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Avatrombopag Tablets

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 9. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Avatrombopag maleate is a thrombopoietin receptor agonist. The chemical name of avatrombopag maleate is 4-piperidinecarboxylic acid, 1-[3-chloro-5-[[[4-(4-chloro-2thienyl)-5-(4-cyclohexyl-1-piperazinyl)-2-thiazolyl]amino]carbonyl]-2-pyridinyl]-, (2Z)-2-butenedioate (1:1). The structural formula is:

Empirical formula: C29H34Cl2N6O3S2 · C4H4O4 - Molecular weight: 765.73 g/mol

The aqueous solubility of avatrombopag maleate at various pH levels indicates that the drug substance is practically insoluble at pH 1 to 11.

Avatrombopag is provided as an immediate-release tablet. Each avatrombopag tablet contains 20 mg avatrombopag (equivalent to 23.6 mg of avatrombopag maleate) and the following inactive ingredients: lactose monohydrate, colloidal silicon dioxide, crospovidone, magnesium stearate and microcrystalline cellulose. Coating film: polyvinyl alcohol, talc, polyethylene glycol, titanium dioxide and ferric oxide yellow.

2. INDICATIONS AND USAGE

Avatrombopag is indicated for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure.

3. DOSAGE AND ADMINISTRATION

3.1 Recommended Dosage

Begin avatrombopag dosing 10-13 days prior to the scheduled procedure. The recommended daily dose of avatrombopag is based on the patient’s platelet count prior to the scheduled procedure (Refer to Table 1). Patients should undergo their procedure 5 to 8 days after the last dose of avatrombopag.

Avatrombopag 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 avatrombopag 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 five days of dosing should be completed.

Table 1: Recommended Dose and Duration

Avatrombopag 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]. Avatrombopag should not be administered to patients with chronic liver disease in an attempt to normalize platelet counts.

3.2 Monitoring

Obtain a platelet count prior to administration of avatrombopag therapy and on the day of a procedure to ensure an adequate increase in platelet count.

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

5.1 Thrombotic/Thromboembolic Complications

Avatrombopag is a thrombopoietin (TPO) receptor agonist and TPO receptor agonists have been associated with thrombotic and thromboembolic complications in patients with chronic liver disease. Portal vein thrombosis has been reported in patients with chronic liver disease treated with TPO receptor agonists. In the ADAPT-1 and ADAPT-2 clinical trials, there was 1 treatment-emergent event of portal vein thrombosis in a patient (n=1/430) with chronic liver disease and thrombocytopenia treated with avatrombopag. Consider the potential increased thrombotic risk when administering avatrombopag to patients with known risk factors for thromboembolism, including genetic prothrombotic conditions (Factor V Leiden, Prothrombin 20210A, Antithrombin deficiency or Protein C or S deficiency).

Avatrombopag should not be administered to patients with chronic liver disease in an attempt to normalize platelet counts.

6. ADVERSE REACTIONS

The following serious adverse reactions are discussed in detail in other sections of the labeling:

 Thrombotic/Thromboembolic Complications [see Warnings and Precautions (5.1)]

6.1 Clinical Trials 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.

The safety of avatrombopag 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 avatrombopag (n=274) or placebo (n=156) daily for 5 days prior to a scheduled procedure, and had 1 post-dose safety assessment. Patients were divided into two groups based on their mean platelet count at baseline:

Low Baseline Platelet Count Cohort (less than 40 x109/L) who received avatrombopag 60 mg once daily for 5 days

High Baseline Platelet Count Cohort (40 to less than 50 x109/ L) who received avatrombopag 40 mg once daily for 5 days

The majority of patients were males (65%) and median subject age was 58 years (ranging from 19-86 years of age). The racial and ethnic distribution was White (60%), Asian (33%), Black (3%), and Other (3%).

The most common adverse reactions (those occurring in ≥3% of patients) in the avatrombopag-treated groups (60 mg or 40 mg) across the pooled data from the two trials are summarized in Table 2.

Table 2: Adverse Reactions with a Frequency ≥3% in Patients treated with Avatrombopag - Pooled Data ADAPT-1 and ADAPT-2

a Treatment emergent adverse reactions are sorted in descending order by Total avatrombopag-treated patients (N=274)

For the Low Baseline Platelet Count Cohort, the incidence of serious adverse reactions was 7% (11/159) in the 60 mg avatrombopag treatment group and 13% (12/91) in the matching placebo treatment group. For the High Baseline Platelet Count Cohort, the incidence of serious adverse reactions was 8% (9/115) in the 40 mg avatrombopag treatment group and 3% (2/65) in the matching placebo treatment group. The most common serious adverse reaction reported with avatrombopag was hyponatremia. Two avatrombopag-treated patients (0.7%) developed hyponatremia as compared to no patients in the combined placebo group.

Adverse reactions resulting in discontinuation of avatrombopag were anemia, pyrexia, and myalgia; each was reported in a single (0.4%) patient in the avatrombopag (60 mg) treatment group.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings from animal reproduction studies, avatrombopag may cause fetal harm when administered to a pregnant woman (see Data). The available data on avatrombopag 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 AUC substantially higher than the AUC observed in patients at the 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 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 between 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 recommended dose of 60 mg once daily.

8.2 Lactation

Risk Summary

There are 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 avatrombopag, breastfeeding is not recommended during treatment with avatrombopag and for at least 2 weeks after the last dose (see Clinical Considerations).

Clinical Considerations

Minimizing Exposure

A lactating woman should interrupt breastfeeding and pump and discard breastmilk during treatment and for two weeks after the last dose of avatrombopag in order to minimize exposure to a breastfed child.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of avatrombopag 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.

9. OVERDOSAGE

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 avatrombopag overdose is known.

Hemodialysis is not expected to enhance the elimination of avatrombopag because avatrombopag is only approximately 6% renally excreted and is highly bound to plasma proteins.

10. 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.

11. PHARMACODYNAMICS

Platelet Response

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.

Cardiac Electrophysiology

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

12. 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.

Absorption

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 avatrombopag 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 avatrombopag was administered with a low-fat or high-fat meal (median Tmax range 5 to 8 hours) compared to the fasted state.

Distribution

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

Elimination

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%).

Metabolism

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 avatrombopag 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

* at steady state, except for cyclosporine which was administered as a single dose

Effect of Avatrombopag

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.

Effect of Transporters

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.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

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

Storage and Handling:

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

Rx only

Rev 05/18