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does the risk for any cardiac arrhythmia
This is just part of what we ’ ll eventually learn from DREAM , which has a total study population of 1,840 predominantly male , middle-aged veterans . 5
Until we learn more , what can be done now ? As Dr . Redeker ’ s research has shown , patients want relief from insomnia , but they rarely if ever
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 )
TIMI Major or Minor bleeding
14.1
4.5
TIMI Major bleeding
11.3
3.6
Fatal
0.9
0
Reoperation
3.8
0.5
Transfusion of ≥5 units
6.6
2.2
Intracranial hemorrhage
0
0
TIMI Minor bleeding
2.8
0.9
a
Patients may be counted in more than one row .
Bleeding Reported as Adverse Reactions – Hemorrhagic events reported as adverse
reactions in TRITON-TIMI 38 were , for Effient and clopidogrel , respectively : epistaxis ( 6.2 %,
3.3 %), gastrointestinal hemorrhage ( 1.5 %, 1.0 %), hemoptysis ( 0.6 %, 0.5 %), subcutaneous
hematoma ( 0.5 %, 0.2 %), post-procedural hemorrhage ( 0.5 %, 0.2 %), retroperitoneal
hemorrhage ( 0.3 %, 0.2 %), pericardial effusion / hemorrhage / tamponade ( 0.3 %, 0.2 %), and
retinal hemorrhage ( 0.0 %, 0.1 %).
Malignancies : During TRITON-TIMI 38 , newly-diagnosed malignancies were reported
in 1.6 % and 1.2 % of patients treated with prasugrel and clopidogrel , respectively . The
sites contributing to the differences were primarily colon and lung . In another Phase 3
clinical study of ACS patients not undergoing PCI , in which data for malignancies were
prospectively collected , newly-diagnosed malignancies were reported in 1.8 % and 1.7 % of
patients treated with prasugrel and clopidogrel , respectively . The site of malignancies
was balanced between treatment groups except for colorectal malignancies . The rates
of colorectal malignancies were 0.3 % prasugrel , 0.1 % clopidogrel and most were
detected during investigation of GI bleed or anemia . It is unclear if these observations
are causally-related , are the result of increased detection because of bleeding , or are
random occurrences .
Other Adverse Events : In TRITON-TIMI 38 , common and other important non-hemorrhagic
adverse events were , for Effient and clopidogrel , respectively : severe thrombocytopenia
( 0.06 %, 0.04 %), anemia ( 2.2 %, 2.0 %), abnormal hepatic function ( 0.22 %, 0.27 %), allergic
reactions ( 0.36 %, 0.36 %), and angioedema ( 0.06 %, 0.04 %). Table 4 summarizes the
adverse events reported by at least 2.5 % of patients .
Table 4 : Non-Hemorrhagic Treatment-Emergent Adverse Events Reported by at
Least 2.5 % of Patients in Either Group
Effient (%) ( N = 6741 )
Clopidogrel (%) ( N = 6716 )
Hypertension
7.5
7.1
Hypercholesterolemia / Hyperlipidemia
7.0
7.4
Headache
5.5
5.3
Back pain
5.0
4.5
Dyspnea
4.9
4.5
Nausea
4.6
4.3
Dizziness
4.1
4.6
Cough
3.9
4.1
Hypotension
3.9
3.8
Fatigue
3.7
4.8
Non-cardiac chest pain
3.1
3.5
Atrial fibrillation
2.9
3.1
Bradycardia
2.9
2.4
Leukopenia (< 4 x 10 9 WBC / L )
2.8
3.5
Rash
2.8
2.4
Pyrexia
2.7
2.2
Peripheral edema
2.7
3.0
Pain in extremity
2.6
2.6
Diarrhea
2.3
2.6
6.2 Postmarketing Experience : The following adverse reactions have been identified during post approval use of Effient . Because these reactions are reported voluntarily from a population of uncertain size , it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure .
Blood and lymphatic system disorders – Thrombocytopenia , Thrombotic thrombocytopenic purpura ( TTP ) [ see Warnings and Precautions ( 5.4 ) and Patient Counseling Information ( 17 )]
Immune system disorders – Hypersensitivity reactions including anaphylaxis [ see Contraindications ( 4.3 )] mention this concern to physicians , whom they perceive as “ just taking your blood and giving you another pill .” They want their physicians to ask “ how they are sleeping ,” and are interested in educational and behavioral strategies to help them sleep and would be willing to “ try anything ,” especially if it decreased their dependence on sleep medications .
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 : Pregnancy Category B – There are no adequate and well-controlled studies of Effient use in pregnant women . Reproductive and developmental toxicology studies in rats and rabbits at doses of up to 30 times the recommended therapeutic exposures in humans ( based on plasma exposures to the major circulating human metabolite ) revealed no evidence of fetal harm ; however , animal studies are not always predictive of a human response . Effient should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus .
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 pup 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 [ see Nonclinical Toxicology ( 13.1 )].
8.3 Nursing Mothers : It is not known whether Effient is excreted in human milk ; however , metabolites of Effient were found in rat milk . Because many drugs are excreted in human milk , prasugrel should be used during nursing only if the potential benefit to the mother justifies the potential risk to the nursing infant .
8.4 Pediatric Use : Safety and effectiveness in pediatric patients have not been established [ see Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].
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 , 2015 Daiichi Sankyo , Inc . and Eli Lilly and Company . All rights reserved .
PGHCPBS13AUG2015
To listen to an interview with Nancy S . Redeker , PhD , RN , on the links between disturbed sleep , aging , and CVD , scan the code . The interview was conducted by James H . Cheseboro , MD .
The good news is Dr . Redeker ’ s work suggests that cognitive behavioral therapy for insomnia seems to reduce these risks we ’ ve been talking about . 6 In a pilot study published in 2015 , cognitive behavioral therapy was feasible , acceptable to patients , and had a statistically significant effect on insomnia and fatigue , while controlling for the effects of comorbidity and age .
Even before they conducted this pilot , patients expressed an interest in this kind of an approach . When asked about their potential interest in behavioral sleep treatment , one participant stated : “ I ’ d eat a bucket of nails if it you told me it would help me sleep .” 2
( Note : Two more reasons you might want to access the July 2016 edition of ACCEL : Virend K . Somers , MD , PhD , discusses obstructive sleep apnea and cardiovascular disease and Arshad Jahangir , MD , PhD , spends quality time addressing restless legs syndrome and its effect on cardiac structure , function and outcomes .)
REFERENCES :
1 . Redeker NS , Muench U , Zucker MJ , et al . Sleep . 2010 ; 33:551-60 .
2 . Andrews LK , Coviello J , Hurley E , et al . Heart Lung . 2013 ; 42:339-45 .
3 . Lewis PE , Emasealu OV , Rohrbeck P , et al . MSMR . 2014 ; 21:6-13 .
4 . Selim BJ , Koo BB , Qin L , et al . J Clin Sleep Med . 2016 [ Epub ahead of print ]. 5 . Koo BB , Won C , Selim BJ , et al . Sleep
Breath . 2016 ; 20:893-900 . 6 . Redeker NS , Jeon S , Andrews L , et al .
J Clin Sleep Med . 2015 ; 11:1109-19 .
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