American College of Cardiology Extended Learning these physicians but a little learning is a dangerous thing , said Alexander Pope , so they are all having a go at them . They go to a course on the topic and they all think they know how to care for these patients .

“ Many of ( these adult congenital patients ) will need to go to special centers ,” she continued , “ centers offering adult cardiology ; these are no longer pediatric patients and they can ’ t be treated in pediatric hospitals .”

Bleeding Related to CABG – In TRITON-TIMI 38 , 437 patients who received a thienopyridine underwent CABG during the course of the study . The rate of CABG-related TIMI Major or Minor bleeding was 14.1 % for the Effient group and 4.5 % in the clopidogrel group ( see Table 3 ). The higher risk for bleeding adverse reactions in patients treated with Effient persisted up to 7 days from the most recent dose of study drug .

Table 3 : CABG-Related Bleeding a ( TRITON-TIMI 38 )

Effient (%) ( N = 213 )

Clopidogrel (%) ( N = 224 )

In the United States , the Adult Congenital Heart Association ( ACHA ) has a directory that currently contains information on 122 ACHD centers in North America . We ’ re doing a little better since Dr . Somerville ’ s comments : 17 of those centers have opened since 2012 . But again , at least as of ACC . 16 , Dr . Somerville has seen little improvement in what she views as suboptimal care of these patients in the United States .

7 DRUG INTERACTIONS

7.1 Warfarin : Coadministration of Effient and warfarin increases the risk of bleeding [ see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].

7.2 Non-Steroidal Anti-Inflammatory Drugs : Coadministration of Effient and NSAIDs ( used chronically ) may increase the risk of bleeding [ see Warnings and Precautions ( 5.1 )].

7.3 Other Concomitant Medications : Effient can be administered with drugs that are inducers or inhibitors of cytochrome P450 enzymes [ see Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].

Effient can be administered with aspirin ( 75-mg to 325-mg per day ), heparin , GPIIb / IIIa inhibitors , statins , digoxin , and drugs that elevate gastric pH , including proton pump inhibitors and H 2 blockers [ see Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy : Risk Summary – There are no data with Effient use in pregnant women to inform a drug-associated risk . No structural malformations were observed in animal reproductive and developmental toxicology studies in rats and rabbits at doses of up to 30 times the recommended therapeutic exposures in humans . Due to the mechanism of action of Effient , and the associated identified risk of bleeding , consider the benefits and risks of Effient and possible risks to the fetus when prescribing Effient to a pregnant woman [ see Boxed Warning , and Warnings and Precautions ( 5.1 , 5.3 )].

In embryo fetal developmental toxicology studies , pregnant rats and rabbits received prasugrel at maternally toxic oral doses equivalent to more than 40 times the human exposure . A slight decrease in fetal body weight was observed ; but , there were no structural malformations in either species . In prenatal and postnatal rat studies , maternal treatment with prasugrel had no effect on the behavioral or reproductive development of the offspring at doses greater than 150 times the human exposure .

8.2 Lactation : Risk Summary – There is no information regarding the presence of prasugrel in human milk , the effects on the breastfed infant , or the effects on milk production . Metabolites of prasugrel were found in rat milk . The developmental and health benefits of breastfeeding should be considered along with the mother ’ s clinical need for Effient and any potential adverse effects on the breastfed child from Effient or from the underlying maternal condition .

Following a 5-mg / kg oral dose of [ 14 C ] -prasugrel to lactating rats , metabolites of prasugrel were detected in the maternal milk and blood .

8.4 Pediatric Use : Safety and effectiveness in pediatric patients have not been established . In a randomized , placebo-controlled trial , the primary objective of reducing the rate of vaso-occlusive crisis ( painful crisis or acute chest syndrome ) in pediatric patients , aged 2 to less than 18 years , with sickle cell anemia was not met .

8.5 Geriatric Use : In TRITON-TIMI 38 , 38.5 % of patients were ≥65 years of age and 13.2 % were ≥75 years of age . The risk of bleeding increased with advancing age in both treatment groups , although the relative risk of bleeding ( Effient compared with clopidogrel ) was similar across age groups .

Patients ≥75 years of age who received Effient 10-mg had an increased risk of fatal bleeding events ( 1.0 %) compared to patients who received clopidogrel ( 0.1 %). In patients ≥75 years of age , symptomatic intracranial hemorrhage occurred in 7 patients ( 0.8 %) who received Effient and in 3 patients ( 0.3 %) who received clopidogrel . Because of the risk of bleeding , and because effectiveness is uncertain in patients ≥75 years of age [ see Clinical Studies ( 14 ) in full Prescribing Information ], use of Effient is generally not recommended in these patients , except in high-risk situations ( diabetes and past history of myocardial infarction ) where its effect appears to be greater and its use may be considered [ see Warnings and Precautions ( 5.1 ), Clinical Pharmacology ( 12.3 ) in full Prescribing Information , and Clinical Studies ( 14 ) in full Prescribing Information ].

8.6 Low Body Weight : In TRITON-TIMI 38 , 4.6 % of patients treated with Effient had body weight < 60 kg . Individuals with body weight < 60 kg had an increased risk of bleeding and an increased exposure to the active metabolite of prasugrel [ see Dosage and Administration ( 2 ), Warnings and Precautions ( 5.1 ), and Clinical Pharmacology ( 12.3 ) in full Prescribing Information ]. Consider lowering the maintenance dose to 5-mg in patients < 60 kg . The effectiveness and safety of the 5-mg dose have not been prospectively studied [ see Dosage and Administration ( 2 ) and Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].

8.7 Renal Impairment : No dosage adjustment is necessary for patients with renal impairment . There is limited experience in patients with end-stage renal disease , but such patients are generally at higher risk of bleeding [ see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].

8.8 Hepatic Impairment : No dosage adjustment is necessary in patients with mild to moderate hepatic impairment ( Child-Pugh Class A and B ). The pharmacokinetics and pharmacodynamics of prasugrel in patients with severe hepatic disease have not been studied , but such patients are generally at higher risk of bleeding [ see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].

8.9 Metabolic Status : In healthy subjects , patients with stable atherosclerosis , and patients with ACS receiving prasugrel , there was no relevant effect of genetic variation in CYP2B6 , CYP2C9 , CYP2C19 , or CYP3A5 on the pharmacokinetics of prasugrel ’ s active metabolite or its inhibition of platelet aggregation .

10 OVERDOSAGE

10.1 Signs and Symptoms : Platelet inhibition by prasugrel is rapid and irreversible , lasting for the life of the platelet , and is unlikely to be increased in the event of an overdose . In rats , lethality was observed after administration of 2000 mg / kg . Symptoms of acute toxicity in dogs included emesis , increased serum alkaline phosphatase , and hepatocellular atrophy . Symptoms of acute toxicity in rats included mydriasis , irregular respiration , decreased locomotor activity , ptosis , staggering gait , and lacrimation .

10.2 Recommendations about Specific Treatment : Platelet transfusion may restore clotting ability . The prasugrel active metabolite is not likely to be removed by dialysis .

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis , Mutagenesis , Impairment of Fertility : Carcinogenesis – No compound-related tumors were observed in a 2-year rat study with prasugrel at oral doses up to 100 mg / kg / day (> 100 times the recommended therapeutic exposures in humans ( based on plasma exposures to the major circulating human metabolite ). There was an increased incidence of tumors ( hepatocellular adenomas ) in mice exposed for 2 years to high doses (> 250 times the human metabolite exposure ).

Mutagenesis – Prasugrel was not genotoxic in two in vitro tests ( Ames bacterial gene mutation test , clastogenicity assay in Chinese hamster fibroblasts ) and in one in vivo test ( micronucleus test by intraperitoneal route in mice ).

Impairment of Fertility – Prasugrel had no effect on fertility of male and female rats at oral doses up to 300 mg / kg / day ( 80 times the human major metabolite exposure at daily dose of 10-mg prasugrel ).

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling ( Medication Guide ) Benefits and Risks

• Summarize the effectiveness features and potential side effects of Effient .

• Tell patients to take Effient exactly as prescribed .

• Remind patients not to discontinue Effient without first discussing it with the physician who prescribed Effient .

• Recommend that patients read the Medication Guide .

Bleeding : Inform patients that they :

• will bruise and bleed more easily .

• will take longer than usual to stop bleeding .

• should report any unanticipated , prolonged , or excessive bleeding , or blood in their stool or urine .

Other Signs and Symptoms Requiring Medical Attention

• Inform patients that TTP is a rare but serious condition that has been reported with Effient .

• Instruct patients to get prompt medical attention if they experience any of the following symptoms that cannot otherwise be explained : fever , weakness , extreme skin paleness , purple skin patches , yellowing of the skin or eyes , or neurological changes .

• Inform patients that they may have hypersensitivity reactions including rash , angioedema , anaphylaxis , or other manifestations . Patients who have had hypersensitivity reactions to other thienopyridines may have hypersensitivity reactions to Effient .

Invasive Procedures : Instruct patients to :

• inform physicians and dentists that they are taking Effient before any invasive procedure is scheduled .

• tell the doctor performing the invasive procedure to talk to the prescribing health care professional before stopping Effient .

Concomitant Medications : Ask patients to list all prescription medications , over-thecounter medications , or dietary supplements they are taking or plan to take so the physician knows about other treatments that may affect bleeding risk ( e . g ., warfarin and NSAIDs ).

Additional information can be found at www . effienthcp . com

Effient ® is a registered trademark of Eli Lilly and Company .

Manufactured by Eli Lilly and Company , Indianapolis , IN 46285 , USA Marketed by Daiichi Sankyo , Inc . and Lilly USA , LLC Copyright © 2009 , 2016 Daiichi Sankyo , Inc . and Eli Lilly and Company . All rights reserved .

PGHCPBS02AUG2016

‘ HOW DID WE GET SO LUCKY ?’ If patients are seeing better care in the UK and elsewhere , Dr . Somerville tries to explain the difference . First , she admits , they established services in the UK with “ considerable difficulty ” over a period of about 25 years . Money is the critical issue and they got lucky , given the “ huge advantage in our national health service being free at the point of entry ,” she said . How long that will be the case , she said , is another discussion .

There were obstructions early on to her ideas regarding specialized care , for example , “ but we got organized ,” she said , and that made a big difference . As she explains it , the government was forced into it by the patient organization that Dr . Somerville inspired and by its leader who understood politics . It is well organized and the centers were deliberately limited due to the number of experts needed to provide optimal care . She is less

To listen to an interview with Jane Somerville , MD , on the topic of pediatric cardiology , scan the code . The interview was conducted by Alfred A . Bove , MD , PhD . interested in total number of centers claiming to be specialty centers , but rather she counts well-staffed centers of excellence ; by that metric , she counts about 6 such centers in the UK and maybe 9 in the United States .

The UK system is built using a huband-spoke design that has a central care facility that branches out and links to other medical centers . With patients “ shouting at the Ministry of Health all the time ,” Dr . Somerville said , care for ACHD patients is broadly available . The UK is lucky , too , because it is geographically a much smaller area to cover with services . “ The lengths of your spokes are very long here ,” said Dr . Somerville , “ and the geographic problem is very large so you need many more centers . The finances ( in the United States ) have got to be dealt with .”

Importantly , she said the patients are changing : the grown-up congenital heart disease she is seeing today is a lot different than it was 25 years ago when she was first shouting for attention . The ability to do more perfect surgery and all the imaging available today has made a huge difference , she said . ■

November 2016