Doptelet Drug Information

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 a procedure.

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 a previous treatment.

Important Use and Administration Instructions Select the recommended product (DOPTELET tablets or DOPTELET SPRINKLE) based on the indication and patient’s age. Administer DOPTELET tablets and DOPTELET SPRINKLE with food. DOPTELET tablets and DOPTELET SPRINKLE are not substitutable on a mg-to-mg basis.

The mixture prepared from the granules in DOPTELET SPRINKLE capsules is more bioavailable than DOPTELET tablets. 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.

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 patient’s platelet count prior to the scheduled procedure (see Table 1 ). Patients should undergo their procedure 5 days to 8 days after the last dose of DOPTELET.

DOPTELET tablets should be taken orally once daily for 5 consecutive days with food. All 5 days of dosing should be completed. Table 1: Recommended DOPTELET Tablets Dosage and Duration in Patients with Chronic Liver Disease Scheduled to Undergo a Procedure DOPTELET tablets have been investigated only as a single 5-day once daily dosing regimen in clinical trials in patients with chronic liver disease.

DOPTELET should not be administered to patients with chronic liver disease in an attempt to normalize platelet counts. Monitoring: Obtain a platelet count prior to administration of DOPTELET therapy and on the day of a procedure to ensure an adequate increase in platelet count.

Recommended Dosage of DOPTELET Tablets for Adult Patients with Chronic Immune Thrombocytopenia and Pediatric Patients 6 Years and Older with Persistent or Chronic Immune Thrombocytopenia Use the lowest dose of DOPTELET needed to achieve and maintain a platelet count greater than or equal to 50×10 9 /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 a stable platelet count greater than or equal to 50×10 9 /L has been achieved, and then obtain platelet counts monthly thereafter.

Obtain platelet counts weekly for at least 4 weeks following discontinuation of DOPTELET. Do not exceed a 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 6 Years and Older with Persistent or Chronic Immune Thrombocytopenia s for Titration in Adult Patients with Chronic Immune Thrombocytopenia and Pediatric Patients 6 Years and Older with Persistent or Chronic Immune Thrombocytopenia 1 *Initial dosage regimen for all patients except those taking Moderate or Strong Dual Inducers or Moderate or Strong Dual Inhibitors of CYP2C9 and CYP3A4.

Discontinue DOPTELET tablets if the platelet count is greater than 400×10 9 /L after 2 weeks of dosing at 20 mg (1 tablet) once weekly.

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 6 years and older with persistent or chronic immune thrombocytopenia are summarized in Table 4. Initial Dosage: Begin DOPTELET SPRINKLE at an initial dosage of 10 mg (content of 1 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 ).

Do not exceed a DOPTELET SPRINKLE daily dose of 20 mg (content of 2 capsules). Table 5: DOPTELET SPRINKLE Dose Adjustments for Patients 1 Year to Less than 6 Years with Persistent or Chronic Immune Thrombocytopenia s for Titration in Pediatric Patients 1 Year to Less than 6 Years with Persistent or Chronic Immune Thrombocytopenia 1 *Initial dose regimen for all patients except those taking Moderate or Strong Dual Inducers or Moderate or Strong Dual Inhibitors of CYP2C9 and CYP3A4. Discontinue DOPTELET SPRINKLE if the platelet count is greater than 400×10 9 /L after 2 weeks of dosing at 10 mg (content of 1 capsule) once weekly.

Important Preparation and Administration Instructions for DOPTELET SPRINKLE Open the capsules and sprinkle the granules onto a small amount of a soft food or liquid in a 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.

Missed Dose In the case of a 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 a missed dose and should take the next dose at the usual time the next day.

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Patients with Chronic Liver Disease The 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 5 days prior to a scheduled procedure, and had 1 post-dose safety assessment. Table 8: Adverse Reactions with a Frequency ≥3% in Patients with C hronic L iver D isease Treated with DOPTELET – Pooled Data ADAPT-1 and ADAPT-2 For 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 a single (0.4%) patient in the DOPTELET (60 mg) treatment group. Adult Patients with Chronic Immune Thrombocytopenia The safety of DOPTELET was evaluated in four clinical trials in adult patients with chronic immune thrombocytopenia: two Phase 3 trials (one randomized, double-blind, placebo-controlled trial, and one randomized, double-blind, active-controlled trial) and two Phase 2 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 majority of patients were female (63%) and median subject age was 50.5 years (ranging from 18-88 years of age).

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. Serious adverse reactions reported in more than 1 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 1 patient included headache, occurring in 1.6% (2/128).

Pediatric Patients with Persistent or Chronic Immune Thrombocytopenia The 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. Table 10 presents the most common adverse reactions (experienced by greater than or equal to 10% of pediatric patients 1 year and older receiving DOPTELET) with a higher incidence for DOPTELET versus placebo. Table 10: Adverse Reactions in Pediatric Patients with Persistent or Chronic Immune Thrombocytopenia Treated with DOPTELET a 0 a 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).

Postmarketing Experience

The following adverse reactions have been identified during post approval use of DOPTELET. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a 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.

Effect of Other Drugs on DOPTELET in Patients with Persistent or Chronic Immune Thrombocytopenia Moderate or Strong Dual Inhibitors of CYP2C9 and CYP3A4 Concomitant use with a moderate or strong dual inhibitor of CYP2C9 and CYP3A4 increases avatrombopag AUC, which may increase the risk of DOPTELET toxicities. Reduce the starting dosage of DOPTELET when used concomitantly with a moderate or strong dual inhibitor of CYP2C9 and CYP3A4 (see Table 4 and Table 7). 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 2 and Table 3; and Table 5 and Table 6).

Moderate or Strong Dual Inducers of CYP2C9 and CYP3A4 Concomitant use with a moderate or strong dual inducer of CYP2C9 and CYP3A4 decreases avatrombopag AUC, which may reduce DOPTELET efficacy. Patients with Chronic Liver Disease No dosage adjustments are required for patients with chronic liver disease.

Pregnancy Risk Summary Based on findings from animal reproduction studies, DOPTELET may cause fetal harm when administered to a pregnant woman ( see Data ). The available data on DOPTELET in pregnant women are insufficient to inform a 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 a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a 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. 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 5 to 600 mg/kg/day.

The 50 mg/kg/day dose also decreased body weight gain in the pups, resulting in a delay in sexual maturation. There were no effects on behavioral or reproductive functions in the offspring.

Pediatric Use The safety and effectiveness of DOPTELET tablet for the treatment of persistent or chronic ITP have been established in pediatric patients aged 6 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 1 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 1 year and older.

Juvenile Animal Toxicity Data In a 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).

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 a medical toxicologist for additional overdose management recommendations.