Doptelet

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 a procedure.

1.2        Treatment of Thrombocytopenia in 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.

2.1        Recommended Dosage for Patients with Chronic Liver Disease

Begin DOPTELET dosing 10 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 to 8 days after the last dose of DOPTELET.

DOPTELET should be taken orally once daily for 5 consecutive days with food. In the case of a missed dose, patients should take the next dose of DOPTELET 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; all 5 days of dosing should be completed.

Table 1:        Recommended Dose and Duration in Patients with Chronic Liver Disease Scheduled to Undergo a Procedure

DOPTELET has been investigated only as a 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 a platelet count prior to administration of DOPTELET therapy and on the day of a procedure to ensure an adequate increase in platelet count.

2.2        Recommended Dosage for Patients with Chronic Immune Thrombocytopenia

Use the lowest dose of DOPTELET needed to achieve and maintain a platelet count greater than or equal to 50×109/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 Dose Regimen: Begin DOPTELET at a starting dose of 20 mg (1 tablet) once daily with food. 

Monitoring: After initiating therapy with DOPTELET, assess platelet counts weekly until a stable platelet count greater than or equal to 50×109/L has been achieved, and then obtain platelet counts monthly thereafter. Obtain platelet counts weekly for at least 4 weeks following discontinuation of DOPTELET.

Dose adjustments (see  Table 2 and Table 3) are based on the platelet count response. Do not exceed a daily dose of 40 mg (2 tablets).

Table 2:        DOPTELET Dose Adjustments for Patients with Chronic Immune Thrombocytopenia

Table 3: DOPTELET Dose Levels for Titration in Patients with Chronic Immune Thrombocytopenia

*Initial dose regimen for all patients except those taking Moderate or Strong Dual Inducers or Moderate or Strong Dual Inhibitors of CYP2C9 and CYP3A4.

In the case of a missed dose, patients should take the missed dose of DOPTELET 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 per the current regimen.

Discontinuation: Discontinue DOPTELET if the platelet count does not increase to greater than or equal to 50×109/L after 4 weeks of dosing at the maximum dose of 40 mg once daily. Discontinue DOPTELET if the platelet count is greater than 400×109/L after 2 weeks of dosing at 20 mg once weekly.

2.3        Recommended Dosage with Concomitant Moderate or Strong Dual Inducers or Inhibitors of CYP2C9 and CYP3A4 in Patients with Chronic Immune Thrombocytopenia

The recommended starting doses of DOPTELET in patients with chronic immune thrombocytopenia receiving concomitant medications are summarized in  Table 4.

Table 4:         DOPTELET Recommended Starting Dose for Patients with Chronic Immune Thrombocytopenia Based on Concomitant Medications

8.1        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.

Data 

Animal Data

In 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 5 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 a dose of 50 mg/kg/day that did not produce clear maternal toxicity, avatrombopag caused increased pup mortality from postnatal days 4 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 a 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 3 times the AUC observed in patients at the maximum recommended dose of 60 mg once daily.

8.2        Lactation

Risk Summary

There 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 a 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 a breastfed child from DOPTELET, breastfeeding is not recommended during treatment with DOPTELET and for at least 2 weeks after the last dose (see Clinical Considerations).

Clinical Considerations 

Minimizing Exposure

A 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 a breastfed child. Advise lactating women receiving chronic DOPTELET therapy not to breastfeed during treatment with DOPTELET and for at least 2 weeks after the last dose.

8.4        Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

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).

8.5         Geriatric Use

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.

5.1        Thrombotic/Thromboembolic Complications

DOPTELET is a thrombopoietin (TPO) receptor agonist and TPO receptor agonists have been associated with thrombotic and thromboembolic complications in patients with chronic liver disease or chronic immune thrombocytopenia. In patients with chronic liver disease, thromboembolic events (portal vein thrombosis) occurred in 0.4% (1/274) of patients receiving DOPTELET. In 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 V Leiden, Prothrombin 20210A, Antithrombin deficiency or Protein C or S deficiency) and acquired risk factors (e.g., antiphospholipid syndrome).

DOPTELET should not be administered to patients with chronic liver disease or chronic 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 ( 2.2)]. Monitor patients receiving DOPTELET for signs and symptoms of thromboembolic events and institute treatment promptly.