Doptelet (Avatrombopag)

Indications and Usage (

Dosage and Administration (

Warnings and Precautions (

DOPTELET is a thrombopoietin receptor agonist indicated for the treatment of:

• Thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. (
  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.
  )
• Thrombocytopenia in adult patients with chronic immune thrombocytopenia who have had an insufficient response to a previous treatment. (
  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 a previous treatment.
  )

• Thrombocytopenia in pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia who have had an insufficient response to a previous treatment (

  1.3 Treatment of Thrombocytopenia in Pediatric Patients 1 Year and Older with Persistent or Chronic Immune Thrombocytopenia (ITP)

  DOPTELET is indicated for the treatment of thrombocytopenia in pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia who have had an insufficient response to a previous treatment.
  )

• DOPTELET tablets and DOPTELET SPRINKLE are not substitutable on a mg-to-mg basis.
• DOPTELET SPRINKLE capsules should be opened, and the contents (oral granules) mixed with a soft food or liquid. Administer immediately after mixing. Do not swallow the capsules whole.
• Administer DOPTELET tablets and DOPTELET SPRINKLE with food. (
  2.1 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_DOPTELETSPRINKLE 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

    [see Clinical Pharmacology ]

    . 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.
  ,
  2.3 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 50×10⁹/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 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 50×10⁹/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

  :

  DOPTELET tablet dose adjustments (see Table 2and Table 3) are based on the platelet count response. 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

  Platelet Count	Dose Adjustment or Action
  Less than 50×109/L after at least 2 weeks of DOPTELET tablets	Increase One Dose Level per Table 3. Wait 2 weeks to assess the effects of this regimen and any subsequent dose adjustments.
  Between 200×109/L and 400×109/L	Decrease One Dose Level per Table 3. Wait 2 weeks to assess the effects of this regimen and any subsequent dose adjustments.
  Greater than 400×109/L	Stop DOPTELET tablets. Increase platelet monitoring to twice weekly. When platelet count is less than 150×109/L, decrease One Dose Level per Table 3 and reinitiate therapy.
  Less than 50×109/L after 4 weeks of DOPTELET 40 mg (2 tablets) once daily	Discontinue DOPTELET tablets.
  Greater than 400×109/L after 2 weeks of DOPTELET 20 mg (1 tablet) weekly	Discontinue DOPTELET tablets.

  Table

  3

  : DOPTELET Tablet Dose Levels for Titration in Adult Patients with Chronic Immune Thrombocytopenia and Pediatric Patients 6 Years and Older with Persistent or Chronic Immune Thrombocytopenia

  Dosage	Dose Level
  40 mg (2 tablets) orally Once Daily	6
  40 mg (2 tablets) orallyThree Times a Week AND 20 mg (1 tablet) orally on the Four Remaining Days of Each Week	5
  20 mg (1 tablet) orally Once Daily*	4
  20 mg (1 tablet) orally Three Times a Week	3
  20 mg (1 tablet) orally Twice a Week OR 40 mg Once Weekly	2
  20 mg (1 tablet) orally Once Weekly	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.

  Discontinuation

  :

  • Discontinue DOPTELET tablets 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 (2 tablets) once daily.
  • Discontinue DOPTELET tablets if the platelet count is greater than 400×10⁹/L after 2 weeks of dosing at 20 mg (1 tablet) once weekly.
  ,
  2.5 Recommended Dosage of DOPTELET SPRINKLE for Patients 1 Year to Less than 6 Years with Persistent or Chronic Immune Thrombocytopenia

  Use the lowest dose of DOPTELET SPRINKLE 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 SPRINKLE to normalize platelet counts.

  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).

  Monitoring

  :

  After initiating therapy with DOPTELET SPRINKLE, 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 SPRINKLE.

  Dose Adjustments

  :

  DOPTELET SPRINKLE dose adjustments (see Table 5and Table 6) are based on the platelet count response. 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

  Platelet Count	Dose Adjustment or Action
  Less than 50×109/L after at least 2 weeks of DOPTELET SPRINKLE	Increase One Dose Level per Table 6. Wait 2 weeks to assess the effects of this regimen and any subsequent dose adjustments.
  Between 200×109/L and 400×109/L	Decrease One Dose Level per Table 6. Wait 2 weeks to assess the effects of this regimen and any subsequent dose adjustments.
  Greater than 400×109/L	Stop DOPTELET SPRINKLE. Increase platelet monitoring to twice weekly. When platelet count is less than 150×109/L, decrease One Dose Level per Table 6 and reinitiate therapy.
  Less than 50×109/L after 4 weeks of DOPTELET SPRINKLE 20 mg (content of 2 capsules) once daily	Discontinue DOPTELET SPRINKLE.
  Greater than 400×109/L after 2 weeks of DOPTELET SPRINKLE 10 mg (content of 1 capsule) weekly	Discontinue DOPTELET SPRINKLE.

  Table 6:  DOPTELET SPRINKLE Dose Levels for Titration in Pediatric Patients 1 Year to Less than 6 Years with Persistent or Chronic Immune Thrombocytopenia

  Dosage	Dose Level
  20 mg (content of 2 capsules) orally Once Daily	6
  20 mg (content of 2 capsules) orally Three Times a Week AND 10 mg (content of 1 capsule) orally on the Four Remaining Days of Each Week	5
  10 mg (content of 1 capsule) orally Once Daily*	4
  10 mg (content of 1 capsule) orally Three Times a Week	3
  10 mg (content of 1 capsule) orally Twice a Week OR 20 mg (content of 2 capsules) orally Once Weekly	2
  10 mg (content of 1 capsule) orally Once Weekly	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.

  Discontinuation

  :

  • Discontinue DOPTELET SPRINKLE 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 20 mg (content of 2 capsules) once daily.
  • Discontinue DOPTELET SPRINKLE if the platelet count is greater than 400×10⁹/L after 2 weeks of dosing at 10 mg (content of 1 capsule) once weekly.
  )
• Chronic Liver Disease
  : Dose DOPTELET tablets based upon platelet count prior to procedure, orally for 5 days beginning 10 days to 13 days before procedure. For platelet count less than 40×10⁹/L, the dose is 60 mg (3 tablets) orally once daily; for platelet count 40 to less than 50×10⁹/L the dose is 40 mg (2 tablets) orally once daily. (
  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 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

  Platelet Count	Recommended DOPTELET Dosage	Duration
  Less than 40×109/L	60 mg (3 tablets) orally once daily	5 days
  40×109/L to less than 50×109/L	40 mg (2 tablets) orally once daily	5 days

  DOPTELET tablets have 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.
  )
• Adult Patients with Chronic Immune Thrombocytopenia and Pediatric Patients 6 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 50×10⁹/L. Do not exceed 40 mg (2 tablets) per day.
• Pediatric Patients 1 Year to Less than 6 Years with Persistent or Chronic Immune Thrombocytopenia
  : Initiate DOPTELET SPRINKLE oral granules at 10 mg (content of 1 capsule) orally once daily. Adjust the dose or frequency of dosing to maintain platelet count greater than or equal to 50×10⁹/L. Do not exceed 20 mg (content of 2 capsules) per day.

DOPTELET Tablets: 20 mg as round, biconvex, yellow, film-coated tablets debossed with “AVA” on one side and “20” on the other side.

DOPTELET SPRINKLE: 10 mg as Size 0 capsules containing white to off-white granules. The capsules have a white opaque body and light blue opaque cap with a black arrow symbol imprinted on the body and cap.

• Pregnancy: May cause fetal harm (
  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.
  )
• Lactation: Advise not to breastfeed. (
  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.
  )