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PHARMACOTHERAPY UPDATE

PHARMACOTHERAPY UPDATE. BENJAMIN GROSS, PHARM D, BCPS, BCACP,CDE,BC-ADM UNIVERSITY OF TENNESSEE COLLEGE OF PHARMACY DEPARTMENT OF CLINICAL PHARMACY CLINICAL PHARMACY DIRECTOR HOLSTON MEDICAL GROUP. OBJECTIVES. Understand recent updates in drug therapy management

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PHARMACOTHERAPY UPDATE

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  1. PHARMACOTHERAPY UPDATE BENJAMIN GROSS, PHARM D, BCPS, BCACP,CDE,BC-ADM UNIVERSITY OF TENNESSEE COLLEGE OF PHARMACY DEPARTMENT OF CLINICAL PHARMACY CLINICAL PHARMACY DIRECTOR HOLSTON MEDICAL GROUP

  2. OBJECTIVES • Understand recent updates in drug therapy management • Review new medications that have recently come to market • Understand recent dosing changes and contraindications of common medication therapies • Discuss recent reported medication adverse reactions

  3. DISCLOSURE • Advisory Board for Sanofi Aventis

  4. CONTACT • OFFICE • 423-578-1537 • 105 WEST STONE DRIVE • KINGSPORT, TN 37660 • EMAIL • BGROSS@UTHSC.EDU • GROSS.BEN@GMAIL.COM

  5. HYPERLIPIDEMIA

  6. HMG-CoA Reductase Inhibitors (STATINS) • ↓LDL (18-63%) • ↑HDL (5-15%) • ↓TG (7-30%) • Adverse effects • Myopathy • Myalgia • Rhabdomyolysis • Rash, headache • GI complaints • Vivid Dreams

  7. SIMVASTATIN • DOSE LIMITIATION • FDA ISSUES SAFETY COMMUNICATION • 80 MG DOSE • INCREASED RISK OF MUSCLE DAMAGE • ONLY USED IN THOSE WHO HAVE BEEN TAKING THE MEDICATION 12 MONTHS OR LONGER WITHOUT EVIDENCE OF MUSCLE INJURY • DO NOT USE IN NEW PATIENTS

  8. SIMVASTATIN • Study of the Effectiveness of Additional Reduction in Cholesterol and Homocysteine (SEARCH) trial • 80mg vs 20 mg • With or without Vitamin B12 (1 mg) and folate (2mg) daily • Survivors of myocardial infarctions: 12, 064 patients • Mean duration: 6.7 years • Incidence of major vascular events • 25.75% in the 20 mg group • 24.5% in the 80 mg group • Am Heart J. 2007 Nov;154(5):815-23

  9. SEARCH: Effects of more vs less STATIN on MORTALITY Simvastatin allocation Risk ratio & 95% CI Cause of death 80mg 20mg 80mg better 20mg better (n=6031) (n=6033) CHD 447 (7.4%) 438 (7.3%) Stroke 57 (0.9%) 67 (1.1%) Other vascular 53 (0.9%) 56 (0.9%) All vascular 557 (9.2%) 561 (9.3%) 0.7% SE 5.9 reduction Neoplastic 245 (4.1%) 266 (4.4%) Respiratory 74 (1.2%) 58 (1.0%) Other medical 75 (1.2%) 70 (1.2%) Non-medical 13 (0.2%) 14 (0.2%) All non-vascular 407 (6.7%) 408 (6.8%) 0.2% SE 7.0 reduction All causes 964 (16.0%) 969 (16.1%) 0.5% SE 4.6 reduction 0.6 0.8 1.0 1.2 1.4

  10. SIMVASTATIN • Myopathy • 55 patients (0.9%) in the 80 mg group • 1 patient (0.02%) in the 20 mg group • Rhabdomyolysis • 22 patients (0.4%) in the 80 mg group • 0 patients in the 20 mg group • Highest in the first 12 months of treatment

  11. SIMVASTATIN • Increased risk • Older and female sex • Calcium channel blockers • Diltiazem • Analysis of FDA’s Adverse Event Reporting System (AERS) database and this trial was the basis of their safety communication

  12. AVOID USE

  13. DOSE LIMITIATIONS

  14. LOVASTATIN

  15. STATINS

  16. RELATIVE EFFICACY

  17. PITAVASTATIN (LIVALO) • NEWEST STATIN • DOSAGE: 2-4 MG • LDL: 38-45% REDUCTION • GFR: 30 to <60 mL/min/1.73m2, or hemodialysis • Initial dose: 1 mg • Max dose 2 mg initial daily dose is 1 mg, max daily dose is 2 mg. • Do not use if GFR <30 mL/min/1.73m2 • Very few drug interactions • Avoid with cyclosporine • 1 mg with erythromycin • 2 mg with rifampin

  18. STATINS AND INCREASE RISK OF DIABETES • Meta-analysis • Five studies • 40,000 patients • No evidence that the use of a statin increased risk of developing type 2 diabetes • Tendency toward reducing the risk with pravastatin • Small, significant increased risk with other statins • Coleman et al. Curr Med Res Opin 2008: 1359-62

  19. STATINS AND INCREASE RISK OF DIABETES • Jupiter Trial • 18, 000 patients: healthy, normal LDL levels • Rosuvastatin 20 mg for two years • Reduced primary end point of heart attack, stroke, arterial revascularization or CV death was reduced • For every 167 patients treated one more case of diabetes • Six more cases per 1000 patients • Were physician reported • Protocol-specified fasting blood glucose did not differ • Ridker et al. NEJM 2008: 2195-2207.

  20. STATINS AND INCREASE RISK OF DIABETES • Meta-analysis • Six studies • 60,000 patients • Statins not found to increase risk • One of the studies excluded (WOSCOPS) • Small increase risk of diabetes • Rajpathak et al. Diabetes Care 2009: 735-42.

  21. STATINS AND INCREASE RISK OF DIABETES • Meta-analysis • Five studies • 32,752 patients • Moderate dose versus intensive dose • High dose significantly more developed diabetes • 2 additional cases for every 1000 patient-years • 6.5 fewer cases of cardiovascular events • Priess et al. JAMA 2011: 2556-64.

  22. STATINS AND INCREASE RISK OF DIABETES • 2010 Lancet meta-analysis, which found a small but measurable risk for new-onset diabetes after all statin use. • Predictors of New-Onset Diabetes in Patients Treated with Atorvastatin • Analysis of three large randomized control trials • TNT • Randomized to atorvastatin 80 mg vs. 10 mg • 9.24% vs. 8.11%, p=0.226 • IDEAL • Randomized to atorvastatin 80 mg vs. 20 mg simvastatin • 6.4% vs. 5.59%, p=0.072 • SPARCL • Randomized to atorvastatin 80 mg vs. placebo • 8.71% vs. 6.06%, p=0.011 • Major cardiovascular events • 11.3% with new-onset diabetes vs. 10.8% without new-onset diabetes, (p=0.69) • JAAC 2011; 57:1535-1545

  23. NEW STATIN LABELING • Routine periodic monitoring of liver enzymes no longer necessary • Before starting therapy and as clinically indicated • FDA has concluded that serious liver injury with statins is rare and unpredictable and that routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury.

  24. NEW STATIN LABELING • Information about the potential for generally non-serious and reversible cognitive side effects (memory loss, confusion, etc.) • Memory loss and confusion have been reported with statin use. These reported events were generally not serious and went away once the drug was no longer being taken.

  25. CRESTOR • Crestor causing heart attacks • Commercial from law firm • Where does this come from? • Based on crestor causing rhabdomyolysis and thus weakening heart muscles • Public Citizen, independent watchdog group claims that crestor causes rhabdomyolysis 22 times more than its lowest dose competitor and 3 times more than its highest dose competitor • www.citizen.org/hrg1729 • FDA findings • Risk of serious muscle damage is similar with Crestor compared to other statins

  26. CRESTOR • Literature review • The safety of rosuvastatin in comparison with other statins in over 100,000 statin users in UK primary care • 10, 289 patients on rosuvastatin • No cases of myopathy, rhabdomyolysis or acute liver injury • Use of multiple international healthcare databases for the detection of rare drug-associated outcomes: a pharmacoepidemiological programme comparing rosuvastatin with other marketed statins • Associated with no significant difference in the incidence of hospitalized myopathy, rhabdomyolysis, or acute renal failure

  27. CRESTOR • Journal of the American College of Cardiology • Expert review panel • The dose of the statin is a greater predictor of myopathy, etc and not the potency of the statin

  28. Triglyceride and Cardiovascular Disease: A Scientific Statement From the American Heart Association • More emphasis on diet and exercise • Less emphasis on meds for most people • For fasting triglyceride levels of 150 to 199 mg/dL, focus on diet and exercise first. • For fasting triglyceride levels of 200 to 499 mg/dL, diet and exercise should still be considered first. However, this is the point at which non-HDL cholesterol levels should be considered as a secondary target to LDL cholesterol • Circulation May 24, 2011 123(20): 2292-2333

  29. Triglyceride and Cardiovascular Disease: A Scientific Statement From the American Heart Association • For high non-HDL cholesterol, consider a statin or a dose increase for patients already taking a statin. Adding omega-3 fatty acids to the statin is also an option. • There is some evidence that a statin plus niacin can reduce surrogate markers of cardiovascular disease, such as carotid artery intima-media thickness. • If LDL cholesterol is controlled and non-HDL cholesterol is still high, a drug therapy for lowering triglycerides such as niacin, fibrates, etc. can be considered. • Circulation May 24, 2011 123(20): 2292-2333

  30. NIASPAN • AIM-HIGH Study • Niacin (1500-2000 mg) and 40 mg Simvastatin • Primary outcome was time to first CHD death, nonfatal MI, ischemic stroke, acute coronary syndrome hospitalization, or symptoms requiring coronary or cerebral revascularization • 3500 patients • Stopped early due to lack of benefit of Niacin/Simvastatin vs simvastatin alone • Most patients had well-controlled LDL on a statin at baseline • LDL vs HDL • Am Heart J 2011; 161:471-77

  31. NEW DRUG THERAPY • JUVISYNC • JANUVIA AND SIMVASTATIN • 100/10, 100/20, 100/40 • Same price as Januvia • Same cautions, contraindications, adverse effects as each component alone

  32. ANTIDEPRESSANTS

  33. ANTIDEPRESSANTS • Celexa (citalopram) • Should no longer be used at doses greater than 40 mg/day • Prolongation of the QT interval • No benefit in doses higher than 40 mg/day

  34. ANTIDEPRESSANTS • Increased risk • CHF • Bradyarrhythmias • Predisposition to hypokalemia or hypomagnesemia • Max dose: 20 mg • Hepatic impairment • >60 years old • CYP2C19 poor metabolizers • CYP2C19 inhibitors • Omeprazole, Cimetidine • Not to exceed 20 mg escitalopram (Lexapro) • Sertraline, paroxetine, and fluoxetine lower risk and alternative agents

  35. CYP2C19 INHIBITORS • chloramphenicol cimetidine citalopram delavirdine efavirenz esomeprazoleethinyl estradiol etravirine felbamate fluconazole fluoxetine fluvoxamine indomethacin isoniazid kavaketoconazolelansoprazole • letrozole moclobemide modafinil nicardipine omeprazoleoxcarbazepine pantoprazole rabeprazole telmisartan ticlopidine topiramate vilazodonevoricon

  36. SWITCHING ANTIDEPRESSANTS • Switching between SSRIs • Usually overlap in their mechanism of action, and the new SSRI will usually prevent discontinuation symptoms that may occur when the first SSRI is stopped. • Substituting a new SSRI at the relatively equivalent dose of the former SSRI is typically well-tolerated

  37. DOSE EQUIVALENTS

  38. SWITCHING ANTIDEPRESSANTS • Switching from SSRI to TCA • Cross-taper • Fluoxetine and Paroxetine • Strong inhibitors of the p450 enzyme 2D6 • Sertraline, citalopram, and escitalopram are milder inhibitors • Enzyme involved in metabolism of many TCAs • Inhibition increase levels and increased risk of toxicity • TCAs should be started at low doses when cross-tapering with an SSRI, particularly with fluoxetine and paroxetine • Inhibition of p450 2D6 will be present to some degree until the SSRI is completely cleared • Most in 5 days; fluoxetine up to 5 weeks

  39. SWITCHING ANTIDEPRESSANTS • SSRI to venlafaxine or duloxetine  • Both have strong serotonergic properties  • Switching immediately from most SSRIs to the equivalent dose • Well tolerated • If higher dose of an SSRI, consider cross-taper • Caution when switching from fluoxetine or paroxetine, because venlafaxine and duloxetine are metabolized by p450 2D6 • Start at lower dose

  40. SWITCHING ANTIDEPRESSANTS • Venlafaxine or duloxetine to antidepressants •  Venlafaxine is associated with uncomfortable discontinuation symptoms upon cessation. • Recommend cross taper as well as duloxetine • Cross-taper also when switching to or from Mirtazapine (Remeron)

  41. SWITCHING ANTIDEPRESSANTS • Bupropion to or from antidepressants • Does not have significant serotonergic properties • Switching from an SSRI, a TCA, venlafaxine, duloxetine, mirtazapine to bupropion • Cross-tapering off the former medication over a one to two week period • Two to three weeks for venlafaxine and duloxetine • Bupropion itself is not frequently associated with discontinuation symptoms • Tapered off over one week while initiating new antidepressant • Avoid prescribing high-dose bupropion concomitantly with paroxetine, fluoxetine, or fluvoxamine due to metabolism of Bupropion

  42. DIABETES

  43. DM med related adverse drug event issues • Avandia – CV events including MI • TZD’s - ↑ fractures • Byetta and Januvia – pancreatitis • Byetta- kidney problems • Lantus-cancer?

  44. PIOGLITAZONE (ACTOS) • Epidemiological study conducted in France • French National Health Insurance Plan data • 1.5 million patients with diabetes • Followed for 4 years • Statically significant increase risk of bladder cancer in patients • Increased risk with cumulative dose >28,000 mg and exposure for longer than one year • Increased risk in males

  45. PIOGLITAZONE • FDA reviewed data from an 5-year interim analysis of an ongoing 10-year epidemiological study • Kaiser Permanente Northern California health plan data • 193,099 patients • New diagnosis of bladder cancer • No overall increased risk • Noted increased risk • Longest exposure (greater than 1 year) • Highest cumulative dose

  46. PIOGLITAZONE • Not to use pioglitazone in patients with active bladder cancer • Use with caution in patients with a prior history of bladder cancer • FYI: Bladder cancer is estimated to occur in 20 per 100,000 persons per year in the U.S. • Higher in diabetics????

  47. NEW DRUG THERAPY • BROMOCRIPTINE (Cycloset) • Dopamine agonist • Parlodel: Parkinson’s disease, acromegaly, hyperprolactinemia • FDA-approved for Type 2 diabetics • Mechanism unclear • May reverse metabolic changes associated with insulin resistance and obesity • Improve blood glucose control • Without increasing insulin levels • A1C reduction: 0.1-0.6% (average of 0.4-0.5%)

  48. NEW DRUG THERAPY • Starting dose 0.8 mg once daily • Increased 0.8 mg/day each week • Max dose 4.8 mg/day • First thing in the morning within 2 hours of rising • Circadian rhythm • If dosed missed, take it the next day • Taken with food • Nausea • Also cause somnolence, hypotension, and syncope • Aggravate psychotic disorders • No increase risk of CV events • Drug-drug interactions • $$$$; will be generic within 5 years

  49. NEW DRUG THERAPY • Tradjenta (Linagliptin) • DPP-IV inhibitor • Dosing • 5 mg once daily • No adjustment for renal or hepatic insufficiency • Efficacy • 0.5-0.8% • Adverse effect • Nasopharyngitis • Pancreatitis has been reported • No contraindications • Drug interaction: P-glycoprotein/ CYP3A4 inducer • Example: Rifampin

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