombopag AUC_0-∞ by 70% (90% CI: 64%, 76%) and C_max by 70% (90% CI: 62 %, 76%) (see Dosage & Administration and Interactions).
Administration of a single 50-mg dose of Revolade with a standard high-calorie, high-fat breakfast that included dairy products reduced plasma eltrombopag AUC_(0-∞) by 59% (90% CI: 54%, 64%) and C_max by 65% (90% CI: 59%, 70%). Whereas, low-calcium food (<50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content (see Dosage & Administration and Interactions).
Special Patient Populations: Renal Impairment: The pharmacokinetics of eltrombopag has been studied after administration of Revolade to adult patients with renal impairment. Following administration of a single 50 mg-dose, the AUC_0-∞ of eltrombopag was decreased by 32% (90% CI: 63% decrease, 26% increase) in patients with mild renal impairment, 36% (90% CI: 66% decrease, 19% increase) in patients with moderate renal impairment, and 60% (90% CI: 18% decrease, 80% decrease) in patients with severe renal impairment compared with healthy volunteers. There was a trend for reduced plasma eltrombopag exposure in patients with renal impairment, but there was a substantial variability and significant overlap in exposures between patients with renal impairment and healthy volunteers. Patients with impaired renal function should use Revolade with caution and close monitoring (see Precautions). For patients with moderate and severe hepatic impairment, initiate Revolade at a reduced dose of 25 mg once daily (see Dosage & Administration).
Hepatic Impairment: The pharmacokinetics of eltrombopag has been studied after administration of Revolade to adult patients with hepatic impairment. Following the administration of a single 50-mg dose, the AUC_0-∞ of eltrombopag was increased by 41% (90% CI: 13% decreased, 128% increased) in patients with mild hepatic impairment, 93% (90% CI: 19%, 213%) in patients with moderate hepatic impairment and 80% (90% CI: 11%, 192%) in patients with severe hepatic impairment compared with healthy volunteers. There was substantial variability and significant overlap in exposures between patients with hepatic impairment and healthy volunteers.
Revolade should be used with caution and close monitoring to patients with hepatic impairment.
Race: The influence of East Asian ethnicity on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 111 healthy adults (31 East Asians) and 88 patients with ITP (18 East Asians). Based on estimates from the population pharmacokinetic analysis, East Asian (ie, Japanese, Chinese, Taiwanese and Korean) ITP patients had approximately 87% higher plasma eltrombopag AUC_0-τ values as compared to non-East Asian patients who were predominantly Caucasian, without adjustment for body weight differences (see Dosage & Administration).
Gender: The influence of gender on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 111 healthy adults (14 females) and 88 patients with ITP (57 females). Based on estimates from the population pharmacokinetic analysis, female ITP patients had approximately 50% higher plasma eltrombopag AUC_0-τ as compared to male patients, without adjustment for body weight differences.
Clinical Studies: The safety and efficacy of Revolade has been demonstrated in 2, randomized, double-blind, placebo-controlled studies (RAlSE TRA102537 and TRA100773B) and 2 open-label studies (REPEAT TRA108057 and EXTEND TRA105325) in adult patients with previously treated chronic ITP.
Double-Blind Placebo-Controlled Studies: TRA102537: In RAISE, the primary efficacy endpoint was the odds of achieving a platelet count ≥50,000/microliter and ≤400,000/microliter, during the 6-month treatment period for subjects receiving Revolade relative to placebo. One hundred and ninety seven (197) subjects were randomized 2:1, Revolade (n=135) to placebo (n=62), and were stratified based upon splenectomy status, use of ITP medication at baseline and baseline platelet count. Subjects received study medication for up to 6 months, during which time the dose of Revolade could be adjusted based on individual platelet counts. In addition, subjects could have tapered off concomitant ITP medications and received rescue treatments as dictated by local standard of care. The odds of achieving a platelet count between 50,000/microliter and 400,000/microliter during the 6-month treatment period were 8 times higher for Revolade-treated subjects than for placebo-treated subjects [Odds Ratio: 8.2 (99% CI:3.59, 18.73) p=<0.001]. Median platelet counts were maintained above 50,000/microliter at all on-therapy visits starting at day 15 in the Revolade group; in contrast, median platelet counts in the placebo group remained below 30,000/microliter throughout the study.
At baseline, 77% of subjects in the placebo group and 73% of subjects in the Revolade group reported any bleeding (WHO grades 1-4); clinically significant bleeding (WHO grades 2-4) at baseline was reported in 28% and 22% of subjects in the placebo and Revolade groups, respectively. The proportion of subjects with any bleeding (grades 1-4) and clinically significant bleeding (grades 2-4) was reduced from baseline by approximately 50% throughout the 6-month treatment period in Revolade-treated subjects. When compared to the placebo group, the odds of any bleeding (grades 1-4) and the odds of clinically significant bleeding (grades 2-4) were 76% and 65% lower in the Revolade-treated subjects compared to the placebo-treated subjects (p<0.001).
Revolade therapy allowed significantly more subjects to reduce or discontinue baseline ITP therapies compared to placebo (59% vs. 32%; p<0.016).
Significantly fewer Revolade-treated subjects required rescue treatment compared to placebo-treated subjects (19% vs. 40%; p=0.001).
Four placebo and 14 Revolade subjects had at least 1 hemostatic challenge (defined as an invasive diagnostic or surgical procedure) during the study. Fewer Revolade-treated subjects (29%) required rescue treatment to manage their hemostatic challenge compared to placebo-treated subjects (50%).
In terms of improvements in health-related quality of life, statistically significant improvements from baseline were observed in the Revolade group in fatigue, including severity and impact on thrombocytopenia-impacted daily activities and concerns [as measured by the vitality subscale of the Short Form(36) (SF36), the motivation and energy inventory and the 6-item extract from the thrombocytopenia subscale of the Functional Assessment of Chronic Illness Therapy with Thrombocytopenia (FACIT-Th)].
Comparing the Revolade group to the placebo group, statistically significant improvements were observed with thrombocytopenia impacted activities and concerns specifically regarding motivation, energy and fatigue, as well as physical and emotional role and overall mental health. The odds of meaningful improvement in health-related quality of life while on therapy was significantly greater among patients treated with Revolade than placebo.
TRA100773B: In TRA100773B, the primary efficacy endpoint was the proportion of responders, defined as patients who had an increase in platelet counts to ≥50,000/microliter at day 43 from a baseline <30,000/microliter; patients who withdrew prematurely due to a platelet count >200,000/microliter were considered responders, those discontinued for any other reason were considered nonresponders irrespective of platelet count. A total of 114 subjects with previously treated chronic ITP were randomized 2:1 into the study, with 76 randomized to Revolade and 38 randomized to placebo.
Fifty-nine percent of subjects on Revolade responded, compared to 16% of subjects on placebo. The odds of responding were 9 times higher for Revolade-treated subjects compared to placebo [Odds Ratio: 9.6 (95% CI: 3.31, 27.86) p<0.001]. At baseline, 61% of subjects in the Revolade group and 66% of subjects in the placebo group reported any bleeding (grade 1-4). At day 43, 39% of subjects in the Revolade treatment group had bleeding compared with 60% in the placebo group. Analysis over the treatment period using a repeated measures model for binary data confirmed that a lower proportion of Revolade subjects had bleeding (grade 1-4) at any point in time over the course of their treatment (day 8 up to day 43) compared to subjects in the placebo group [OR=0.49, 95% Cl=(0.26, 0.89), p=0.021]. Two placebo and 1 Revolade subject had at least 1 hemostatic challenge during the study.
In both RAISE and TRA100773B, the response to Revolade relative to placebo was similar irrespective of ITP medication use, splenectomy status and baseline platelet count (≤15,000/microliter, >15,000/microliter) at randomization.
Open Label Studies: TRA108057: REPEAT was an open-label, repeat-dose, study which evaluated the efficacy, safety and consistency of response following repeated, intermittent, short-term dosing of Revolade over 3 cycles of therapy in adults with previously treated chronic ITP. A cycle was defined as an up to 6-week on-therapy period followed by an up to 4-week off-therapy period. The primary endpoint in REPEAT was the proportion of subjects who achieved a platelet count of ≥50,000/microliter and at least 2x baseline in Cycle 2 or 3, given this response in Cycle 1.

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Of the 52 subjects who responded in Cycle 1, 33 (63%) achieved a platelet count of ≥50,000/microliter and at least 2x baseline on day 8 in Cycle 1; on day 15, 37 (79%) of 47 evaluable subjects achieved this level of response. A reduction in any bleeding (WHO grade 1-4) and clinically significant bleeding (WHO grade 2-4) during the treatment phases was demonstrated in each cycle. At the baseline visit of Cycle 1, 50% and 19% of subjects reported any bleeding and clinically significant bleeding, respectively. At the day 43 visit of Cycle 1, the proportion of subjects bleeding was reduced; 12% and 0% of subjects reported any bleeding and clinically significant bleeding, respectively. Similar results were found during the subsequent treatment cycles.
Eight subjects successfully managed 10 hemostatic challenges without need for additional therapy to elevate platelet counts and without unexpected bleeding.
TRA105325: EXTEND is an open-label extension study which has evaluated the safety and efficacy of Revolade in subjects with chronic ITP who were previously enrolled in an Revolade trial. In this study, subjects were permitted to modify their dose of study medication as well as decrease or eliminate concomitant ITP medications.
Revolade was administered to 207 patients; 104 completed 3 months of treatment, 74 completed 6 months and 27 patients completed 1 year of therapy. The median baseline platelet count was 18,000/microliter prior to Revolade administration. Median platelet counts at 3, 6 and 9 months on study were 86,000, 67,000 and 92,500/microliter, respectively. The median daily dose of Revolade following 6 months of therapy was 50 mg (n=74).
At baseline, 59% of subjects had any bleeding (WHO bleeding grades 1-4) and 18% had clinically significant bleeding. The proportion of subjects with any bleeding and clinically significant bleeding decreased from baseline by approximately 50% for the majority of assessments up to 1 year.
Seventy percent of subjects who reduced a baseline medication permanently discontinued or had a sustained reduction of their baseline ITP medication and did not require any subsequent rescue treatment. Sixty-five percent of these subjects maintained this discontinuation or reduction for at least 24 weeks. Sixty-one percent of subjects completely discontinued at least 1 baseline ITP medication and 55% of subjects permanently discontinued all baseline ITP medications, without subsequent rescue treatment.
Twenty-four subjects experienced at least 1 hemostatic challenge during the study. No subject experienced unexpected bleeding complications related to the procedure while on study.
Toxicology: Preclinical Safety Data: 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 and 5 times the human clinical exposure based on AUC, respectively). 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 the in vitro mouse lymphoma assay, eltrombopag was marginally positive (<3-fold increase in mutation frequency). These in vitro and in vivo findings suggest that Revolade does not pose a genotoxic risk to humans.
Eltrombopag was not teratogenic in rats or rabbits. Eltrombopag did not affect female fertility, early embryonic development or embryofetal development in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC). Also, there was no effect on embryofetal development in rabbits at doses up to 150 mg/kg/day, the highest dose tested (0.5 times the human clinical exposure based on AUC). However, at a maternally toxic dose of 60 mg/kg/day (6 times the human clinical exposure based on AUC) in rats, eltrombopag treatment was associated with embryo lethality (increased pre- and post-implantation loss) in the female fertility study, a low incidence of cervical ribs (a nonteratogenic fetal variation) in the embryofetal development study and reduced fetal body weight in both studies. 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).
Eltrombopag is phototoxic and photoclastogenic in vitro. However, in vitro photoclastogenic effects were observed only at drug concentrations that were cytotoxic (≥15 mcg/mL) in the presence of high UV light exposure intensity [30 minimal erythematous dose (MED)]. There was no evidence of in vivo cutaneous phototoxicity in mice at exposures up to 10 times the human clinical exposure based on AUC or photo-ocular toxicity in mice or rats at exposures up to 11 and 6 times the human clinical exposure based on AUC, respectively. Furthermore, a clinical pharmacology study in 36 subjects showed no evidence that photosensitivity was increased following administration of Revolade 75 mg once daily for 6 days. This was measured by delayed phototoxic index.
Treatment-related cataracts were detected in rodents and were dose and time-dependent. At ≥6 times the human clinical exposure based on AUC, cataracts were observed in mice after 6 weeks and rats after 28 weeks of dosing. At ≥4 times the human clinical exposure based on AUC, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing. Cataracts have not been observed in dogs after 52 weeks of dosing 2 times the human clinical exposure based on AUC. The clinical relevance of these findings is unknown (see Precautions).
Renal tubular toxicity was observed in studies of up to 14 days 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. Effects were less severe at lower doses and were characterized by a spectrum of regenerative changes. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC. Renal effects were not observed in rats after 28 weeks or in dogs after 52 weeks at exposures 4 and 2 times respectively, the human clinical exposure based on AUC. The clinical relevance of these findings is unknown.

Eltrombopag (Revolade) is indicated: for the treatment of previously treated adult and pediatric patients 1 year and older with immune thrombocytopenia (ITP) lasting 6 months or longer from diagnosis to increase platelet counts and reduce or prevent bleeding.
Patients with chronic hepatitis C virus (HCV) infection for the treatment of thrombocytopenia to: enable the initiation of interferon based therapy; optimize interferon based therapy.
In combination with standard immunosuppressive therapy for the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia (first-line SAA).
For the treatment of cytopenias in patients with severe aplastic anemia (refractory SAA) who have had an insufficient response to immunosuppressive therapy.

Revolade dosing regimens must be individualized based on the patient's platelet counts.
Use the lowest effective dosing regimen to maintain platelet counts, as clinically indicated.
In most patients, measurable elevations in platelet count take 1-2 weeks (see Clinical Studies under Actions).
Adults: Recommended Starting Dose: 50 mg once daily.
Monitoring and Dose Adjustment: After initiating Revolade, adjust the dose to achieve and maintain a platelet count of ≥50,000/microliter as necessary to reduce the risk for bleeding. Do not exceed a dose of 75 mg daily.
Clinical hematology and liver function tests should be monitored regularly throughout therapy with Revolade and the dose regimen modified based on platelet counts as outlined in the following text. During therapy with Revolade, complete blood counts (CBCs), including platelet count and peripheral blood smears, should be assessed weekly until a stable platelet count (≥50,000/microliter for at least 4 weeks) has been achieved. Complete blood counts including platelet counts and peripheral blood smears should be obtained monthly thereafter.
The lowest effective dosing regimen to maintain platelet counts should be used as clinically indicated.
Dose Adjustments of Revolade: Platelet Count: <50,000/microliter. Dose Adjustment or Response: Increase daily dose by 25 mg to a maximum of 75 mg/day following at least 2 weeks of therapy.
≥200,000-≤400,000/microliter: Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.
>400,000/microliter: Stop Revolade; increase the frequency of platelet monitoring to twice weekly. Once the platelet count is <150,000/microliter, reinitiate therapy at a lower daily dose.
After any Revolade dose adjustment, platelet counts should be monitored at least weekly for 2-3 weeks. Wait for at least 2 weeks to see the effect of any dose adjustment on the patient's platelet response prior to considering another dose adjustment.
The standard Revolade dose adjustment, either decrease or increase, would be 25 mg once daily. However, in a few patients, a combination of different tablet strengths on different days may be required.
East Asian Patients: Revolade should be initiated at a reduced dose of 25 mg once daily for patients of East Asian ancestry (eg, Chinese, Japanese, Taiwanese or Korean) (see Pharmacokinetics: Special Patient Populations under Actions). Patient platelet count should continue to be monitored and the standard criteria for further dose modification followed.
Hepatic Impairment: Initiate 25 mg once daily (see Pharmacokinetics: Special Patient Populations under Actions).
Discontinuation of Treatment: Revolade should be discontinued if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of Revolade therapy at 75 mg once daily.
Administration: Revolade should be taken at least 4 hrs before or after any products eg, antacids, dairy products or mineral supplements containing polyvalent cations (eg, aluminium, calcium, iron, magnesium, selenium and zinc) (see Pharmacokinetics: Absorption under Actions and Interactions).
Revolade may be taken with food containing little (<50 mg) or preferably no calcium (see Pharmacokinetics under Actions and Interactions).

Symptoms: In the clinical trials, there was 1 report of overdose where the subject ingested Revolade 5000 mg. Reported adverse events included mild rash, transient bradycardia, fatigue and elevated transaminases. Liver enzymes measured between days 2 and 18 after ingestion peaked at a 1.6-fold upper limit of normal (ULN) in aspartate aminotransferase (AST), a 3.9-fold ULN in alanine transaminase (ALT) and a 2.4-fold ULN in total bilirubin. The platelet counts were 672,000/microliter on day 18 after ingestion and the maximum platelet count was 929,000/microliter. All events were resolved without sequelae following treatment.
Treatment: In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In case of an overdose, consider oral administration of a metal cation-containing preparation eg, calcium, aluminium or magnesium preparations to chelate eltrombopag and thus limit absorption. Closely monitor platelet counts. Reinitiate treatment with Revolade in accordance with dosing and administration recommendations (see Dosage & Administration).
Because eltrombopag is not significantly renally excreted and is highly bound to plasma proteins, hemodialysis would not be expected to be an effective method to enhance the elimination of eltrombopag.

There are no known contraindications associated with Revolade.

The effectiveness and safety of Revolade have not been established for use in other thrombocytopenic conditions including chemotherapy-induced thrombocytopenia and myelodysplastic syndromes (MDS).
Hepatic Monitoring: Revolade administration can cause hepatobiliary laboratory abnormalities. In clinical trials with Revolade, increases in ALT, AST and indirect bilirubin were observed (see Adverse Reactions).
These findings were mostly mild (grade 1-2), reversible and not accompanied by clinically significant symptoms that would indicate an impaired liver function. In 2 placebo-controlled studies, adverse events of ALT increase were reported in 5.7% and 4% of Revolade- and placebo-treated patients, respectively.
Measure serum ALT, AST and bilirubin prior to initiation of Revolade, every 2 weeks during the dose adjustment phase and monthly following establishment of a stable dose. Evaluate abnormal serum liver tests with repeat testing within 3-5 days. If the abnormalities are confirmed, monitor serum liver tests until the abnormalities resolve, stabilize or return to baseline levels. Discontinue Revolade if ALT levels increase (≥3x ULN) and are progressive or persistent for ≥4 weeks, or accompanied by increased direct bilirubin or clinical symptoms of liver injury or evidence for hepatic decompensation.
Exercise caution and close monitoring when administering Revolade to patients with hepatic disease/impairment.
Thrombotic/Thromboembolic (TEE) Complications: Thromboembolic events may occur in patients with ITP. Platelet counts above the normal range present a theoretical risk for TEE complications. In Revolade clinical trials, thromboembolic events were observed at low and normal platelet counts. In ITP studies, 21 TEE events were observed in 17 out of 446 subjects (3.8%). The TEE events included: Embolism including pulmonary embolism, deep vein thrombosis, transient ischemic attack, myocardial infarction, ischemic stroke and suspected prolonged reversible ischemic neurologic deficiency (PRlND).
Use caution when administering Revolade to patients with known risk factors for thromboembolism [eg, factor V Leiden, antithrombin III (ATlll) deficiency, antiphospholipid syndrome]. Platelet counts should be closely monitored and consideration given to reducing the dose or discontinuing Revolade treatment if the platelet counts exceeds the target levels (see Dosage & Administration).
In a controlled study in thrombocytopenic patients with chronic liver disease (n=288) undergoing elective invasive procedures, the risk of thrombotic events was increased in patients treated with Revolade 75 mg once daily for 14 days. Six thrombotic complications were reported within the group that received Revolade and 1 within the placebo group. All of the thrombotic complications reported within the Revolade group were of the portal venous system.
Bleeding Following Discontinuation of Revolade: Following discontinuation of Revolade, platelet counts return to baseline levels within 2 weeks in the majority of patients (see Pharmacokinetics: Clinical Studies under Actions), which increases the bleeding risk and in some cases may lead to bleeding. Platelet counts must be monitored weekly for 4 weeks following discontinuation of Revolade.
Bone Marrow Reticulin Formation and Risk of Bone Marrow Fibrosis: Thrombopoietin receptor agonists, including Revolade, may increase the risk for development or progression of reticulin fibers within the bone marrow.
Prior to initiation of Revolade, examine the peripheral blood smear closely to establish a baseline level of cellular morphologic abnormalities. Following identification of a stable dose of Revolade, perform CBC with white blood cell count (WBC) differential monthly. If immature or dysplastic cells are observed, examine peripheral blood smears for new or worsening morphological abnormalities (eg, teardrop and nucleated red blood cells, immature WBC) or cytopenia(s). If the patient develops new or worsening morphological abnormalities or cytopenia(s), discontinue treatment with Revolade and consider a bone marrow biopsy, including staining for fibrosis.
Malignancies and Progression of Malignancies: There is a theoretical concern that TPO-R agonists may stimulate the progression of existing hematological malignancies eg, MDS. Across the clinical trials in ITP (n=493), no difference in the incidence of malignancies or hematological malignancies was demonstrated between placebo- and Revolade-treated patients. This is consistent with information derived from nonclinical research, where no malignant cell proliferation has been demonstrated upon co-incubation of Revolade with MDS cell lines, multiple leukemic cell lines and solid tumor cell lines (colon, prostate, ovary and lung).
Cataracts: Cataracts were observed in toxicology studies of Revolade in rodents. The clinical relevance of this finding is unknown. Routine monitoring of patients for cataracts is recommended.
Effects on the Ability to Drive or Operate Machinery: There have been no studies to investigate the effect of Revolade on driving performance or the ability to operate machinery. A detrimental effect on such activities would not be anticipated from the pharmacology of eltrombopag. The clinical status of the patient and the adverse event profile of Revolade should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor and cognitive skills.
Use in pregnancy & lactation: Eltrombopag was not teratogenic when studied in pregnant rats and rabbits but caused a low incidence of cervical ribs (a fetal variation) and reduced fetal body weight at doses that were maternally toxic.
There are no adequate and well-controlled studies of Revolade in pregnant women. The effect of Revolade on human pregnancy is unknown. Revolade should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus.
It is not known whether eltrombopag is excreted in human milk. Revolade is not recommended for nursing mothers unless the expected benefit justifies the potential risk to the infant.
Use in children: The safety and efficacy of Revolade in children have not been established.
Use in the elderly: There are limited data on the use of Revolade in patients ≥65 years. In the clinical studies of Revolade, overall no clinically significant differences in safety of Revolade were observed between subjects at least 65 years and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Eltrombopag was not teratogenic when studied in pregnant rats and rabbits but caused a low incidence of cervical ribs (a fetal variation) and reduced fetal body weight at doses that were maternally toxic.
There are no adequate and well-controlled studies of Revolade in pregnant women. The effect of Revolade on human pregnancy is unknown. Revolade should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus.
It is not known whether eltrombopag is excreted in human milk. Revolade is not recommended for nursing mothers unless the expected benefit justifies the potential risk to the infant.

The safety and efficacy of Revolade has been demonstrated in 2 randomized, double-blind, placebo-controlled studies (RAISE TRA102537 and TRA100773B) in adults with previously treated chronic ITP. In the RAISE study, 197 subjects were randomized 2:1, Revolade (n=135) to placebo (n=62). Subjects received study medication for up to 6 months. In TRA100773B, 114 patients were randomized and treated for up to 42 days with either placebo (n=38) or Revolade (n=76).
Most undesirable reactions associated with Revolade were mild to moderate in severity, early in onset and rarely treatment limiting.
Adverse reactions are listed as follows by MedDRA body system organ class and by frequency. The frequency categories used are: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000).
The adverse reactions identified in subjects treated with Revolade are presented as follows: Infections and Infestations: Common: Pharyngitis, urinary tract infection.
Gastrointestinal Disorders: Very Common: Nausea, diarrhea. Common: Dry mouth, vomiting.
Hepatobiliary Disorders: Common: Increased AST and ALT.
Skin and Subcutaneous Tissue Disorders: Common: Alopecia, rash.
Musculoskeletal and Connective Tissue Disorder: Common: Back pain, musculoskeletal chest and musculoskeletal pain, myalgia.
Post-Marketing Data: No post-marketing data are currently available.

Drug Interactions: Rosuvastatin: In vitro studies demonstrated that eltrombopag is not a substrate for the OATP1B1 but is an inhibitor of this transporter and that eltrombopag is a BCRP substrate and inhibitor. When Revoladem and rosuvastatin were co-administered in a clinical drug interaction study (see Pharmacokinetics under Actions) there was increased plasma rosuvastatin exposure. When co-administered with Revolade, a reduced dose of rosuvastatin should be considered and careful monitoring should be undertaken. In clinical trials with Revolade, a dose reduction of rosuvastatin by 50% was recommended for co-administration of rosuvastatin and Revolade. Concomitant administration of Revolade and other OATP1B1 and BCRP substrates should be undertaken with caution.
Polyvalent Cations (Chelation): Eltrombopag chelates with polyvalent cations eg, aluminium, calcium, iron, magnesium, selenium and zinc (see Pharmacokinetics under Actions). Antacids, dairy products and other products containing polyvalent cations eg, mineral supplements should be administered at least 4 hrs apart from Revolade dosing to avoid significant reduction in eltrombopag absorption (see Dosage & Administration).
Food Interaction: Administration of a single 50 mg-dose of Revolade with a standard high-calorie, high-fat breakfast that included dairy products reduced plasma eltrombopag AUC_0-∞ by 59% (90% CI: 54%, 64%) and C_max by 65% (90% CI: 59%, 70%). Food low in calcium (<50 mg calcium) including fruit, lean ham, beef and unfortified (no added calcium, magnesium, iron) fruit juice, soy milk and grain did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content (see Dosage & Administration).

Store at temperatures not exceeding 30°C.

Haemostatics

B02BX05 - eltrombopag ; Belongs to the class of other systemic hemostatics. Used in the treatment of hemorrhage.

Rx