ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are discussed in detail in other sections of the labeling:Thrombotic/Thromboembolic Complications see Warnings and Precautions 5.1 ] Thrombotic/Thromboembolic Complications see Warnings and Precautions 5.1 ] In adult patients with chronic liver disease, the most common adverse reactions (>=3%) were pyrexia, abdominal pain, nausea, headache, fatigue, and edema peripheral. (6.1)In adult patients with chronic immune thrombocytopenia, the most common adverse reactions (>=10%) were headache, fatigue, contusion, epistaxis, upper respiratory tract infection, arthralgia, gingival bleeding, petechiae and nasopharyngitis. (6.1)In pediatric patients with persistent or chronic immune thrombocytopenia, the most common adverse reactions (>=10%) were viral infection, nasopharyngitis, cough, pyrexia, and oropharyngeal pain. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Sobi, Inc. at 1-866-773-5274 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Patients with Chronic Liver DiseaseThe safety of DOPTELET was evaluated in two international, identically designed, randomized, double-blind, placebo-controlled trials, ADAPT-1 and ADAPT-2, in which 430 patients with chronic liver disease and thrombocytopenia received either DOPTELET (n=274) or placebo (n=156) daily for days prior to scheduled procedure, and had post-dose safety assessment. Patients were divided into two groups based on their mean platelet count at baseline:Low Baseline Platelet Count Cohort (less than 40x109/L) who received DOPTELET 60 mg once daily for daysHigh Baseline Platelet Count Cohort (40 to less than 50x109/L) who received DOPTELET 40 mg once daily for daysThe majority of patients were males (65%) and median subject age was 58 years (ranging from 19-86 years of age). The racial and ethnic distribution was White (60%), Asian (33%), Black (3%) and Other (3%).The most common adverse reactions (those occurring in >=3% of patients) in the DOPTELET-treated groups (60 mg or 40 mg) across the pooled data from the two trials are summarized in Table 8.Table 8: Adverse Reactions with Frequency >=3% in Patients with Chronic Liver Disease Treated with DOPTELET Pooled Data ADAPT-1 and ADAPT-2Adverse ReactionsLow Baseline Platelet Count Cohort(40x109/L)High Baseline Platelet Count Cohort(>=40 to 50x109/L)Combined Baseline Platelet Count Cohorts(50x109/L)DOPTELET60 mg(N=159) %Placebo(N=91) %DOPTELET40 mg(N=115) %Placebo(N=65)%TotalDOPTELET(N=274)%TotalPlacebo(N=156)%Pyrexia11989109Abdominal Pain677676Nausea687677Headache487566Fatigue443243Edema Peripheral324232For the Low Baseline Platelet Count Cohort, the incidence of serious adverse reactions was 7% (11/159) in the 60 mg DOPTELET treatment group. For the High Baseline Platelet Count Cohort, the incidence of serious adverse reactions was 8% (9/115) in the 40 mg DOPTELET treatment group. The most common serious adverse reaction reported with DOPTELET was hyponatremia. Two DOPTELET-treated patients (0.7%) developed hyponatremia.Adverse reactions resulting in discontinuation of DOPTELET were anemia, pyrexia, and myalgia; each was reported in single (0.4%) patient in the DOPTELET (60 mg) treatment group.Adult Patients with Chronic Immune ThrombocytopeniaThe safety of DOPTELET was evaluated in four clinical trials in adult patients with chronic immune thrombocytopenia: two Phase trials (one randomized, double-blind, placebo-controlled trial, and one randomized, double-blind, active-controlled trial) and two Phase trials (one randomized, double-blind, placebo-controlled, dose-ranging, trial, and one open-label extension trial) in 161 patients with chronic immune thrombocytopenia in both the double-blind and open-label extension phases.The pooled safety data from these four clinical trials includes 128 patients who received 2.5 to 40 mg of DOPTELET once daily for median duration of exposure of 29.1 weeks and had post-dose safety assessment. The majority of patients were female (63%) and median subject age was 50.5 years (ranging from 18-88 years of age). The racial and ethnic distribution was White (84%), Black (6%), Asian (6%) and Other (6%).The most common adverse reactions (those occurring in >=10% of patients) in the DOPTELET-treated patients across the pooled safety data from the four trials are summarized in Table 9.Table 9: Adverse Reactions with Frequency >=10% in Adult Patients with Chronic Immune Thrombocytopenia Treated with DOPTELET Pooled Data from Clinical TrialsAdverse ReactionsDOPTELET (N=128)%Placebo (N= 22)%Headache3114Fatigue289Contusion2618Epistaxis1918Upper Respiratory Tract Infection155Arthralgia130Gingival Bleeding130Petechiae119Nasopharyngitis100The incidence of serious adverse reactions was 9% (12/128) in the DOPTELET treatment group. Serious adverse reactions reported in more than individual DOPTELET-treated patient included headache, occurring in 1.6% (2/128).Adverse reactions resulting in discontinuation of DOPTELET that were reported in more than patient included headache, occurring in 1.6% (2/128).Pediatric Patients with Persistent or Chronic Immune ThrombocytopeniaThe data described below reflect median exposure to DOPTELET of 12 weeks for 54 pediatric patients (>=1 to <18 years of age) with persistent or chronic immune thrombocytopenia across the core phase of one double-blind, placebo-controlled trial [see Clinical Studies 14.3 )].Table 10 presents the most common adverse reactions (experienced by greater than or equal to 10% of pediatric patients year and older receiving DOPTELET) with higher incidence for DOPTELET versus placebo.Table 10: Adverse Reactions in Pediatric Patients with Persistent or Chronic Immune Thrombocytopenia Treated with DOPTELETa Adverse ReactionsDOPTELET(N=54) %Placebo(N=21) %Viral Infectionb 205Nasopharyngitis2010Cough170Pyrexia170Oropharyngeal Pain130a Adverse reactions that occurred in >=10% of DOPTELET-treated patients and >=2% more than placebo-treated patients.b Viral infection includes viral upper respiratory infection, viral infection, COVID-19, parainfluenza virus infection, and rhinovirus infection.Two patients experienced serious adverse reactions: thrombocytosis and headache. Two patients experienced adverse reactions resulting in discontinuation of DOPTELET: vomiting and headache (in one patient) and leukocytosis (in one patient).. Low Baseline Platelet Count Cohort (less than 40x109/L) who received DOPTELET 60 mg once daily for days. High Baseline Platelet Count Cohort (40 to less than 50x109/L) who received DOPTELET 40 mg once daily for days. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post approval use of DOPTELET. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Immune System Disorders: Hypersensitivity reactions including pruritus, rash, choking sensation, erythema, pharyngeal edema, pruritus generalized, rash macular, swelling face, and swollen tongue.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In two-year carcinogenicity studies, avatrombopag was administered orally at doses of 20, 60, and 160 mg/kg/day in mice and doses of 20, 50, and 160 mg/kg/day in rats. Avatrombopag induced statistically significant increase in neuroendocrine cell (enterochromaffin-like cell, ECL cell) gastric tumors (carcinoids) in the stomach at 160 mg/kg in female rats. The 160 mg/kg/day dose resulted in exposures 117 times the AUC observed in patients at the maximum recommended dose of 60 mg once daily. The gastric carcinoids were considered likely due to prolonged hypergastrinemia observed in toxicity studies. Hypergastrinemia-related gastric carcinoids in rodents are generally considered to be of low risk or relevance to humans.Avatrombopag was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro human lymphocyte chromosomal aberrations assay or in an in vivo rat bone marrow micronucleus assay.Avatrombopag did not affect fertility or early embryonic development in male rats at exposures 22 times, or in female rats at exposures 114 times, the AUC observed in patients at the maximum recommended dose of 60 mg once daily.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Avatrombopag is an orally bioavailable, small molecule TPO receptor agonist that stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells, resulting in an increased production of platelets. Avatrombopag does not compete with TPO for binding to the TPO receptor and has an additive effect with TPO on platelet production.. 12.2 Pharmacodynamics. Platelet ResponseDOPTELET tablet administered to adult patients resulted in dose- and exposure-dependent elevations in platelet counts. The onset of the platelet count increase was observed within to days of the start of treatment, with peak effect after 10 to 13 days. Post treatment, platelet counts decreased gradually, returning to near baseline values.Cardiac ElectrophysiologyAt exposures similar to that achieved at the 40 mg and 60 mg tablet dose, DOPTELET did not prolong the QT interval to any clinically relevant extent. Mean QTc prolongation effects >20 ms are not anticipated with the highest recommended therapeutic dosing regimen based on analysis of data from the pooled clinical trials in patients with chronic liver disease.. 12.3 Pharmacokinetics. The pharmacokinetics of avatrombopag were determined following administration of DOPTELET tablets, and pharmacokinetic parameters are presented as geometric mean (CV%) unless otherwise specified. Avatrombopag demonstrated dose-proportional pharmacokinetics after single doses from 10 mg (0.5 times the lowest approved dosage) to 80 mg (1.3 times the highest recommended dosage). Healthy subjects administered 40 mg of avatrombopag had geometric mean (%CV) maximal concentration (Cmax) of 166 (84%) ng/mL and area under the time-concentration curve extrapolated to infinity (AUC0-inf) of 4198 (83%) ng.hr/mL. The pharmacokinetics of avatrombopag were similar in both healthy subjects and the chronic liver disease population.The relative bioavailability of DOPTELET SPRINKLE compared to DOPTELET tablet has not been studied. However, prototype of DOPTELET SPRINKLE demonstrated 22% higher geometric mean Cmax and 38% higher geometric mean AUC for avatrombopag compared to DOPTELET tablet, both administered to healthy adult subjects under the fed condition.Table 11 summarizes avatrombopag exposure in virtual adult population and in pediatric patients with persistent or chronic immune thrombocytopenia.Table 11: Summary of Avatrombopag Exposure in Virtual Adult Population and Pediatric Patients with Persistent or Chronic Immune Thrombocytopenia CohortAdults20 mg daily DOPTELET tablet>=12 to <18 yearsN=2120 mg daily DOPTELET tablet>=6 to <12 yearsN=2020 mg daily DOPTELET tablet>=1 to <6 yearsN=1210 mg daily DOPTELET SPRINKLECmax,ss (ng/mL) Geometric mean (CV)165 (61.3)168 (36.7)267 (25.7)221 (35.6)AUCss (ng h/mL) Geometric mean (CV)3277 (62.2)3372 (41.5)4942 (28.7)4030 (38.6)AUCss area under the concentration time curve at steady-state; Cmax,ss maximal concentration at steady-state; CV coefficient of variation expressed as percent; = number of individuals.AbsorptionThe median time to maximal concentration (Tmax) occurred at to hours post-dose.Effect of FoodAvatrombopag AUC0-inf and Cmax were not affected when DOPTELET tablets were co-administered with low-fat meal (500 calories, g fat, 15 protein, and 108 carbohydrates) or high-fat meal (918 calories, 59 fat, 39 protein, and 59 carbohydrates). The variability of avatrombopag exposure was reduced by 40% to 60% with food. The Tmax of avatrombopag was delayed by to hours when DOPTELET tablets were administered with low-fat or high-fat meal (median Tmax range to hours) compared to the fasted state.Geometric mean exposure increased by approximately 19% and 32% for Cmax and AUC, respectively, when prototype of DOPTELET SPRINKLE was administered in the fed state compared to the fasted state, and between-subject variability estimates for AUC and Cmax were decreased after administration in the fed state.DistributionAvatrombopag has an estimated mean apparent volume of distribution (%CV) of 180 (25%). Avatrombopag is greater than 96% bound to human plasma proteins.EliminationThe mean plasma elimination half-life (%CV) of avatrombopag is approximately 19 hours (19%). The mean (%CV) of the apparent clearance of avatrombopag is estimated to be 6.9 L/hr (29%).MetabolismAvatrombopag is primarily metabolized by cytochrome P450 CYP2C9 and CYP3A4.ExcretionFecal excretion accounted for 88% of the administered dose, with 34% of the dose excreted as unchanged avatrombopag. Only 6% of the administered dose was found in urine.Specific PopulationsAge (1-86 years), sex, race [Whites, African-Americans, and East Asians (i.e., Japanese, Chinese and Koreans)], and any hepatic impairment (Child-Turcotte-Pugh (CTP) grade A, B, and C, or Model for End-Stage Liver Disease (MELD) score 4-23) and mild to moderate renal impairment (CLcr >=30 mL/min) did not have clinically meaningful effects on the pharmacokinetics of avatrombopag.Lower body weight was associated with higher avatrombopag Cmax and AUC following the proposed starting dose in patients aged years and older weighing 16.3 to 175 kg. Pediatric patients aged to less than years had 34% higher Cmax and 23% higher AUC following administration of 10 mg daily DOPTELET SPRINKLE compared to adults who received 20 mg daily DOPTELET tablets.The effect of severe renal impairment (CLcr <30 mL/min, Cockcroft-Gault), including patients requiring hemodialysis, on avatrombopag pharmacokinetics is unknown.Drug InteractionsClinical StudiesTable 12 summarizes the effect of other drugs on the pharmacokinetics of avatrombopag.Table 12: Drug Interactions: Changes in Pharmacokinetics of Avatrombopag in the Presence of Co-Administered Drug Co-administered DrugGeometric Mean Ratio (90% CI) of Avatrombopag PK with/without Co-administered Drug [No Effect=1.00]AUC0-inf Cmax Strong CYP3A InhibitorItraconazole1.37 (1.10, 1.72)1.07 (0.86, 1.35)Moderate CYP3A and CYP2C9 InhibitorFluconazole2.16 (1.71, 2.72)1.17 (0.96, 1.42)Moderate CYP2C9 and Strong CYP3A InducerRifampin0.57 (0.47, 0.62)1.04 (0.88, 1.23)P-gp InhibitorCyclosporine0.83 (0.65, 1.04)0.66 (0.54, 0.82)P-gp and Moderate CYP3A InhibitorVerapamil1.61 (1.21, 2.15)1.26 (0.96, 1.66)at steady state, except for cyclosporine which was administered as single dose.In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated ClinicallyCYP enzymes: Avatrombopag does not inhibit CYP1A, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A, does not induce CYP1A, CYP2B6, CYP2C or CYP3A, and weakly induces CYP2C8 and CYP2C9.Transporter systems: Avatrombopag inhibits organic anion transporter (OAT) and breast cancer resistance protein (BCRP), but not organic anion transporter polypeptide (OATP) 1B1 or 1B3, organic cation transporter (OCT) or OAT1.Avatrombopag is not substrate for OATP1B1, OATP1B3, OCT2, OAT1 or OAT3.. 12.5 Pharmacogenomics. The CYP2C92 and CYP2C93 loss-of-function polymorphisms result in reduced CYP2C9 enzymatic activity. In pooled pharmacogenomic analysis of avatrombopag studies, subjects heterozygous for CYP2C9 loss-of-function polymorphisms (intermediate metabolizers [n=24]) had approximately 1.4-fold higher exposure and subjects homozygous for CYP2C9 loss-of-function polymorphisms (poor metabolizers [n=2]) had approximately 2-fold higher exposure compared to subjects wild-type for CYP2C9 (normal metabolizers [n=94]).

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Patients with Chronic Liver Disease. The efficacy of DOPTELET for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo procedure was established in identically-designed multicenter, randomized, double-blind, placebo-controlled trials (ADAPT-1 [NCT01972529] and ADAPT-2 [NCT01976104]). In each trial, patients were assigned to the Low Baseline Platelet Count Cohort (<40x10] and ADAPT-2 [NCT01976104]). In each trial, patients were assigned to the Low Baseline Platelet Count Cohort (<40x109/L) or the High Baseline Platelet Count Cohort (>=40 to <50x109/L) based on their platelet count at baseline. Patients were then randomized in 2:1 ratio to either DOPTELET or placebo. Patients were stratified according to hepatocellular cancer (HCC) status and risk of bleeding associated with the elective procedure (low, moderate, or high). Patients undergoing neurosurgical interventions, thoracotomy, laparotomy or organ resection were not eligible for enrollment.Patients in the Low Baseline Platelet Count Cohort received 60 mg DOPTELET or matching placebo once daily for days, and patients in the High Baseline Platelet Count Cohort received 40 mg DOPTELET or matching placebo once daily for days. Eligible patients were scheduled to undergo their procedure (low, moderate, or high bleeding risk) to days after their last dose of treatment. Patient populations were similar between the pooled Low and High Baseline Platelet Count Cohorts and consisted of 66% male and 35% female; median age 58 years and 61% White, 34% Asian, and 3% Black.In ADAPT-1, total of 231 patients were randomized, 149 patients were treated with DOPTELET and 82 patients were treated with placebo. In the Low Baseline Platelet Count Cohort, the mean baseline platelet count for the DOPTELET-treated group was 31.1x109/L and for the placebo-treated patients was 30.7x109/L. In the High Baseline Platelet Count Cohort, the mean baseline platelet count for the DOPTELET-treated patients was 44.3x109/L and for placebo-treated patients was 44.9x109/L.In ADAPT-2, total of 204 patients were randomized, 128 patients were treated with DOPTELET and 76 patients were treated with placebo. In the Low Baseline Platelet Count Cohort, the mean baseline platelet count for the DOPTELET-treated group was 32.7x109/L and for the placebo-treated patients was 32.5x109/L. In the High Baseline Platelet Count Cohort, the mean baseline platelet count for the DOPTELET-treated patients was 44.3x109/L and for the placebo-treated patients was 44.5x109/L.Across both baseline platelet count cohorts and the avatrombopag and placebo treatment groups, patients underwent broad spectrum of types of scheduled procedures that ranged from low to high bleeding risk. Overall, the majority of patients (60.8% [248/430] subjects) in all treatment groups underwent low bleeding risk procedures, 17.2% (70/430) of patients underwent procedures associated with moderate bleeding risk, and 22.1% (90/430) of subjects underwent procedures associated with high bleeding risk. The proportions of patients undergoing low, moderate, and high-risk procedures were similar between the avatrombopag and placebo treatment groups.The major efficacy outcome was the proportion of patients who did not require platelet transfusion or any rescue procedure for bleeding after randomization and up to days following an elective procedure. Additional secondary efficacy outcomes were the proportion of patients who achieved platelet counts of >50x109/L on the day of procedure, and the change in platelet count from baseline to procedure day.Responders were defined as patients who did not require platelet transfusion or any rescue procedure for bleeding after randomization and up to days following scheduled procedure. The following were considered rescue therapies to manage the risk of bleeding associated with procedure: whole blood transfusion, packed red blood cell (RBC) transfusion, platelet transfusion, fresh frozen plasma (FFP) or cryoprecipitate administration, Vitamin K, desmopressin, recombinant activated factor VII, aminocaproic acid, tranexamic acid, or surgical or interventional radiology procedures performed to achieve hemostasis and control blood loss. In both baseline platelet count cohorts, patients in the DOPTELET treatment groups had greater proportion of responders than the corresponding placebo treatment groups that was both clinically meaningful and statistically significant as detailed in Table 13. Table 13: Proportion of Patients Not Requiring Platelet Transfusion or Any Rescue Procedure for Bleeding by Baseline Platelet Count Cohort and Treatment Group ADAPT-1 andADAPT-2Low Baseline Platelet Count Cohort (<40x109/L)CategoryADAPT-1ADAPT-2DOPTELET60 mg(n=90)Placebo(n=48)DOPTELET60 mg(n=70)Placebo(n=43)Responders95% CIa66%(56, 75)23%(11, 35)69%(58, 79)35%(21, 49)Difference of Proportion vs. Placebob95% CIc43%(27, 58)34%(16, 52)p-valued0.00010.0006High Baseline Platelet Count Cohort(>=40 to <50x109/L)CategoryADAPT-1ADAPT-2DOPTELET40 mg(n=59)Placebo(n= 34)DOPTELET40 mg(n=58)Placebo(n=33)Responders 95% CIa88%(80, 96)38%(22, 55)88%(80, 96)33%(17, 49)Difference of Proportion vs. Placebob95% CIc50%(32, 68)55%(37, 73)p-valued0.00010.0001Two-sided 95% confidence interval based on normal approximation.Difference of Proportion vs. placebo Proportion of Responders for DOPTELET Proportion of Responders for placebo.95% confidence interval calculated based on normal approximation.By Cohhran-Mantel-Haenszel Testing stratified by bleeding risk for the procedure.In addition, both trials demonstrated higher proportion of patients who achieved the target platelet count of >=50x109/L on the day of procedure, secondary efficacy endpoint, in both DOPTELET-treated groups versus the placebo-treated groups for both cohorts (Low Baseline Platelet Count Cohort ADAPT-1: 69% vs 4%, respectively; p0.0001, ADAPT-2: 67% vs 7%, respectively; <0.0001; High Baseline Platelet Count Cohort ADAPT-1: 88% vs 21%, respectively; <0.0001: ADAPT-2: 93% vs 39%, respectively; <0.0001). Further, both trials demonstrated greater mean change in platelet counts from baseline to the day of the procedure, secondary efficacy endpoint, in both DOPTELET-treated groups versus the placebo-treated groups for both cohorts (Low Baseline Platelet Count Cohort ADAPT-1: 32x109/L vs 0.8x109/L, respectively; p<0.0001; ADAPT-2: 31.3x109/L vs 3.0x109/L, respectively; <0.0001; High Baseline Platelet Count Cohort ADAPT-1: 37.1x109/L vs 1.0x109/L, respectively; <0.0001; ADAPT-2: 44.9x109/L vs 5.9x109/L, respectively; <0.0001).A measured increase in platelet counts was observed in both DOPTELET treatment groups over time beginning on Day post-dose, that peaked on Day 10-13, decreased days post-procedure, and then returned to near baseline values by Day 35.. Two-sided 95% confidence interval based on normal approximation.. Difference of Proportion vs. placebo Proportion of Responders for DOPTELET Proportion of Responders for placebo.. 95% confidence interval calculated based on normal approximation.. By Cohhran-Mantel-Haenszel Testing stratified by bleeding risk for the procedure.. 14.2 Adult Patients with Chronic Immune Thrombocytopenia. Randomized Phase Clinical TrialThe efficacy of DOPTELET in adult patients with chronic immune thrombocytopenia was evaluated in Phase 3, multicenter, randomized, double-blind, placebo-controlled trial (NCT01438840). Patients had previously received one or more prior chronic immune thrombocytopenia therapies and had an average of screening and baseline platelet counts <30x109/L. Patients were centrally stratified by splenectomy status, baseline platelet count (<=15x109/L or >15x109/L to <30x109/L), and use of concomitant chronic immune thrombocytopenia medication, and then randomized (2:1) to receive either DOPTELET or placebo for months. Patients received starting dose of 20 mg once daily, with doses subsequently titrated based on platelet response.Forty-nine patients were randomized, 32 to DOPTELET and 17 to placebo, with similar mean [SD] baseline platelet counts in the treatment groups (14.1 [8.6]x109/L and 12.7 [7.8]x109/L, respectively). The median age was 44 years, 63% were female, and 94% were Caucasian, 4% Asian and 2% Black. The median duration of exposure was 26 weeks for DOPTELET-treated patients and weeks for placebo-treated patients. The major efficacy outcome in this trial was the cumulative number of weeks in which the platelet count was >=50x109/L during the 6-month treatment period in the absence of rescue therapy. DOPTELET-treated patients had longer duration of platelet counts >=50x109/L in the absence of rescue therapy than those who received placebo (median 12.4 [0, 25] vs [0, 2] weeks, respectively, p<0.0001) (see Table 14).Table 14: Cumulative Number of Weeks of Platelet Response-Phase Trial in Adult Patients with Chronic Immune ThrombocytopeniaPrimary Efficacy AnalysisDOPTELET (n=32)Placebo (n=17)Cumulative Number of Weeks with Platelet ResponseMean (SD)12.0 (8.75)0.1 (0.49)Median12.40.0Min, Max0, 250, 2p-value of Wilcoxon rank sum test<0.0001Max=maximum, Min=minimum, SD=Standard deviation.Cumulative number of weeks of platelet response is defined as the total numbers of weeks in which the platelet count was >=50x109/L during months of treatment in the absence of rescue therapy.In addition, larger proportion of patients in the DOPTELET treatment group had platelet counts >=50x109/L at Day compared to placebo (21/32; 66% vs 0/17; 0.0%, respectively; p<0.0001).. 14.3 Pediatric Patients with Persistent or Chronic Immune Thrombocytopenia. The efficacy and safety of DOPTELET was evaluated in pediatric patients >=1 to <18 years of age with persistent or chronic immune thrombocytopenia in randomized, double-blind, placebo-controlled trial (NCT 04516967), which included 12-week randomized treatment phase (Core Phase).Patients were required to have had diagnosis of primary ITP for >=6 months and had an insufficient response to at least one previous treatment, with an average of baseline platelet counts less than 30x109/L. Patients (n=75) were randomized (3:1) to receive DOPTELET (n=54) or placebo (n=21). The starting dose for patients years and older was 20 mg (tablet), while the starting dose for the youngest cohort was 10 mg (oral granules mixed with soft food or liquid). Doses could be subsequently titrated based on platelet response.Enrollment was 52% male and 48% female. The median age of patients receiving DOPTELET was 8.5 years (range to 17) while the median age of patients receiving placebo was 10.0 years (range to 17). Patients identified their race as White (84%), Asian (5.3%), and Other (5.3%); 5.3% did not report race. Patients identified their ethnicity as Not Hispanic or Latino (86.7%) and Hispanic or Latino (6.7%); 2.7% did not report ethnicity and 4% had unknown ethnicity.The median baseline platelet counts were 10.4x109/L in the DOPTELET group and 11.5x109/L in the placebo group. The percentage of patients who had received or more prior ITP therapies was 68.5% in the avatrombopag group and 66.7% in the placebo group. Most patients in the trial received at least one other TPO receptor agonist as prior therapy (74.1% in the DOPTELET group and 71.4% in the placebo group).The efficacy of DOPTELET in this trial was evaluated by durable platelet response, defined as the proportion of patients achieving at least out of weekly platelet counts >=50x109/L during the last weeks of the 12-week Treatment Period in the Core Phase in the absence of rescue medication (Table 15).Efficacy was also evaluated by platelet response, defined as the proportion of subjects achieving at least consecutive platelet assessments >=50x109/L in the Core Phase in the absence of rescue medication.Table 15: Durable Platelet Response and Platelet Response Phase Trial in Pediatric Patients with Persistent or Chronic ITP Full Analysis SetEndpointDOPTELET (N=54)Placebo (N=21)Durable platelet response, n% Yes15 (27.8)0No39 (72.2)21 (100.0)Difference of proportion (avatrombopag placebo) (95% CI)27.8 (15.8, 39.7)CMH (avatrombopag vs. placebo) p-value p=0.0077a Platelet response, n% Yes44 (81.5)0No10 (18.5)21 (100.0)Difference of proportion (avatrombopag placebo) (95% CI)81.5 (71.1, 91.8)CMH (avatrombopag vs. placebo) p-value <0.0001a CI, Confidence interval; CMH, Cochran-Mantel-Haenszel; N, Total number of subjects; n, Number of subjects; Full Analysis Set includes all randomized subjects.a Denotes p-value from Fishers Exact Test, which was used in place of CMH test due to sparse number of responders in the strata.Note: The CMH test is adjusted for age cohort and baseline platelet counts.DOPTELET was superior to placebo in other major efficacy outcomes that evaluated platelet counts. At Day 8, 55.6% (95% CI: 41.4%, 69.1%) of DOPTELET versus no placebo patients (95% CI: 0.0%, 16.1%) had platelet count >=50x109/L in the absence of rescue therapy (p <0.0001). The mean percentage of weeks that subjects had platelet count >=50x109/L during the Core Phase in the absence of rescue therapy was significantly higher for DOPTELET versus placebo, 48.9% (SD: 25.22%) versus 1.2% (SD: 3.92%) (p <0.0001).The proportion of subjects who required rescue therapy during the Core Phase was significantly lower (p=0.0008) in the DOPTELET group (7.4% [95% CI: 2.1%, 17.9%]) than in the placebo group (42.9% [95% CI: 21.8%, 66.0%]).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Patients with Chronic Liver DiseaseThe safety of DOPTELET was evaluated in two international, identically designed, randomized, double-blind, placebo-controlled trials, ADAPT-1 and ADAPT-2, in which 430 patients with chronic liver disease and thrombocytopenia received either DOPTELET (n=274) or placebo (n=156) daily for days prior to scheduled procedure, and had post-dose safety assessment. Patients were divided into two groups based on their mean platelet count at baseline:Low Baseline Platelet Count Cohort (less than 40x109/L) who received DOPTELET 60 mg once daily for daysHigh Baseline Platelet Count Cohort (40 to less than 50x109/L) who received DOPTELET 40 mg once daily for daysThe majority of patients were males (65%) and median subject age was 58 years (ranging from 19-86 years of age). The racial and ethnic distribution was White (60%), Asian (33%), Black (3%) and Other (3%).The most common adverse reactions (those occurring in >=3% of patients) in the DOPTELET-treated groups (60 mg or 40 mg) across the pooled data from the two trials are summarized in Table 8.Table 8: Adverse Reactions with Frequency >=3% in Patients with Chronic Liver Disease Treated with DOPTELET Pooled Data ADAPT-1 and ADAPT-2Adverse ReactionsLow Baseline Platelet Count Cohort(40x109/L)High Baseline Platelet Count Cohort(>=40 to 50x109/L)Combined Baseline Platelet Count Cohorts(50x109/L)DOPTELET60 mg(N=159) %Placebo(N=91) %DOPTELET40 mg(N=115) %Placebo(N=65)%TotalDOPTELET(N=274)%TotalPlacebo(N=156)%Pyrexia11989109Abdominal Pain677676Nausea687677Headache487566Fatigue443243Edema Peripheral324232For the Low Baseline Platelet Count Cohort, the incidence of serious adverse reactions was 7% (11/159) in the 60 mg DOPTELET treatment group. For the High Baseline Platelet Count Cohort, the incidence of serious adverse reactions was 8% (9/115) in the 40 mg DOPTELET treatment group. The most common serious adverse reaction reported with DOPTELET was hyponatremia. Two DOPTELET-treated patients (0.7%) developed hyponatremia.Adverse reactions resulting in discontinuation of DOPTELET were anemia, pyrexia, and myalgia; each was reported in single (0.4%) patient in the DOPTELET (60 mg) treatment group.Adult Patients with Chronic Immune ThrombocytopeniaThe safety of DOPTELET was evaluated in four clinical trials in adult patients with chronic immune thrombocytopenia: two Phase trials (one randomized, double-blind, placebo-controlled trial, and one randomized, double-blind, active-controlled trial) and two Phase trials (one randomized, double-blind, placebo-controlled, dose-ranging, trial, and one open-label extension trial) in 161 patients with chronic immune thrombocytopenia in both the double-blind and open-label extension phases.The pooled safety data from these four clinical trials includes 128 patients who received 2.5 to 40 mg of DOPTELET once daily for median duration of exposure of 29.1 weeks and had post-dose safety assessment. The majority of patients were female (63%) and median subject age was 50.5 years (ranging from 18-88 years of age). The racial and ethnic distribution was White (84%), Black (6%), Asian (6%) and Other (6%).The most common adverse reactions (those occurring in >=10% of patients) in the DOPTELET-treated patients across the pooled safety data from the four trials are summarized in Table 9.Table 9: Adverse Reactions with Frequency >=10% in Adult Patients with Chronic Immune Thrombocytopenia Treated with DOPTELET Pooled Data from Clinical TrialsAdverse ReactionsDOPTELET (N=128)%Placebo (N= 22)%Headache3114Fatigue289Contusion2618Epistaxis1918Upper Respiratory Tract Infection155Arthralgia130Gingival Bleeding130Petechiae119Nasopharyngitis100The incidence of serious adverse reactions was 9% (12/128) in the DOPTELET treatment group. Serious adverse reactions reported in more than individual DOPTELET-treated patient included headache, occurring in 1.6% (2/128).Adverse reactions resulting in discontinuation of DOPTELET that were reported in more than patient included headache, occurring in 1.6% (2/128).Pediatric Patients with Persistent or Chronic Immune ThrombocytopeniaThe data described below reflect median exposure to DOPTELET of 12 weeks for 54 pediatric patients (>=1 to <18 years of age) with persistent or chronic immune thrombocytopenia across the core phase of one double-blind, placebo-controlled trial [see Clinical Studies 14.3 )].Table 10 presents the most common adverse reactions (experienced by greater than or equal to 10% of pediatric patients year and older receiving DOPTELET) with higher incidence for DOPTELET versus placebo.Table 10: Adverse Reactions in Pediatric Patients with Persistent or Chronic Immune Thrombocytopenia Treated with DOPTELETa Adverse ReactionsDOPTELET(N=54) %Placebo(N=21) %Viral Infectionb 205Nasopharyngitis2010Cough170Pyrexia170Oropharyngeal Pain130a Adverse reactions that occurred in >=10% of DOPTELET-treated patients and >=2% more than placebo-treated patients.b Viral infection includes viral upper respiratory infection, viral infection, COVID-19, parainfluenza virus infection, and rhinovirus infection.Two patients experienced serious adverse reactions: thrombocytosis and headache. Two patients experienced adverse reactions resulting in discontinuation of DOPTELET: vomiting and headache (in one patient) and leukocytosis (in one patient).. Low Baseline Platelet Count Cohort (less than 40x109/L) who received DOPTELET 60 mg once daily for days. High Baseline Platelet Count Cohort (40 to less than 50x109/L) who received DOPTELET 40 mg once daily for days.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. The active ingredient in DOPTELET is avatrombopag maleate, thrombopoietin receptor agonist. The chemical name of avatrombopag maleate is 4-piperidinecarboxylic acid, 1-[3-chloro-5-[[[4-(4-chloro-2-thienyl)-5-(4-cyclohexyl-1-piperazinyl)-2-thiazolyl]amino]carbonyl]-2-pyridinyl]-, (2Z)-2-butenedioate (1:1). It has the molecular formula C29H34Cl2N6O3S2 C4H4O4. The molecular weight is 765.73.The structural formula is:The aqueous solubility of avatrombopag maleate at various pH levels indicates that the drug substance is practically insoluble at pH to 11.DOPTELET is provided as an immediate-release tablet and as sprinkle capsule that contains oral granules.Each DOPTELET tablet contains 20 mg avatrombopag (equivalent to 23.6 mg of avatrombopag maleate) and the following inactive ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Coating film: ferric oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.Each DOPTELET SPRINKLE capsule contains 10 mg avatrombopag (equivalent to 11.8 mg of avatrombopag maleate) and the following inactive ingredients: crospovidone Type A, magnesium stearate, mannitol, microcrystalline cellulose, and sodium lauryl sulfate. Capsule shells: Hypromellose.. image description.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. DOPTELET tablets and DOPTELET SPRINKLE are not substitutable on mg-to-mg basis.DOPTELET SPRINKLE capsules should be opened, and the contents (oral granules) mixed with soft food or liquid. Administer immediately after mixing. Do not swallow the capsules whole.Administer DOPTELET tablets and DOPTELET SPRINKLE with food. (2.1, 2.3, 2.5)Chronic Liver Disease: Dose DOPTELET tablets based upon platelet count prior to procedure, orally for days beginning 10 days to 13 days before procedure. For platelet count less than 40x109/L, the dose is 60 mg (3 tablets) orally once daily; for platelet count 40 to less than 50x109/L the dose is 40 mg (2 tablets) orally once daily. (2.2)Adult Patients with Chronic Immune Thrombocytopenia and Pediatric Patients Years and Older with Persistent or Chronic Immune Thrombocytopenia: Initiate DOPTELET tablets at 20 mg (1 tablet) orally once daily. Adjust the dose or frequency of dosing to maintain platelet count greater than or equal to 50x109/L. Do not exceed 40 mg (2 tablets) per day.Pediatric Patients Year to Less than Years with Persistent or Chronic Immune Thrombocytopenia: Initiate DOPTELET SPRINKLE oral granules at 10 mg (content of capsule) orally once daily. Adjust the dose or frequency of dosing to maintain platelet count greater than or equal to 50x109/L. Do not exceed 20 mg (content of capsules) per day.. DOPTELET tablets and DOPTELET SPRINKLE are not substitutable on mg-to-mg basis.. DOPTELET SPRINKLE capsules should be opened, and the contents (oral granules) mixed with soft food or liquid. Administer immediately after mixing. Do not swallow the capsules whole.. Administer DOPTELET tablets and DOPTELET SPRINKLE with food. (2.1, 2.3, 2.5). Chronic Liver Disease: Dose DOPTELET tablets based upon platelet count prior to procedure, orally for days beginning 10 days to 13 days before procedure. For platelet count less than 40x109/L, the dose is 60 mg (3 tablets) orally once daily; for platelet count 40 to less than 50x109/L the dose is 40 mg (2 tablets) orally once daily. (2.2). Adult Patients with Chronic Immune Thrombocytopenia and Pediatric Patients Years and Older with Persistent or Chronic Immune Thrombocytopenia: Initiate DOPTELET tablets at 20 mg (1 tablet) orally once daily. Adjust the dose or frequency of dosing to maintain platelet count greater than or equal to 50x109/L. Do not exceed 40 mg (2 tablets) per day.. Pediatric Patients Year to Less than Years with Persistent or Chronic Immune Thrombocytopenia: Initiate DOPTELET SPRINKLE oral granules at 10 mg (content of capsule) orally once daily. Adjust the dose or frequency of dosing to maintain platelet count greater than or equal to 50x109/L. Do not exceed 20 mg (content of capsules) per day.. 2.1 Important Use and Administration Instructions. Select the recommended product (DOPTELET tablets or DOPTELET SPRINKLE) based on the indication and patients age.Administer DOPTELET tablets and DOPTELET SPRINKLE with food.DOPTELET tablets and DOPTELET SPRINKLE are not substitutable on mg-to-mg basis.The mixture prepared from the granules in DOPTELET SPRINKLE capsules is more bioavailable than DOPTELET tablets [see Clinical Pharmacology (12.3)]. There is no experience from clinical trials in switching between dosing with the granules and the tablet. If the formulation is switched, monitor platelet counts weekly until stable platelet counts are obtained and adjust dosing as needed before resuming monthly monitoring.. Select the recommended product (DOPTELET tablets or DOPTELET SPRINKLE) based on the indication and patients age.. Administer DOPTELET tablets and DOPTELET SPRINKLE with food.. DOPTELET tablets and DOPTELET SPRINKLE are not substitutable on mg-to-mg basis.. The mixture prepared from the granules in DOPTELET SPRINKLE capsules is more bioavailable than DOPTELET tablets [see Clinical Pharmacology (12.3)]. There is no experience from clinical trials in switching between dosing with the granules and the tablet. If the formulation is switched, monitor platelet counts weekly until stable platelet counts are obtained and adjust dosing as needed before resuming monthly monitoring.. 2.2 Recommended Dosage of DOPTELET Tablets for Patients with Chronic Liver Disease. Begin DOPTELET tablets dosing 10 days to 13 days prior to the scheduled procedure. The recommended daily dose of DOPTELET is based on the patients platelet count prior to the scheduled procedure (see Table 1). Patients should undergo their procedure days to days after the last dose of DOPTELET.DOPTELET tablets should be taken orally once daily for consecutive days with food. All days of dosing should be completed.Table 1: Recommended DOPTELET Tablets Dosage and Duration in Patients with Chronic Liver Disease Scheduled to Undergo ProcedurePlatelet Count Recommended DOPTELET DosageDurationLess than 40x109/L60 mg (3 tablets) orally once daily5 days40x109/L to less than 50x109/L40 mg (2 tablets) orally once daily5 daysDOPTELET tablets have been investigated only as single 5-day once daily dosing regimen in clinical trials in patients with chronic liver disease see Clinical Studies 14.1 ]. DOPTELET should not be administered to patients with chronic liver disease in an attempt to normalize platelet counts.Monitoring: Obtain platelet count prior to administration of DOPTELET therapy and on the day of procedure to ensure an adequate increase in platelet count.. 2.3 Recommended Dosage of DOPTELET Tablets for Adult Patients with Chronic Immune Thrombocytopenia and Pediatric Patients Years and Older with Persistent or Chronic Immune Thrombocytopenia. Use the lowest dose of DOPTELET needed to achieve and maintain platelet count greater than or equal to 50x109/L as necessary to reduce the risk for bleeding. Dose adjustments are based on platelet count response. Do not use DOPTELET to normalize platelet counts.Initial Dosage:Begin DOPTELET tablets at an initial dosage of 20 mg (1 tablet) orally once daily with food (see Table 3).The recommended initial dosages of DOPTELET tablets are different for patients receiving certain concomitant medications (see Table 4).Monitoring: After initiating therapy with DOPTELET, assess platelet counts weekly until stable platelet count greater than or equal to 50x109/L has been achieved, and then obtain platelet counts monthly thereafter. Obtain platelet counts weekly for at least weeks following discontinuation of DOPTELET.Dose Adjustments:DOPTELET tablet dose adjustments (see Table and Table 3) are based on the platelet count response. Do not exceed DOPTELET daily dose of 40 mg (2 tablets).Table 2: DOPTELET Tablets Recommended Dose Adjustments for Adult Patients with Chronic Immune Thrombocytopenia and Pediatric Patients Years and Older with Persistent or Chronic Immune ThrombocytopeniaPlatelet CountDose Adjustment or ActionLess than 50x109/L after at least weeks of DOPTELET tabletsIncrease One Dose Level per Table 3.Wait weeks to assess the effects of this regimen and any subsequent dose adjustments.Between 200x109/L and 400x109/LDecrease One Dose Level per Table 3.Wait weeks to assess the effects of this regimen and any subsequent dose adjustments.Greater than 400x109/LStop DOPTELET tablets.Increase platelet monitoring to twice weekly.When platelet count is less than 150x109/L, decrease One Dose Level per Table and reinitiate therapy.Less than 50x109/L after weeks of DOPTELET 40 mg (2 tablets) once dailyDiscontinue DOPTELET tablets.Greater than 400x109/L after weeks of DOPTELET 20 mg (1 tablet) weeklyDiscontinue DOPTELET tablets.Table 3: DOPTELET Tablet Dose Levels for Titration in Adult Patients with Chronic Immune Thrombocytopenia and Pediatric Patients Years and Older with Persistent or Chronic Immune ThrombocytopeniaDosageDose Level40 mg (2 tablets) orally Once Daily640 mg (2 tablets) orallyThree Times Week AND 20 mg (1 tablet) orally on the Four Remaining Days of Each Week520 mg (1 tablet) orally Once Daily420 mg (1 tablet) orally Three Times Week320 mg (1 tablet) orally Twice Week OR 40 mg Once Weekly220 mg (1 tablet) orally Once Weekly1Initial dosage regimen for all patients except those taking Moderate or Strong Dual Inducers or Moderate or Strong Dual Inhibitors of CYP2C9 and CYP3A4. Discontinuation:Discontinue DOPTELET tablets if the platelet count does not increase to greater than or equal to 50x109/L after weeks of dosing at the maximum dose of 40 mg (2 tablets) once daily.Discontinue DOPTELET tablets if the platelet count is greater than 400x109/L after weeks of dosing at 20 mg (1 tablet) once weekly.. Begin DOPTELET tablets at an initial dosage of 20 mg (1 tablet) orally once daily with food (see Table 3).. The recommended initial dosages of DOPTELET tablets are different for patients receiving certain concomitant medications (see Table 4).. Increase One Dose Level per Table 3.. Wait weeks to assess the effects of this regimen and any subsequent dose adjustments.. Decrease One Dose Level per Table 3.. Wait weeks to assess the effects of this regimen and any subsequent dose adjustments.. Stop DOPTELET tablets.. Increase platelet monitoring to twice weekly.. When platelet count is less than 150x109/L, decrease One Dose Level per Table and reinitiate therapy.. Discontinue DOPTELET tablets.. Discontinue DOPTELET tablets.. Discontinue DOPTELET tablets if the platelet count does not increase to greater than or equal to 50x109/L after weeks of dosing at the maximum dose of 40 mg (2 tablets) once daily.. Discontinue DOPTELET tablets if the platelet count is greater than 400x109/L after weeks of dosing at 20 mg (1 tablet) once weekly.. 2.4 Recommended Initial Dosage of DOPTELET Tablets with Concomitant Moderate or Strong Dual Inducers or Inhibitors of CYP2C9 and CYP3A4. The recommended initial dosages of DOPTELET tablets with concomitant moderate or strong dual inducers or inhibitors of CYP2C9 and CYP3A4 in adult patients with chronic immune thrombocytopenia and pediatric patients years and older with persistent or chronic immune thrombocytopenia are summarized in Table 4.Table 4: DOPTELET Tablets Recommended Initial Dosage with Concomitant Moderate or Strong Dual Inducers or Inhibitors of CYP2C9 and CYP3A4 for Adult Patients with Chronic Immune Thrombocytopenia and Pediatric Patients Years and Older with Persistent or Chronic Immune Thrombocytopenia Concomitant MedicationsRecommended Initial DosageModerate or strong dual inhibitors of CYP2C9 and CYP3A4 20 mg (1 tablet) orally three times week Moderate or strong dual inducers of CYP2C9 and CYP3A4 40 mg (2 tablets) orally once daily 2.5 Recommended Dosage of DOPTELET SPRINKLE for Patients Year to Less than Years with Persistent or Chronic Immune Thrombocytopenia. Use the lowest dose of DOPTELET SPRINKLE needed to achieve and maintain platelet count greater than or equal to 50x109/L as necessary to reduce the risk for bleeding. Dose adjustments are based on platelet count response. Do not use DOPTELET SPRINKLE to normalize platelet counts. Initial Dosage:Begin DOPTELET SPRINKLE at an initial dosage of 10 mg (content of capsule) orally once daily with food (see Table 6). The recommended initial dosages of DOPTELET SPRINKLE are different for patients receiving certain concomitant medications (see Table 7). Monitoring:After initiating therapy with DOPTELET SPRINKLE, assess platelet counts weekly until stable platelet count greater than or equal to 50x109/L has been achieved, and then obtain platelet counts monthly thereafter. Obtain platelet counts weekly for at least weeks following discontinuation of DOPTELET SPRINKLE.Dose Adjustments:DOPTELET SPRINKLE dose adjustments (see Table and Table 6) are based on the platelet count response. Do not exceed DOPTELET SPRINKLE daily dose of 20 mg (content of capsules).Table 5: DOPTELET SPRINKLE Dose Adjustments for Patients Year to Less than Years with Persistent or Chronic Immune Thrombocytopenia Platelet CountDose Adjustment or Action Less than 50x109/L after at least weeks of DOPTELET SPRINKLEIncrease One Dose Level per Table 6.Wait weeks to assess the effects of this regimen and any subsequent dose adjustments.Between 200x109/L and 400x109/LDecrease One Dose Level per Table 6.Wait weeks to assess the effects of this regimen and any subsequent dose adjustments.Greater than 400x109/LStop DOPTELET SPRINKLE.Increase platelet monitoring to twice weekly.When platelet count is less than 150x109/L, decrease One Dose Level per Table and reinitiate therapy.Less than 50x109/L after weeks of DOPTELET SPRINKLE 20 mg (content of capsules) once dailyDiscontinue DOPTELET SPRINKLE.Greater than 400x109/L after weeks of DOPTELET SPRINKLE 10 mg (content of capsule) weeklyDiscontinue DOPTELET SPRINKLE.Table 6: DOPTELET SPRINKLE Dose Levels for Titration in Pediatric Patients Year to Less than Years with Persistent or Chronic Immune Thrombocytopenia DosageDose Level20 mg (content of capsules) orally Once Daily620 mg (content of capsules) orally Three Times Week AND 10 mg (content of capsule) orally on the Four Remaining Days of Each Week510 mg (content of capsule) orally Once Daily410 mg (content of capsule) orally Three Times Week310 mg (content of capsule) orally Twice Week OR 20 mg (content of capsules) orally Once Weekly210 mg (content of capsule) orally Once Weekly1Initial dose regimen for all patients except those taking Moderate or Strong Dual Inducers or Moderate or Strong Dual Inhibitors of CYP2C9 and CYP3A4.Discontinuation: Discontinue DOPTELET SPRINKLE if the platelet count does not increase to greater than or equal to 50x109/L after weeks of dosing at the maximum dose of 20 mg (content of capsules) once daily.Discontinue DOPTELET SPRINKLE if the platelet count is greater than 400x109/L after weeks of dosing at 10 mg (content of capsule) once weekly.. Begin DOPTELET SPRINKLE at an initial dosage of 10 mg (content of capsule) orally once daily with food (see Table 6). The recommended initial dosages of DOPTELET SPRINKLE are different for patients receiving certain concomitant medications (see Table 7). Increase One Dose Level per Table 6.. Wait weeks to assess the effects of this regimen and any subsequent dose adjustments.. Decrease One Dose Level per Table 6.. Wait weeks to assess the effects of this regimen and any subsequent dose adjustments.. Stop DOPTELET SPRINKLE.. Increase platelet monitoring to twice weekly.. When platelet count is less than 150x109/L, decrease One Dose Level per Table and reinitiate therapy.. Discontinue DOPTELET SPRINKLE.. Discontinue DOPTELET SPRINKLE.. Discontinue DOPTELET SPRINKLE if the platelet count does not increase to greater than or equal to 50x109/L after weeks of dosing at the maximum dose of 20 mg (content of capsules) once daily.. Discontinue DOPTELET SPRINKLE if the platelet count is greater than 400x109/L after weeks of dosing at 10 mg (content of capsule) once weekly.. 2.6 Recommended Initial Dosage of DOPTELET SPRINKLE with Concomitant Moderate or Strong Dual Inducers or Inhibitors of CYP2C9 and CYP3A4. The recommended initial dosages of DOPTELET SPRINKLE with concomitant moderate or strong dual inducers or inhibitors of CYP2C9 and CYP3A4 in pediatric patients year to less than years with persistent or chronic immune thrombocytopenia are summarized in Table 7.Table 7: DOPTELET SPRINKLE Recommended Initial Dosage with Concomitant Moderate or Strong Dual Inducers or Inhibitors of CYP2C9 and CYP3A4 for Pediatric Patients Year to Less than Years with Persistent or Chronic Immune Thrombocytopenia Concomitant MedicationsRecommended Initial DosageModerate or strong dual inhibitors of CYP2C9 and CYP3A410 mg (content of capsule) orally three times weekModerate or strong dual inducers of CYP2C9 and CYP3A420 mg (content of capsules) orally once daily. 2.7 Important Preparation and Administration Instructions for DOPTELET SPRINKLE. Open the capsules and sprinkle the granules onto small amount of soft food or liquid in spoon or cup.Do not swallow the capsules whole. Do not chew or crush the granules.Use the entire contents of the capsules to achieve the dose.The following soft foods and liquids are suitable:Soft foods: applesauce; strawberry jelly; yogurt (plain)Liquids: milk (whole or skim); orange juice; pediatric electrolyte solution (unflavored); water Mix the granules into the soft food or liquid; the granules will not dissolve.Consume the mixture immediately after preparation; it should not be saved for future use.Rinse the spoon or cup with the soft food or liquid to ensure that the full dose is administered.. Open the capsules and sprinkle the granules onto small amount of soft food or liquid in spoon or cup.. Do not swallow the capsules whole. Do not chew or crush the granules.. Use the entire contents of the capsules to achieve the dose.The following soft foods and liquids are suitable:Soft foods: applesauce; strawberry jelly; yogurt (plain)Liquids: milk (whole or skim); orange juice; pediatric electrolyte solution (unflavored); water The following soft foods and liquids are suitable:Soft foods: applesauce; strawberry jelly; yogurt (plain)Liquids: milk (whole or skim); orange juice; pediatric electrolyte solution (unflavored); water Soft foods: applesauce; strawberry jelly; yogurt (plain). Liquids: milk (whole or skim); orange juice; pediatric electrolyte solution (unflavored); water. Mix the granules into the soft food or liquid; the granules will not dissolve.. Consume the mixture immediately after preparation; it should not be saved for future use.. Rinse the spoon or cup with the soft food or liquid to ensure that the full dose is administered.. 2.8 Missed Dose. In the case of missed dose of DOPTELET tablets or DOPTELET SPRINKLE, patients should take the missed dose as soon as they remember. Patients should not take two doses at one time to make up for missed dose and should take the next dose at the usual time the next day.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. TabletsDOPTELET Tablets: 20 mg as round, biconvex, yellow, film-coated tablets debossed with AVA on one side and 20 on the other side.Oral GranulesDOPTELET SPRINKLE: 10 mg as Size capsules containing white to off-white granules. The capsules have white opaque body and light blue opaque cap with black arrow symbol imprinted on the body and cap.. Tablet: 20 mg (3)Oral Granules: 10 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Moderate or Strong Dual CYP2C9 and CYP3A4 Inducers or Inhibitors: Dose adjustments are recommended for patients with persistent or chronic immune thrombocytopenia. (7.1). 7.1 Effect of Other Drugs on DOPTELET in Patients with Persistent or Chronic Immune Thrombocytopenia. Moderate or Strong Dual Inhibitors of CYP2C9 and CYP3A4Concomitant use with moderate or strong dual inhibitor of CYP2C9 and CYP3A4 increases avatrombopag AUC see Clinical Pharmacology 12.3 )], which may increase the risk of DOPTELET toxicities. Reduce the starting dosage of DOPTELET when used concomitantly with moderate or strong dual inhibitor of CYP2C9 and CYP3A4 (see Table and Table 7) see Dosage and Administration 2.4 and 2.6 )].In patients starting moderate or strong dual inhibitors of CYP2C9 and CYP3A4 while receiving DOPTELET, monitor platelet counts and adjust DOPTELET dose as necessary (see Table and Table 3; and Table and Table 6) see Dosage and Administration 2.3 and 2.5 )].Moderate or Strong Dual Inducers of CYP2C9 and CYP3A4Concomitant use with moderate or strong dual inducer of CYP2C9 and CYP3A4 decreases avatrombopag AUC see Clinical Pharmacology 12.3 )], which may reduce DOPTELET efficacy. Increase the recommended starting dosage of DOPTELET when used concomitantly with moderate or strong dual inducer of CYP2C9 and CYP3A4 (see Table and Table 7) see Dosage and Administration 2.4 and 2.6 )].In patients starting moderate or strong dual inducers of CYP2C9 and CYP3A4 while receiving DOPTELET, monitor platelet counts and adjust DOPTELET dose as necessary (see Table and Table 3; and Table and Table 6) see Dosage and Administration 2.3 and 2.5 )].Patients with Chronic Liver DiseaseNo dosage adjustments are required for patients with chronic liver disease.

GERIATRIC USE SECTION.

8.5 Geriatric Use. There were 112 patients 65 years of age and older in the clinical studies for Chronic Liver Disease and Chronic Immune Thrombocytopenia [see Clinical Studies 14.1 and 14.2 )]. Of the total number of DOPTELET-treated patients in these studies, 71 (23%) were 65 years of age and older, while 12 (4%) were 75 years of age and older. Clinical studies of DOPTELET did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 DOPTELET Tablets. DOPTELET 20 mg tablets are supplied as round, biconvex, yellow, film-coated tablets, and debossed with AVA on one side and 20 on the other side.How SuppliedCarton NDCBlister Card NDCCarton of one blister card with 10 tabletsNDC 71369-020-10NDC 71369-020-11Carton of one blister card with 15 tabletsNDC 71369-020-15NDC 71369-020-16Carton of two blister cards, each with 15 tablets (30 tablets total)NDC 71369-020-30NDC 71369-020-16Store DOPTELET tablets at room temperature from 20C to 25C (68F to 77F), excursions permitted from 15C to 30C (59F to 86F). Store tablets in the original package.. 16.2 DOPTELET SPRINKLE. DOPTELET SPRINKLE is supplied as 10 mg capsules with white opaque body and light blue opaque cap with black arrow symbol imprinted on the body and cap. The capsule is filled with white to off-white granules.How Supplied Carton and Bottle NDCCarton with one bottle of 30 capsules (containing oral granules) NDC 71369-010-30Store DOPTELET SPRINKLE capsules at room temperature from 20C to 25C (68F to 77F), excursions permitted from 15C to 30C (59F to 86F).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. DOPTELET is thrombopoietin receptor agonist indicated for the treatment of:Thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo procedure. (1.1)Thrombocytopenia in adult patients with chronic immune thrombocytopenia who have had an insufficient response to previous treatment. (1.2)Thrombocytopenia in pediatric patients year and older with persistent or chronic immune thrombocytopenia who have had an insufficient response to previous treatment (1.3). Thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo procedure. (1.1). Thrombocytopenia in adult patients with chronic immune thrombocytopenia who have had an insufficient response to previous treatment. (1.2). Thrombocytopenia in pediatric patients year and older with persistent or chronic immune thrombocytopenia who have had an insufficient response to previous treatment (1.3). 1.1 Treatment of Thrombocytopenia in Patients with Chronic Liver Disease (CLD). DOPTELET is indicated for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo procedure.. 1.2 Treatment of Thrombocytopenia in Adult Patients with Chronic Immune Thrombocytopenia (ITP). DOPTELET is indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia who have had an insufficient response to previous treatment.. 1.3 Treatment of Thrombocytopenia in Pediatric Patients Year and Older with Persistent or Chronic Immune Thrombocytopenia (ITP). DOPTELET is indicated for the treatment of thrombocytopenia in pediatric patients year and older with persistent or chronic immune thrombocytopenia who have had an insufficient response to previous treatment.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient or caregiver to read the FDA-approved patient labeling: Patient Information and, for DOPTELET SPRINKLE, Instructions for Use.Prior to treatment, patients should fully understand and be informed of the following risks and considerations for DOPTELET:RisksThrombotic/Thromboembolic ComplicationsDOPTELET is thrombopoietin (TPO) receptor agonist and TPO receptor agonists have been associated with thrombotic and thromboembolic complications in patients with chronic liver disease or immune thrombocytopenia. Portal vein thrombosis has been reported in patients with chronic liver disease treated with TPO receptor agonists. Various thromboembolic complications (arterial and venous) have been reported in patients treated with DOPTELET see Warnings and Precautions 5.1 )].Drug InteractionsDOPTELET may be affected by other drugs and may require dose adjustment when co-administered with other drugs; therefore, advise patients to report their use of any other prescription or nonprescription medications or dietary supplements see Dosage and Administration 2.4 and 2.6 ), Drug Interactions 7 )].PregnancyAdvise pregnant women of the potential risk to fetus. Advise females of reproductive potential to inform their prescriber of known or suspected pregnancy see Use in Specific Populations 8.1 )].LactationAdvise women not to breastfeed during treatment with DOPTELET and for at least weeks after the last dose see Use in Specific Populations 8.2 )].Administration Instructions for DOPTELET SPRINKLE Inform patients and caregivers to open the capsules and mix the contents with the recommended soft foods or liquids. Administer immediately after mixing. Do not swallow the capsules whole. Do not chew or crush the granules.Advise patients and caregivers to read and follow the Instructions for Use for DOPTELET SPRINKLE.DOPTELET and DOPTELET SPRINKLE are not substitutable on milligram-to-milligram basisAdvise patients and caregivers that DOPTELET and DOPTELET SPRINKLE are not substitutable on milligram-to-milligram basis.To avoid dosing error from using the wrong dosage form, strongly advise patients and caregivers to visually inspect the product to verify the correct dosage form each time the prescription is filled.DOPTELET is registered trademark of AkaRx, Inc.Manufactured for AkaRx, Inc., Morrisville, North Carolina 27560(C)2025For more information, go to www.DOPTELET.com or call 1-855-454-3887.PI0002 R8. Inform patients and caregivers to open the capsules and mix the contents with the recommended soft foods or liquids. Administer immediately after mixing. Do not swallow the capsules whole. Do not chew or crush the granules.. Advise patients and caregivers to read and follow the Instructions for Use for DOPTELET SPRINKLE.. Advise patients and caregivers that DOPTELET and DOPTELET SPRINKLE are not substitutable on milligram-to-milligram basis.. To avoid dosing error from using the wrong dosage form, strongly advise patients and caregivers to visually inspect the product to verify the correct dosage form each time the prescription is filled.

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USEDOPTELET(R) SPRINKLE (dop-TEL-et SPRINK-el) (avatrombopag) oral granules Read these Instructions for Use to prepare and give dose of DOPTELET SPRINKLE correctly. Important information that you need to know before giving DOPTELET SPRINKLE: The contents of DOPTELET SPRINKLE should be sprinkled onto soft food or liquid, as described below. DOPTELET SPRINKLE that comes in bottle is not the same dosage form as DOPTELET tablets that come in blister card and these products cannot be directly substituted for each other. Contact your childs pharmacist or healthcare provider if your child did not receive the correct dosage form.DOPTELET SPRINKLE contains granules inside of capsule.The capsule must be opened, and the granules inside must be sprinkled onto soft food or liquid to give dose of DOPTELET SPRINKLE. Do not swallow the capsule whole or the empty capsule shells.Do not chew or crush the granules. Use all of the granules in the capsule. Do not use part of capsule to try to prepare dose.Steps to prepare and give dose of DOPTELET SPRINKLE:Gather supplies to prepare dose of DOPTELET SPRINKLE: capsule(s), liquid or soft food, cup or spoon, and mixing utensil (e.g., stir stick or small spoon); then wash your hands.Put small amount of soft food or liquid in cup or spoon. The following soft foods and liquids can be used:Soft foodsapplesaucestrawberry jellyyogurt (plain)Liquidsmilk (whole or skim)orange juicepediatric electrolyte solution (unflavored)water3. Carefully open the capsule (or capsules if prescribed) by pulling it apart. Sprinkle the entire contents of the capsule onto the soft food or liquid that you put in the spoon or cup. Make sure that all of the granules from the capsule have been completely emptied.4. Mix or stir the granules into the soft food or liquid. The granules will not dissolve.5. Give the mixture right away; do not save for later use. 6. Rinse the spoon or cup with additional soft food or liquid to make sure that the entire dose is given.7. Throw the empty capsule shells away in the trash.How should store DOPTELET SPRINKLEStore DOPTELET SPRINKLE at room temperature from 68F to 77F (20C to 25C).Keep DOPTELET SPRINKLE and all medicines out of the reach of children.DOPTELET is registered trademark of AkaRx, Inc.Manufactured for AkaRx, Inc., Morrisville, North Carolina 27560For more information, go to www.DOPTELET.com or call 1-855-454-3887.This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 07/2025 PI0003 R1. Important information that you need to know before giving DOPTELET SPRINKLE: DOPTELET SPRINKLE that comes in bottle is not the same dosage form as DOPTELET tablets that come in blister card and these products cannot be directly substituted for each other. Contact your childs pharmacist or healthcare provider if your child did not receive the correct dosage form.. DOPTELET SPRINKLE contains granules inside of capsule.The capsule must be opened, and the granules inside must be sprinkled onto soft food or liquid to give dose of DOPTELET SPRINKLE. Do not swallow the capsule whole or the empty capsule shells.Do not chew or crush the granules. The capsule must be opened, and the granules inside must be sprinkled onto soft food or liquid to give dose of DOPTELET SPRINKLE. Do not swallow the capsule whole or the empty capsule shells.. Do not chew or crush the granules.. Use all of the granules in the capsule. Do not use part of capsule to try to prepare dose.. Gather supplies to prepare dose of DOPTELET SPRINKLE: capsule(s), liquid or soft food, cup or spoon, and mixing utensil (e.g., stir stick or small spoon); then wash your hands.. Put small amount of soft food or liquid in cup or spoon. The following soft foods and liquids can be used:. applesauce. strawberry jelly. yogurt (plain). milk (whole or skim). orange juice. pediatric electrolyte solution (unflavored). water. Sprinkle the entire contents of the capsule onto the soft food or liquid that you put in the spoon or cup. Make sure that all of the granules from the capsule have been completely emptied.. Store DOPTELET SPRINKLE at room temperature from 68F to 77F (20C to 25C).

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere is no information regarding the presence of avatrombopag in human milk, the effects on the breastfed child, or the effects on milk production. Avatrombopag was present in the milk of lactating rats. When drug is present in animal milk, it is likely the drug will be present in human milk. Due to the potential for serious adverse reactions in breastfed child from DOPTELET, breastfeeding is not recommended during treatment with DOPTELET and for at least weeks after the last dose (see Clinical Considerations ).Clinical ConsiderationsMinimizingExposureA lactating woman receiving DOPTELET for brief periods, such as prior to an invasive procedure, should interrupt breastfeeding and pump and discard breastmilk during treatment and for two weeks after the last dose of DOPTELET in order to minimize exposure to breastfed child. Advise lactating women receiving chronic DOPTELET therapy not to breastfeed during treatment with DOPTELET and for at least weeks after the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Avatrombopag is an orally bioavailable, small molecule TPO receptor agonist that stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells, resulting in an increased production of platelets. Avatrombopag does not compete with TPO for binding to the TPO receptor and has an additive effect with TPO on platelet production.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In two-year carcinogenicity studies, avatrombopag was administered orally at doses of 20, 60, and 160 mg/kg/day in mice and doses of 20, 50, and 160 mg/kg/day in rats. Avatrombopag induced statistically significant increase in neuroendocrine cell (enterochromaffin-like cell, ECL cell) gastric tumors (carcinoids) in the stomach at 160 mg/kg in female rats. The 160 mg/kg/day dose resulted in exposures 117 times the AUC observed in patients at the maximum recommended dose of 60 mg once daily. The gastric carcinoids were considered likely due to prolonged hypergastrinemia observed in toxicity studies. Hypergastrinemia-related gastric carcinoids in rodents are generally considered to be of low risk or relevance to humans.Avatrombopag was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro human lymphocyte chromosomal aberrations assay or in an in vivo rat bone marrow micronucleus assay.Avatrombopag did not affect fertility or early embryonic development in male rats at exposures 22 times, or in female rats at exposures 114 times, the AUC observed in patients at the maximum recommended dose of 60 mg once daily.

OVERDOSAGE SECTION.

10 OVERDOSAGE In the event of overdose, platelet count may increase excessively and result in thrombotic or thromboembolic complications. Closely monitor the patient and platelet count. Treat thrombotic complications in accordance with standard of care.No antidote for DOPTELET overdose is known.Hemodialysis is not expected to enhance the elimination of DOPTELET because avatrombopag is only approximately 6% renally excreted and is highly bound to plasma proteins.Consider contacting the Poison Help line (1-800-222-1222) or medical toxicologist for additional overdose management recommendations.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. NDC 71369-020-1020 mg per tabletRx OnlyDopteletone blister card with 10 tablets. image description.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of DOPTELET tablet for the treatment of persistent or chronic ITP have been established in pediatric patients aged years and older. The safety and effectiveness of DOPTELET SPRINKLE for the treatment of persistent or chronic ITP have been established in pediatric patients aged to <6 years. Use of DOPTELET tablet and DOPTELET SPRINKLE for their respective populations is supported by evidence from an adequate and well-controlled study in pediatric patients aged year and older [see Adverse Reactions 6.1 ), Clinical Pharmacology 12.3 ), and Clinical Studies 14.3 )].Juvenile Animal Toxicity DataIn 10-week juvenile toxicology study in rats, avatrombopag was administered at doses ranging from 20 to 300 mg/kg/day. There was no test article-related mortality and there were no clinical signs at doses up to 300 mg/kg/day. In the stomach, dose-dependent degeneration, regenerative hyperplasia, and atrophy of the glandular epithelium occurred at 100 and 300 mg/kg/day; exposures at 100 mg/kg/day in male rats were 14 times the AUC in patients at the highest recommended dose of 60 mg once daily. An increased incidence of background focal mineralization was also observed in the kidneys of females at 300 mg/kg/day (female rat exposure was 50 times the human exposure based on AUC at the 60 mg daily dose).

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Platelet ResponseDOPTELET tablet administered to adult patients resulted in dose- and exposure-dependent elevations in platelet counts. The onset of the platelet count increase was observed within to days of the start of treatment, with peak effect after 10 to 13 days. Post treatment, platelet counts decreased gradually, returning to near baseline values.Cardiac ElectrophysiologyAt exposures similar to that achieved at the 40 mg and 60 mg tablet dose, DOPTELET did not prolong the QT interval to any clinically relevant extent. Mean QTc prolongation effects >20 ms are not anticipated with the highest recommended therapeutic dosing regimen based on analysis of data from the pooled clinical trials in patients with chronic liver disease.

PHARMACOGENOMICS SECTION.

12.5 Pharmacogenomics. The CYP2C92 and CYP2C93 loss-of-function polymorphisms result in reduced CYP2C9 enzymatic activity. In pooled pharmacogenomic analysis of avatrombopag studies, subjects heterozygous for CYP2C9 loss-of-function polymorphisms (intermediate metabolizers [n=24]) had approximately 1.4-fold higher exposure and subjects homozygous for CYP2C9 loss-of-function polymorphisms (poor metabolizers [n=2]) had approximately 2-fold higher exposure compared to subjects wild-type for CYP2C9 (normal metabolizers [n=94]).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of avatrombopag were determined following administration of DOPTELET tablets, and pharmacokinetic parameters are presented as geometric mean (CV%) unless otherwise specified. Avatrombopag demonstrated dose-proportional pharmacokinetics after single doses from 10 mg (0.5 times the lowest approved dosage) to 80 mg (1.3 times the highest recommended dosage). Healthy subjects administered 40 mg of avatrombopag had geometric mean (%CV) maximal concentration (Cmax) of 166 (84%) ng/mL and area under the time-concentration curve extrapolated to infinity (AUC0-inf) of 4198 (83%) ng.hr/mL. The pharmacokinetics of avatrombopag were similar in both healthy subjects and the chronic liver disease population.The relative bioavailability of DOPTELET SPRINKLE compared to DOPTELET tablet has not been studied. However, prototype of DOPTELET SPRINKLE demonstrated 22% higher geometric mean Cmax and 38% higher geometric mean AUC for avatrombopag compared to DOPTELET tablet, both administered to healthy adult subjects under the fed condition.Table 11 summarizes avatrombopag exposure in virtual adult population and in pediatric patients with persistent or chronic immune thrombocytopenia.Table 11: Summary of Avatrombopag Exposure in Virtual Adult Population and Pediatric Patients with Persistent or Chronic Immune Thrombocytopenia CohortAdults20 mg daily DOPTELET tablet>=12 to <18 yearsN=2120 mg daily DOPTELET tablet>=6 to <12 yearsN=2020 mg daily DOPTELET tablet>=1 to <6 yearsN=1210 mg daily DOPTELET SPRINKLECmax,ss (ng/mL) Geometric mean (CV)165 (61.3)168 (36.7)267 (25.7)221 (35.6)AUCss (ng h/mL) Geometric mean (CV)3277 (62.2)3372 (41.5)4942 (28.7)4030 (38.6)AUCss area under the concentration time curve at steady-state; Cmax,ss maximal concentration at steady-state; CV coefficient of variation expressed as percent; = number of individuals.AbsorptionThe median time to maximal concentration (Tmax) occurred at to hours post-dose.Effect of FoodAvatrombopag AUC0-inf and Cmax were not affected when DOPTELET tablets were co-administered with low-fat meal (500 calories, g fat, 15 protein, and 108 carbohydrates) or high-fat meal (918 calories, 59 fat, 39 protein, and 59 carbohydrates). The variability of avatrombopag exposure was reduced by 40% to 60% with food. The Tmax of avatrombopag was delayed by to hours when DOPTELET tablets were administered with low-fat or high-fat meal (median Tmax range to hours) compared to the fasted state.Geometric mean exposure increased by approximately 19% and 32% for Cmax and AUC, respectively, when prototype of DOPTELET SPRINKLE was administered in the fed state compared to the fasted state, and between-subject variability estimates for AUC and Cmax were decreased after administration in the fed state.DistributionAvatrombopag has an estimated mean apparent volume of distribution (%CV) of 180 (25%). Avatrombopag is greater than 96% bound to human plasma proteins.EliminationThe mean plasma elimination half-life (%CV) of avatrombopag is approximately 19 hours (19%). The mean (%CV) of the apparent clearance of avatrombopag is estimated to be 6.9 L/hr (29%).MetabolismAvatrombopag is primarily metabolized by cytochrome P450 CYP2C9 and CYP3A4.ExcretionFecal excretion accounted for 88% of the administered dose, with 34% of the dose excreted as unchanged avatrombopag. Only 6% of the administered dose was found in urine.Specific PopulationsAge (1-86 years), sex, race [Whites, African-Americans, and East Asians (i.e., Japanese, Chinese and Koreans)], and any hepatic impairment (Child-Turcotte-Pugh (CTP) grade A, B, and C, or Model for End-Stage Liver Disease (MELD) score 4-23) and mild to moderate renal impairment (CLcr >=30 mL/min) did not have clinically meaningful effects on the pharmacokinetics of avatrombopag.Lower body weight was associated with higher avatrombopag Cmax and AUC following the proposed starting dose in patients aged years and older weighing 16.3 to 175 kg. Pediatric patients aged to less than years had 34% higher Cmax and 23% higher AUC following administration of 10 mg daily DOPTELET SPRINKLE compared to adults who received 20 mg daily DOPTELET tablets.The effect of severe renal impairment (CLcr <30 mL/min, Cockcroft-Gault), including patients requiring hemodialysis, on avatrombopag pharmacokinetics is unknown.Drug InteractionsClinical StudiesTable 12 summarizes the effect of other drugs on the pharmacokinetics of avatrombopag.Table 12: Drug Interactions: Changes in Pharmacokinetics of Avatrombopag in the Presence of Co-Administered Drug Co-administered DrugGeometric Mean Ratio (90% CI) of Avatrombopag PK with/without Co-administered Drug [No Effect=1.00]AUC0-inf Cmax Strong CYP3A InhibitorItraconazole1.37 (1.10, 1.72)1.07 (0.86, 1.35)Moderate CYP3A and CYP2C9 InhibitorFluconazole2.16 (1.71, 2.72)1.17 (0.96, 1.42)Moderate CYP2C9 and Strong CYP3A InducerRifampin0.57 (0.47, 0.62)1.04 (0.88, 1.23)P-gp InhibitorCyclosporine0.83 (0.65, 1.04)0.66 (0.54, 0.82)P-gp and Moderate CYP3A InhibitorVerapamil1.61 (1.21, 2.15)1.26 (0.96, 1.66)at steady state, except for cyclosporine which was administered as single dose.In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated ClinicallyCYP enzymes: Avatrombopag does not inhibit CYP1A, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A, does not induce CYP1A, CYP2B6, CYP2C or CYP3A, and weakly induces CYP2C8 and CYP2C9.Transporter systems: Avatrombopag inhibits organic anion transporter (OAT) and breast cancer resistance protein (BCRP), but not organic anion transporter polypeptide (OATP) 1B1 or 1B3, organic cation transporter (OCT) or OAT1.Avatrombopag is not substrate for OATP1B1, OATP1B3, OCT2, OAT1 or OAT3.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during post approval use of DOPTELET. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Immune System Disorders: Hypersensitivity reactions including pruritus, rash, choking sensation, erythema, pharyngeal edema, pruritus generalized, rash macular, swelling face, and swollen tongue.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on findings from animal reproduction studies, DOPTELET may cause fetal harm when administered to pregnant woman (see Data ). The available data on DOPTELET in pregnant women are insufficient to inform drug-associated risk of adverse developmental outcomes. In animal reproduction studies, oral administration of avatrombopag resulted in adverse developmental outcomes when administered during organogenesis in rabbits and during organogenesis and the lactation period in rats. However, these findings were observed at exposures based on an AUC substantially higher than the AUC observed in patients at the maximum recommended dose of 60 mg once daily. Advise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.DataAnimal DataIn embryo-fetal development studies, avatrombopag was administered during organogenesis at doses of 100, 300, and 1000 mg/kg/day in rats and doses of 100, 300, and 600 mg/kg/day in rabbits. Minimal decreases in fetal weights were observed in rats at the maternally toxic dose of 1000 mg/kg/day with exposures 190 times the human exposure based on AUC. Spontaneous abortions were observed at all doses tested in rabbits and were associated with decreased body weights and food consumption at 300 and 600 mg/kg/day; exposures at the lowest dose of 100 mg/kg/day were 10 times the AUC in patients at the maximum recommended dose of 60 mg once daily. There were no embryo-fetal effects in rats administered avatrombopag at doses up to 100 mg/kg/day (53 times the human exposure based on AUC) or rabbits administered avatrombopag at doses up to 600 mg/kg (35 times the human exposure based on AUC).In pre- and postnatal development studies in rats, avatrombopag was administered during both the organogenesis and lactation periods at doses ranging from to 600 mg/kg/day. Doses of 100, 300, and 600 mg/kg/day caused maternal toxicity leading to total litter losses, decreased body weight in pups, and increased pup mortality, with the majority of the pup mortality occurring from postnatal days 14 to 21. At dose of 50 mg/kg/day that did not produce clear maternal toxicity, avatrombopag caused increased pup mortality from postnatal days to 21, and mortality continued through postnatal day 25. The 50 mg/kg/day dose also decreased body weight gain in the pups, resulting in delay in sexual maturation. There were no effects on behavioral or reproductive functions in the offspring. The 50 mg/kg/day dose resulted in maternal exposures 43 times and pup exposures approximately times the AUC observed in patients at the maximum recommended dose of 60 mg once daily.

RECENT MAJOR CHANGES SECTION.

RECENT MAJOR CHANGES. Indications and Usage (1.3) 07/2025Dosage and Administration (2.1, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8) 07/2025Warnings and Precautions (5.1) 07/2024.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION DOPTELET(R) (dop-TEL-et)(avatrombopag) tablets, for oral useDOPTELET(R) SPRINKLE (dop-TEL-et SPRINK-el)(avatrombopag) oral granulesWhat are DOPTELET and DOPTELET SPRINKLEDOPTELET is prescription medicine used to treat low blood platelet counts in:adults with long-lasting (chronic) liver disease (CLD) who are scheduled to have medical or dental procedure.adults with chronic immune thrombocytopenia (ITP) when other treatments have not worked well enough.children year and older with persistent or chronic ITP when other treatments have not worked well enough. DOPTELET tablets and DOPTELET SPRINKLE are different dosage forms of DOPTELET. DOPTELET SPRINKLE is capsule that contains granules that are mixed with soft food or liquid for dosing. DOPTELET tablets and DOPTELET SPRINKLE are not used to make platelet counts normal.It is not known if DOPTELET tablets or DOPTELET SPRINKLE are safe and effective in children younger than year of age. Before you take DOPTELET or DOPTELET SPRINKLE, tell your healthcare provider about all of your medical conditions, including if you:have ever had blood clot.are pregnant or plan to become pregnant. DOPTELET may harm your unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with DOPTELET.are breastfeeding or plan to breastfeed. It is not known if DOPTELET passes into your breast milk. Do not breastfeed during your treatment with DOPTELET and for at least weeks after the last dose. Talk to your healthcare provider about the best way to feed your baby during this time.Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. DOPTELET or DOPTELET SPRINKLE may affect the way other medicines work, and other medicines may affect the way DOPTELET or DOPTELET SPRINKLE works.How should take DOPTELETDOPTELET tablets that come in blister package are not the same dosage form as DOPTELET SPRINKLE that come in bottle and cannot be directly substituted for each other. Contact your or your childs pharmacist or healthcare provider if you did not receive the correct dosage form.Take DOPTELET exactly as your healthcare provider tells you to take it.Your healthcare provider will tell you how much DOPTELET to take and when to start taking it.Your healthcare provider may change your dose of DOPTELET depending on your blood platelet counts.Take DOPTELET with food.If you take DOPTELET to treat your low blood platelet counts due to chronic liver disease before medical or dental procedure, your healthcare provider will check your platelet count before treatment and on the day of your scheduled procedure.If you take DOPTELET to treat your low blood platelet counts due to persistent or chronic immune thrombocytopenia, your healthcare provider will check your platelet count before, during and for at least weeks after stopping your treatment with DOPTELET.If you are taking DOPTELET before scheduled medical procedure and you miss dose, contact your healthcare provider for further dosing instructions.If you are taking DOPTELET for persistent or chronic immune thrombocytopenia and you miss dose, take it as soon as you remember. Do not take doses at one time to make up for missed dose. Take your next dose at your usual scheduled time.If you take too much DOPTELET, call your healthcare provider or Poison Help Line at 1-800-222-1222, or go to the nearest hospital emergency room right away.How should give DOPTELET SPRINKLEDOPTELET SPRINKLE oral granules that come in bottle are not the same dosage form as DOPTELET tablets that come in blister card and cannot be directly substituted for each other. Contact your childs pharmacist or healthcare provider if you did not receive the correct dosage form.If your child is prescribed DOPTELET SPRINKLE: See the Instructions for Use on how to prepare and give dose.Open the capsules and sprinkle the contents onto small amount of soft food or liquid. Mix or stir the granules into the soft food or liquid and take right away.Do not swallow the capsules whole or the empty capsule shells.Do not chew or crush the oral granules.Give DOPTELET SPRINKLE exactly as your childs healthcare provider tells you to give it.Your childs healthcare provider will tell you how much DOPTELET SPRINKLE to give and when to start taking it.Your childs healthcare provider may change the dose of DOPTELET SPRINKLE.Give your child DOPTELET SPRINKLE with food.If your child is taking DOPTELET SPRINKLE to treat low blood platelet counts due to persistent or chronic immune thrombocytopenia, your childs healthcare provider will check your childs platelet count before, during and for at least weeks after stopping treatment with DOPTELET SPRINKLE.If you are giving DOPTELET SPRINKLE for your childs persistent or chronic immune thrombocytopenia and miss dose, give it as soon as you remember. Do not give doses at one time to make up for missed dose. Give the next dose at the usual scheduled time.If your child takes too much DOPTELET SPRINKLE, call your childs healthcare provider or Poison Help Line at 1-800-222-1222 or go to the nearest hospital emergency room right away.What are the possible side effects of DOPTELET or DOPTELET SPRINKLEDOPTELET or DOPTELET SPRINKLE may cause serious side effects, including:Blood clots. People with chronic liver disease or persistent or chronic immune thrombocytopenia and people with certain blood clotting conditions may have an increased risk of developing blood clots. Tell your healthcare provider right away if you get signs and symptoms of blood clot, including:o swelling, pain, or tenderness in your legs fast heartbeato shortness of breath stomach (abdominal) pain or tendernesso chest painThe most common side effects of DOPTELET when used to treat low blood platelet counts in adults with chronic liver disease (CLD) who are scheduled to have medical or dental procedure are:o fever headacheo stomach (abdominal) pain tirednesso nausea swelling of hands or feetThe most common side effects of DOPTELETwhen used to treat low blood platelet counts in adults with chronic immune thrombocytopenia (ITP) are:o headache joint paino tiredness bleeding gumso bruising purple or red spots on your skino nosebleed runny noseo upper respiratory infectionThe most common side effects of DOPTELETor DOPTELET SPRINKLEwhen used to treat low blood platelet counts in children year and older with persistent or chronic immune thrombocytopenia (ITP) are:o viral infection fevero runny nose pain in the mouth or throato coughThese are not all of the possible side effects of DOPTELET or DOPTELET SPRINKLE.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store DOPTELET tablets or DOPTELET SPRINKLEStore DOPTELET tablets or DOPTELET SPRINKLE at room temperature from 68F to 77F (20C to 25C).Store DOPTELET tablets in the original package.Keep DOPTELET tablets,DOPTELET SPRINKLE and all medicines out of the reach of children.General information about the safe and effective use of DOPTELET or DOPTELET SPRINKLE.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use DOPTELET or DOPTELET SPRINKLE for condition for which it was not prescribed. Do not give DOPTELET tablets or DOPTELET SPRINKLE to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about DOPTELET or DOPTELET SPRINKLE that is written for health professionals.What are the ingredients in DOPTELET tablets or DOPTELET SPRINKLEActive ingredient: avatrombopagInactive ingredients in DOPTELET tablets: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate and microcrystalline cellulose. Tablet coating film: ferric oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.Inactive ingredients in DOPTELET SPRINKLE: crospovidone Type A, magnesium stearate, mannitol, microcrystalline cellulose, and sodium lauryl sulfate. Capsule shells: Hypromellose.DOPTELET is registered trademark of AkaRx, Inc.Manufactured for AkaRx, Inc., Morrisville, North Carolina 27560For more information, go to www.DOPTELET.com or call 1-855-454-3887.This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 07/2025 PI0001 R8. DOPTELET is prescription medicine used to treat low blood platelet counts in:adults with long-lasting (chronic) liver disease (CLD) who are scheduled to have medical or dental procedure.adults with chronic immune thrombocytopenia (ITP) when other treatments have not worked well enough.children year and older with persistent or chronic ITP when other treatments have not worked well enough. adults with long-lasting (chronic) liver disease (CLD) who are scheduled to have medical or dental procedure.. adults with chronic immune thrombocytopenia (ITP) when other treatments have not worked well enough.. children year and older with persistent or chronic ITP when other treatments have not worked well enough.. have ever had blood clot.. are pregnant or plan to become pregnant. DOPTELET may harm your unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with DOPTELET.. are breastfeeding or plan to breastfeed. It is not known if DOPTELET passes into your breast milk. Do not breastfeed during your treatment with DOPTELET and for at least weeks after the last dose. Talk to your healthcare provider about the best way to feed your baby during this time.. DOPTELET tablets that come in blister package are not the same dosage form as DOPTELET SPRINKLE that come in bottle and cannot be directly substituted for each other. Contact your or your childs pharmacist or healthcare provider if you did not receive the correct dosage form.. Take DOPTELET exactly as your healthcare provider tells you to take it.. Your healthcare provider will tell you how much DOPTELET to take and when to start taking it.. Your healthcare provider may change your dose of DOPTELET depending on your blood platelet counts.. Take DOPTELET with food.. If you take DOPTELET to treat your low blood platelet counts due to chronic liver disease before medical or dental procedure, your healthcare provider will check your platelet count before treatment and on the day of your scheduled procedure.. If you take DOPTELET to treat your low blood platelet counts due to persistent or chronic immune thrombocytopenia, your healthcare provider will check your platelet count before, during and for at least weeks after stopping your treatment with DOPTELET.. If you are taking DOPTELET before scheduled medical procedure and you miss dose, contact your healthcare provider for further dosing instructions.. If you are taking DOPTELET for persistent or chronic immune thrombocytopenia and you miss dose, take it as soon as you remember. Do not take doses at one time to make up for missed dose. Take your next dose at your usual scheduled time.. If you take too much DOPTELET, call your healthcare provider or Poison Help Line at 1-800-222-1222, or go to the nearest hospital emergency room right away.. DOPTELET SPRINKLE oral granules that come in bottle are not the same dosage form as DOPTELET tablets that come in blister card and cannot be directly substituted for each other. Contact your childs pharmacist or healthcare provider if you did not receive the correct dosage form.. If your child is prescribed DOPTELET SPRINKLE: See the Instructions for Use on how to prepare and give dose.. Open the capsules and sprinkle the contents onto small amount of soft food or liquid. Mix or stir the granules into the soft food or liquid and take right away.. Do not swallow the capsules whole or the empty capsule shells.. Do not chew or crush the oral granules.. Give DOPTELET SPRINKLE exactly as your childs healthcare provider tells you to give it.. Your childs healthcare provider will tell you how much DOPTELET SPRINKLE to give and when to start taking it.. Your childs healthcare provider may change the dose of DOPTELET SPRINKLE.. Give your child DOPTELET SPRINKLE with food.. If your child is taking DOPTELET SPRINKLE to treat low blood platelet counts due to persistent or chronic immune thrombocytopenia, your childs healthcare provider will check your childs platelet count before, during and for at least weeks after stopping treatment with DOPTELET SPRINKLE.. If you are giving DOPTELET SPRINKLE for your childs persistent or chronic immune thrombocytopenia and miss dose, give it as soon as you remember. Do not give doses at one time to make up for missed dose. Give the next dose at the usual scheduled time.. If your child takes too much DOPTELET SPRINKLE, call your childs healthcare provider or Poison Help Line at 1-800-222-1222 or go to the nearest hospital emergency room right away.. Store DOPTELET tablets or DOPTELET SPRINKLE at room temperature from 68F to 77F (20C to 25C).. Store DOPTELET tablets in the original package.

SPL UNCLASSIFIED SECTION.

1.1 Treatment of Thrombocytopenia in Patients with Chronic Liver Disease (CLD). DOPTELET is indicated for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo procedure.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: May cause fetal harm (8.1)Lactation: Advise not to breastfeed. (8.2). Pregnancy: May cause fetal harm (8.1). Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on findings from animal reproduction studies, DOPTELET may cause fetal harm when administered to pregnant woman (see Data ). The available data on DOPTELET in pregnant women are insufficient to inform drug-associated risk of adverse developmental outcomes. In animal reproduction studies, oral administration of avatrombopag resulted in adverse developmental outcomes when administered during organogenesis in rabbits and during organogenesis and the lactation period in rats. However, these findings were observed at exposures based on an AUC substantially higher than the AUC observed in patients at the maximum recommended dose of 60 mg once daily. Advise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.DataAnimal DataIn embryo-fetal development studies, avatrombopag was administered during organogenesis at doses of 100, 300, and 1000 mg/kg/day in rats and doses of 100, 300, and 600 mg/kg/day in rabbits. Minimal decreases in fetal weights were observed in rats at the maternally toxic dose of 1000 mg/kg/day with exposures 190 times the human exposure based on AUC. Spontaneous abortions were observed at all doses tested in rabbits and were associated with decreased body weights and food consumption at 300 and 600 mg/kg/day; exposures at the lowest dose of 100 mg/kg/day were 10 times the AUC in patients at the maximum recommended dose of 60 mg once daily. There were no embryo-fetal effects in rats administered avatrombopag at doses up to 100 mg/kg/day (53 times the human exposure based on AUC) or rabbits administered avatrombopag at doses up to 600 mg/kg (35 times the human exposure based on AUC).In pre- and postnatal development studies in rats, avatrombopag was administered during both the organogenesis and lactation periods at doses ranging from to 600 mg/kg/day. Doses of 100, 300, and 600 mg/kg/day caused maternal toxicity leading to total litter losses, decreased body weight in pups, and increased pup mortality, with the majority of the pup mortality occurring from postnatal days 14 to 21. At dose of 50 mg/kg/day that did not produce clear maternal toxicity, avatrombopag caused increased pup mortality from postnatal days to 21, and mortality continued through postnatal day 25. The 50 mg/kg/day dose also decreased body weight gain in the pups, resulting in delay in sexual maturation. There were no effects on behavioral or reproductive functions in the offspring. The 50 mg/kg/day dose resulted in maternal exposures 43 times and pup exposures approximately times the AUC observed in patients at the maximum recommended dose of 60 mg once daily.. 8.2 Lactation. Risk SummaryThere is no information regarding the presence of avatrombopag in human milk, the effects on the breastfed child, or the effects on milk production. Avatrombopag was present in the milk of lactating rats. When drug is present in animal milk, it is likely the drug will be present in human milk. Due to the potential for serious adverse reactions in breastfed child from DOPTELET, breastfeeding is not recommended during treatment with DOPTELET and for at least weeks after the last dose (see Clinical Considerations ).Clinical ConsiderationsMinimizingExposureA lactating woman receiving DOPTELET for brief periods, such as prior to an invasive procedure, should interrupt breastfeeding and pump and discard breastmilk during treatment and for two weeks after the last dose of DOPTELET in order to minimize exposure to breastfed child. Advise lactating women receiving chronic DOPTELET therapy not to breastfeed during treatment with DOPTELET and for at least weeks after the last dose.. 8.4 Pediatric Use. The safety and effectiveness of DOPTELET tablet for the treatment of persistent or chronic ITP have been established in pediatric patients aged years and older. The safety and effectiveness of DOPTELET SPRINKLE for the treatment of persistent or chronic ITP have been established in pediatric patients aged to <6 years. Use of DOPTELET tablet and DOPTELET SPRINKLE for their respective populations is supported by evidence from an adequate and well-controlled study in pediatric patients aged year and older [see Adverse Reactions 6.1 ), Clinical Pharmacology 12.3 ), and Clinical Studies 14.3 )].Juvenile Animal Toxicity DataIn 10-week juvenile toxicology study in rats, avatrombopag was administered at doses ranging from 20 to 300 mg/kg/day. There was no test article-related mortality and there were no clinical signs at doses up to 300 mg/kg/day. In the stomach, dose-dependent degeneration, regenerative hyperplasia, and atrophy of the glandular epithelium occurred at 100 and 300 mg/kg/day; exposures at 100 mg/kg/day in male rats were 14 times the AUC in patients at the highest recommended dose of 60 mg once daily. An increased incidence of background focal mineralization was also observed in the kidneys of females at 300 mg/kg/day (female rat exposure was 50 times the human exposure based on AUC at the 60 mg daily dose).. 8.5 Geriatric Use. There were 112 patients 65 years of age and older in the clinical studies for Chronic Liver Disease and Chronic Immune Thrombocytopenia [see Clinical Studies 14.1 and 14.2 )]. Of the total number of DOPTELET-treated patients in these studies, 71 (23%) were 65 years of age and older, while 12 (4%) were 75 years of age and older. Clinical studies of DOPTELET did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Thrombotic/Thromboembolic Complications: DOPTELET is thrombopoietin (TPO) receptor agonist and TPO receptor agonists have been associated with thrombotic and thromboembolic complications in patients with chronic liver disease or immune thrombocytopenia.Monitor platelet counts. Monitor for signs and symptoms of thromboembolic events and institute treatment promptly. (5.1). 5.1 Thrombotic/Thromboembolic Complications. DOPTELET is thrombopoietin (TPO) receptor agonist and TPO receptor agonists have been associated with thrombotic and thromboembolic complications in patients with chronic liver disease or immune thrombocytopenia. In patients with chronic liver disease, thromboembolic events (portal vein thrombosis) occurred in 0.4% (1/274) of patients receiving DOPTELET. In adult patients with chronic immune thrombocytopenia, thromboembolic events (arterial or venous) occurred in 7% (9/128) of patients receiving DOPTELET.Consider the potential increased thrombotic risk when administering DOPTELET to patients with known risk factors for thromboembolism, including genetic prothrombotic conditions (e.g., Factor Leiden, Prothrombin 20210A, Antithrombin deficiency or Protein or deficiency) and acquired risk factors (e.g., antiphospholipid syndrome).DOPTELET should not be administered to patients with chronic liver disease or immune thrombocytopenia in an attempt to normalize platelet counts. Monitor platelet counts and follow the dosing guidelines to achieve target platelet counts [see Dosage and Administration (2.3 and 2.5 )]. Monitor patients receiving DOPTELET for signs and symptoms of thromboembolic events and institute treatment promptly.