BRIEF SUMMARY

AVTROMBOPAG-(May 2018)

Indn-    To treat low blood platelet count (thrombocytopenia) in adults with chronic liver disease who  are scheduled to undergo a medical or dental procedure

Comp-  Tablet: 20 mg   Platelet Count (x109 /L) Once Daily Dose Duration Less than 40 60 mg (3 tablets) 5 days 40 to less than 50 40 mg (2 tablets) 5 days 

ADR-   Most common adverse reactions (= 3%) are: pyrexia, abdominal pain, nausea, headache, fatigue, and edema peripheral. 

CI-   None. 

 WARNINGS-

 Thrombotic/Thromboembolic Complications:                                                               It is a thrombopoietin (TPO) receptor agonist and TPO receptor agonists have been associated with thrombotic and thromboembolic complications in patients with chronic liver disease.

Pat Infrm-

Risks-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.

Portal vein thrombosis has been reported in patients with chronic liver disease treated with TPO receptor agonists.

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  13

ADVERSE REACTIONS -

 Most common adverse reactions (= 3%) are: pyrexia, abdominal pain, nausea, headache, fatigue, and edema peripheral. 

 CONTRAINDICATIONS-                                                                                                        None. 

 WARNINGS AND PRECAUTIONS

 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.

Monitor platelet counts and for thromboembolic events and institute treatment promptly. 

 PATIENT COUNSELING INFORMATION

Advise the patient or caregiver to read the FDA-approved patient labeling (Patient Information).                                                                                                                   

Prior to treatment, patients should fully understand and be informed of the following risks and considerations for DOPTELET:

Risks-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.

Portal vein thrombosis has been reported in patients with chronic liver disease treated with TPO receptor agonists.

Pregnancy -                                                                                                               Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their prescriber of a known or suspected pregnancy.

Lactation-                                                                                                                   Advise women not to breastfeed during treatment with DOPTELET and for at least 2 weeks after the final dose.

Manufactured for: AkaRx, Inc., Durham, North Carolina 27707 Distributed and Marketed by Dova Pharmaceuticals, Inc., Durham, North Carolina 27707

CLINICAL PHARMACOLOGY 

1. 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.

2. 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, 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.

3.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 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 lowfat 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 DOPTELET dose and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions

 USE IN SPECIFIC POPULATIONS

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 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.

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 DOPTELET, breastfeeding is not recommended during treatment with DOPTELET and for at least 2 weeks after the last dose 

 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 DOPTELET in order to minimize exposure to a breastfed child

3. Pediatric Use-                                                                                                          Safety and effectiveness in pediatric patients have not been established.

4.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.

 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 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.