Avatrombopag Tablets

Dosage Forms And Strengths

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

Storage And Handling

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.

NDC 71369-020-10: carton with one blister card of ten 20 mg tablets
NDC 71369-020-11: one blister card with ten 20 mg tablets
NDC 71369-020-15: carton with one blister card of fifteen 20 mg tablets
NDC 71369-020-16: one blister card of fifteen 20 mg tablets

Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F). Store tablets in original package.

Distributed by: Dova Pharmaceuticals, Inc., Durham, North Carolina 27707. Revised: May 2018

Included as part of the "PRECAUTIONS" Section

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 DOPTELET is only approximately 6% renally excreted and is highly bound to plasma proteins.

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.

Pharmacodynamics

Avatrombopag resulted in dose- and exposure-dependent elevations in platelet counts in adults. The onset of the platelet count increase was observed within 3 to 5 days of the start of a 5-day treatment course, with peak effect observed after 10 to 13 days. Subsequently, platelet counts decreased gradually, returning to near baseline values after 35 days.

At exposures similar to that achieved at the 40 mg and 60 mg dose, DOPTELET does 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.

Pharmacokinetics

Avatrombopag demonstrated dose-proportional pharmacokinetics after single doses from 10 mg (0.25-times the lowest approved dosage) to 80 mg (1.3-times the highest recommended dosage). Healthy subjects administered 40 mg of avatrombopag had a 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 median time to maximal concentration (Tmax) occurred at 5 to 6 hours post-dose.

Effect of Food

Avatrombopag AUC0-inf and Cmax were not affected when DOPTELET was co-administered with a low-fat meal (500 calories, 3 g fat, 15 g proteins, and 108 g carbohydrates) or a high-fat meal (918 calories, 59 g fat, 39 g proteins, and 59 g carbohydrates). The variability of avatrombopag exposure was reduced by 40% to 60% with food. The Tmax of avatrombopag was delayed by 0 to 2 hours when DOPTELET was administered with a low-fat or high-fat meal (median Tmax range 5 to 8 hours) compared to the fasted state.

Avatrombopag has an estimated mean volume of distribution (%CV) of 180 L (25%). Avatrombopag is greater than 96% bound to human plasma proteins.

The mean plasma elimination half-life (%CV) of avatrombopag is approximately 19 hours (19%). The mean (%CV) of the clearance of avatrombopag is estimated to be 6.9 L/hr (29%).

Avatrombopag is primarily metabolized by cytochrome P450 (CYP) 2C9 and CYP3A4.

Excretion

Fecal 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 Populations

Age (18-86 years), body weight (39-175 kg), 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.

The effect of age (< 18 years) and severe renal impairment (CLcr < 30 mL/min, Cockcroft-Gault) including patients requiring hemodialysis on avatrombopag pharmacokinetics is unknown.

Drug Interactions

Drug interaction studies were performed in healthy subjects with single 20 mg DOPTELET dose and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions (see Table 3).

Table 3: Drug Interactions: Changes in Pharmacokinetics of Avatrombopag in the Presence of Co-administered Drug

Avatrombopag does not inhibit CYP1A, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A, does not induce CYP1A, CYP2B6, CYP2C, and CYP3A, and weakly induces CYP2C8 and CYP2C9 in vitro.

Avatrombopag inhibits organic anion transporter (OAT) 3 and breast cancer resistance protein (BCRP) but not organic anion transporter polypeptide (OATP) 1B1 and 1B3, organic cation transporter (OCT) 2, and OAT1 in vitro.

Avatrombopag is a substrate for P-glycoprotein (P-gp) mediated transport [see Table 3]. Avatrombopag is not a substrate for OATP1B1, OATP1B3, OCT2, OAT1, and OAT3.

Clinical Studies

The efficacy of DOPTELET for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure was established in 2 identically-designed multicenter, randomized, double-blind, placebo-controlled trials (ADAPT-1 (NCT01972529) and ADAPT-2 (NCT01976104)). In each study, patients were assigned to the Low Baseline Platelet Count Cohort (<40 x109L) or the High Baseline Platelet Count Cohort (≥40 to <50 x109 L) based on their platelet count at Baseline. Patients were then randomized in a 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 5 days, and patients in the High Baseline Platelet Count Cohort received 40 mg DOPTELET or matching placebo once daily for 5 days. Eligible patients were scheduled to undergo their procedure (low, moderate, or high bleeding risk) 5 to 8 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, a 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 31.1 x109/L and for placebo-treated patients was 30.7 x109/L. In the High Baseline Platelet Count Cohort, the mean Baseline platelet count for the DOPTELET-treated patients was 44.3 x109/L and for placebo-treated patients was 44.9 x109/L.

In ADAPT-2, a 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 32.7 x109/L and for placebo-treated patients was 32.5 x109/L. In the High Baseline Platelet Count Cohort, the mean Baseline platelet count for the DOPTELET-treated patients was 44.3 x109/L and for placebo-treated patients was 44.5 x109/L.

Across both baseline platelet count cohorts and the avatrombopag and placebo treatment groups, patients underwent a 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 a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following an elective procedure. Additional secondary efficacy outcomes were the proportion of patients who achieved platelet counts of >50 x109/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 a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following a scheduled procedure. The following were considered rescue therapies to manage risk of bleeding associated with a 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 a greater proportion of responders than the corresponding placebo treatment groups that was both clinically meaningful and statistically significant as detailed in Table 4.

Table 4: Proportion of Subjects Not Requiring a Platelet Transfusion or Any Rescue Procedure for Bleeding by Baseline Platelet Count Cohort and Treatment Group – ADAPT-1 and ADAPT-2

In addition, both trials demonstrated a higher proportion of patients who achieved the target platelet count of ≥ 50 x109/L on the day of the procedure, a 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; P <0.0001; ADAPT-2: 67% vs 7%, respectively; P <0.0001; High Baseline Platelet Count Cohort- ADAPT-1: 88% vs 21%, respectively; P <0.0001; ADAPT-2: 93% vs 39%, respectively; P <0.0001).

Further, both trials demonstrated a greater mean change in platelet counts from baseline to the day of the procedure, a secondary efficacy endpoint, in both DOPTELET-treated groups versus the placebo-treated groups for both cohorts (Low Baseline Platelet Count Cohort-ADAPT-1: 32 x109/L vs 0.8 x109/L, respectively; P <0.0001; ADAPT-2: 31.3 x109/L vs 3.0 x109/L, respectively; P <0.0001; High Baseline Platelet Count Cohort-ADAPT-1: 37.1 x109/L vs 1.0 x109/L, respectively; P <0.0001;ADAPT-2: 44.9 x109/L vs 5.9 x109/L, respectively; P <0.0001).

A measured increase in platelet counts was observed in both DOPTELET treatment groups over time beginning on Day 4 post-dose, that peaked on Day 10-13, decreased 7 days post-procedure, and then returned to near baseline values by Day 35.

DOPTELET®
(dop-TEL-et)
(avatrombopag) tablets, for oral use

What is DOPTELET?

DOPTELET is a prescription medicine used to treat low blood platelet counts in adults with long-lasting (chronic) liver disease who are scheduled to have a medical or dental procedure.

DOPTELET is not used to make platelet counts normal in adults with chronic liver disease.
It is not known if DOPTELET is safe and effective in children.

Before you take DOPTELET, tell your healthcare provider about all of your medical conditions, including if you:

• have ever had a 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 2 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.

How should I take DOPTELET?

• 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.
• Take your prescribed dose of DOPTELET 1 time per day for five days in a row as instructed by your healthcare provider.
• Take DOPTELET with food.
• Your healthcare provider will check your platelet count before treatment with DOPTELET and on the day of your scheduled procedure.
• If you forget to take a dose of DOPTELET, take it as soon as you remember. Do not take two doses at one time to make up for a missed dose. Take your next dose at your usual time the next day and complete all five days of dosing.
• If you take too much DOPTELET, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of DOPTELET?

DOPTELET may cause serious side effects, including:

• Blood clots. People with chronic liver disease and people with certain blood clotting conditions may have an increased risk of developing blood clots. Tell your healthcare provider right away if you have signs and symptoms of a blood clot, including:
  • swelling, pain, or tenderness in your leg
  • shortness of breath
  • chest pain
  • fast heartbeat
  • stomach (abdominal) pain or tenderness

The most common side effects of DOPTELET are:

• fever
• headache
• tiredness
• swelling of the hands or feet
• stomach (abdominal) pain
• nausea

These are not all the possible side effects of DOPTELET.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store DOPTELET?

• Store DOPTELET at room temperature between 68°F to 77°F (20°C to 25°C).
• Store DOPTELET tablets in the original package.

Keep DOPTELET and all medicines out of the reach of children.

General information about the safe and effective use of DOPTELET.

Medicines are sometimes prescribed for purposes other than those listed in the Patient Information. Do not use DOPTELET for a condition for which it was not prescribed. Do not give DOPTELET to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about DOPTELET that is written for health professionals.

What are the ingredients in DOPTELET?

Active ingredient: avatrombopag

Inactive ingredients: lactose monohydrate, colloidal silicon dioxide, crospovidone, magnesium stearate and microcrystalline cellulose. Tablet coating film: polyvinyl alcohol, talc, polyethylene glycol, titanium dioxide and ferric oxide yellow.

This Patient Information has been approved by the U.S. Food and Drug Administration.