FDA Approves DOPTELET (Avatrombopag) for the Treatment of Thrombocytopenia in Adult Patients with Chronic Liver Disease who are Scheduled to Undergo a Procedure
On May 21, 2018, the U.S. Food and Drug Administration (FDA) approved DOPTELET®(avatrombopag) for the treatment of thrombocytopenia in adult patients with chronic liver disease (CLD) who are scheduled to undergo a procedure. DOPTELET is administered once daily with food for 5 consecutive days, and the approved recommended dosage is based on the baseline platelet counts asfollows:
- 60 mg (three 20 mg tablets) if platelet count is < 40 x 109/L
- 40 mg (two 20 mg tablets) if platelet count is 40 to < 50 x 109/L
Therapy should begin 10 to 13 days prior to a scheduled procedure. Monitor platelet count prior to DOPTELET administration and on the day of a procedure to ensure an adequate increase in platelet count. Consider the potential for increased thrombotic risk when administering DOPTELET to patients with known risk factors for thromboembolism, including genetic prothrombotic conditions. DOPTELET should not be used to normalize platelet counts in CLD patients.
Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD)
- MOA: Avatrombopag is a thrombopoietin receptor agonist.
- Dose Proportionality: Avatrombopag exposure increases proportionally with single doses from 10 mg (0.25 times the lowest approved recommended dosage) to 80 mg (1.3 times the highest approved recommended dosage).
- Absorption: Median time to peak concentration occurred 5 to 6 hours post-dose.
- Effect of Food: Variability of avatrombopag AUC0-inf and C max are reduced by 40% to 60% with food.
- Plasma Protein Binding: > 96%.
- Terminal Half-Life (mean): 19 hours.
- Metabolism: Primarily metabolized by CYP2C9 and CYP3A4.
- Excretion: Approximately 88% of the administered avatrombopag dose was eliminated in feces (34% of the dose as unchanged drug), and 6% in urine.
- Platelet Response: Avatrombopag resulted in dose- and exposure-dependent elevations in platelet counts. The onset of the platelet count increase was within 3 to 5 days of the start of a 5-day treatment course, with peak effect after 10 to 13 days, and returning to near baseline after 35 days.
Use in Specific Populations
No clinically significant effects on the pharmacokinetics of avatrombopag were observed based on age (18-86 years), sex, race, any hepatic impairment, or mild to moderate renal impairment (CLcr ≥ 30 mL/min). The effect of age (< 18 years) and severe renal impairment (CLcr < 30 mL/min) including patients requiring hemodialysis on the pharmacokinetics of avatrombopag is unknown.
Efficacy and Safety
Clinical efficacy and safety of DOPTELET in CLD patients scheduled to undergo a procedure were demonstrated at the recommended dosages with food in two identically designed randomized, placebo-controlled trials. The major efficacy outcome was the proportion of responders, defined as patients who did not require a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following an elective procedure. Additional information regarding the efficacy trials can be found in the full prescribing information linked below.
The most common adverse reactions (> 3%) of DOPTELET were pyrexia, abdominal pain, nausea, headache, fatigue, and edema peripheral.
Full prescribing information is available at https://go.usa.gov/xQmwp.
Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online athttp://www.fda.gov/medwatch/
report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
The Office of Clinical Pharmacology (OCP) is pleased to offer the e-mail subscription service Clinical Pharmacology Corner. This is a free service from FDA to provide occasional updates from OCP regarding newly approved therapies, new regulatory and scholarly publications, upcoming events and other items of interest. Subscribe today at http://go.fda.gov/
subscriptionmanagement (note: this link does not work with Internet Explorer) and select Clinical Pharmacology Corner under Drugs.
We always welcome your thoughts regarding the format, content, and utility of the communication. Comments may be sent via email to email@example.com.
This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.