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New Drug Update 2008 C. Wayne Weart, Pharm D Professor of Pharmacy and Family Medicine South Carolina College of Pharmacy MUSC campus Faculty Disclosures Speakers Bureau: Pfizer (CV, DM, Pain, Smoking Cessation) Novartis (CV) Merck (DM, Immunizations) Sanofi-Aventis (DM) Consultant: Merck (Diabetes, CV) Tobacco’s Toll in South Carolina as of 12/6/2006 Adults in SC who smoke 22.6% (729,500) Adults who die each year in SC from their own smoking 5,900 Annual health care costs in SC directly caused by smoking $1.09 Billion High school students in SC who smoke 19.1% and total youth smoking rate of 23.5% Kids (under 18) who become new daily smokers each year 6,500 Kids exposed to second hand smoke at home 240,000 SC cigarette tax $0.07 (lowest in the US, range is from $2.575 in NJ to $0.07 in SC) National average $1.07.3 per pack (last increase in SC was 1977) Packs sold in SC 2006 - 410.4 million with a SC revenue of $27.7 million and a CDC estimated health care cost per pack sold in SC of $7.66 Typical retail cost per pack in SC $3.35 lowest in US vs. $6.45 in NJ highest in US (National average $4.54 per pack) Nicotine Addiction Tobacco users maintain a minimum serum nicotine concentration in order to Prevent withdrawal symptoms Maintain pleasure/arousal Modulate mood Users self-titrate nicotine intake by Smoking more frequently Smoking more intensely Obstructing vents on low-nicotine brand cigarettes Nicotine Pharmacodynamics: Withdrawal Effects Depression Insomnia Irritability/frustration/anger Anxiety Difficulty concentrating Restlessness Increased appetite/weight gain Decreased heart rate Cravings* * Not considered a withdrawal symptom by DSM-IV criteria. Most symptoms peak 24–48 hr after quitting and subside within 2–4 weeks. American Psychiatric Association. (1994). DSM-IV. Hughes et al. (1991). Arch Gen Psychiatry 48:52–59. Hughes & Hatsukami. (1998). Tob Control 7:92–93. Nicotine Agonist—VARENICLINE Chantix, marketed by Pfizer Partial nicotinic receptor agonist – – Approved by the FDA May 2006, to hit the market in the fall of 2006 Much DTC marketing anticipated in 2007 Early trials (JAMA) show better results than bupropion Lessens withdrawal symptoms and inhibits the “buzz” from a smoke Main side effect is nausea VARENICLINE: Mechanism of Action Binds with high affinity and selectivity at 42 neuronal nicotinic acetylcholine receptors Stimulates low-level agonist activity Competitively inhibits binding of nicotine Clinical effects symptoms of nicotine withdrawal Blocks dopaminergic stimulation responsible for reinforcement & reward associated with smoking VARENICLINE: Dosing Patients should begin therapy 1 week PRIOR to their quit date. The dose is gradually increased to minimize treatment-related nausea and insomnia. Treatment Day Initial dose titration Dose Day 1 to day 3 0.5 mg qd Day 4 to day 7 0.5 mg bid Day 8 to end of treatment* 1 mg bid * Up to 12 weeks FDA MedWatch 11/20/2007 11/20/2007] FDA informed healthcare professionals of reports of suicidal thoughts and aggressive and erratic behavior in patient who have taken Chantix, a smoking cessation product. There are also reports of patients experiencing drowsiness that affected their ability to drive or operate machinery. FDA is currently reviewing these cases, along with other recent reports. A preliminary assessment reveals that many of the cases reflect new-onset of depressed mood, suicidal ideation, and changes in emotion and behavior within days to weeks of initiating Chantix treatment. The role of Chantix in these cases is not clear because smoking cessation, with or without treatment, is associated with nicotine withdrawal symptoms and has also been associated with the exacerbation of underlying psychiatric illness. Patients taking this product should report behavior or mood changes to their doctor and use caution when driving or operating machinery until they know how quitting smoking with Chantix may affect them. 2008 ADA/EASD Update Diabetes Care 2008;31:174 Figure 1—Algorithm for the metabolic management of type 2 diabetes. a - Check A1C every 3 months until 7% and then at least every 6 months. b - Associated with increased risk of fluid retention, CHF, and fractures. Rosiglitazone, but probably not pioglitazone, may be associated with an increased risk of myocardial infarction. c - Although three oral agents can be used, initiation and intensification of insulin therapy is preferred based on effectiveness and lower expense. MedWatch 2/20/2007 • Glaxo SmithKline (GSK) notified healthcare professionals of the results of a randomized, double-blind parallel group study [ADOPT] of 4,360 patients with recently diagnosed type 2 diabetes mellitus followed for 4-6 years to compare glycemic control with rosiglitazone relative to metformin and glyburide monotherapies. – Significantly more female patients who received rosiglitazone experienced fractures of the upper arm, hand, or foot, than did female patients who received either metformin or glyburide. – At GSK's request, an independent safety committee reviewed an interim analysis of fractures in another large; ongoing; controlled clinical trial and preliminary analysis was reported as being consistent with the observations from ADOPT. • Takeda/Lilly have also gone back and the same association has been seen with pioglitazone • Healthcare professionals should consider the risk of fracture when initiating or treating female patients with type 2 diabetes mellitus withrosiglitazone and pioglitazone. MedWatch 5/21/07 • The FDA issued a Safety Alert along with a 42 trial meta-analysis in the NEJM that reported a 43% increase in acute MI related to the use of rosiglitazone compared to other antidiabetic agents. • The FDA had previously received a GSK metaanalysis which had also shown a 31% increase in the risk of acute MI with rosglitazone (1.99% vs 1.51% or a 31% RRI or an NNH of about 200) FDA Advisory Committees 7-30-07 • Voted 22-1 to allow rosiglitazone to remain on the market • Voted 20-3 to recommend updated CV warnings in labeling and that they was a clear signal of harm including ischemic heart disease • Panel members also bemoaned the fact that the FDA had not had foresight to mandate appropriate trials • On-going trials RECORD, ACCORD and BARI-2D are under-powered and not designed to answer the key questions about whether ischemic events will be higher and which patient sub-sets will be affected • FDA analysis suggested that nitrate use and concurrent insulin therapy may increase the risk of ischemic heart disease with rosiglitazone FDA Alert 11/19/2007 • Recommendations and Considerations for Healthcare Professionals/Label Change • Rosiglitazone may cause myocardial ischemia in some patients. • Co-administration of rosiglitazone and insulin is not recommended. A higher risk of myocardial ischemia was observed in controlled, double-blind clinical trials where rosiglitazone was added on to established insulin therapy. • Rosiglitazone is not recommended for patients with heart disease who are taking nitrates. A subgroup analysis of 42 clinical studies identified that patients with heart disease who are taking nitrates are at an increased risk of myocardial ischemia. Relative Contribution of FPG and PPG to Overall Hyperglycemia Depending on A1C Quintiles Postprandial glucose Fasting glucose Contribution, % 100 80 60 40 20 0 <7.3 n=58 7.3–8.4 n=58 8.5–9.2 9.3–10.2 >10.2 n=58 n=58 n=58 A1C Monnier L et al. Diabetes Care. 2003;26:881–885. Higher A1C Baseline Level Correlates With Larger A1C Reduction With Pharmacologic Intervention Baseline A1C% 6.0–6.9 7.0–7.9 8.0–8.9 9.0–9.9 10.0–11.8 Number of patients enrolled in clinical trials n=410 n=1,620 n=5,269 n=1,228 n=266 0 -0.1 -0.2 A1C Reduction, % -0.2 -0.4 -0.6 -0.6 -0.8 -1 -1.0 -1.2 Change in A1C from baseline -1.4 Adapted from Bloomgarden ZT et al. Diabetes Care. 2006;29:2137-2139. -1.2 European Assoc for the Study of Diabetes (EASD) Consensus Report 9-06 Calls for urgent action to drastically improve the management of DM, particularly urging the increased acceptance of insulin All patients with Type 2 DM, if they live long enough, will need insulin Recent survey found that the major patient barrier to achieving optimal blood sugar control was patient resistance to insulin European Assoc for the Study of Diabetes (EASD) Consensus Report 9-06 Clinical research shows that one half of patients who are not at goal on oral medications are delaying at least 4-6 years to add insulin The new non-injectable insulin could be a way to increase patient acceptance and thus lead to better outcomes Initiating Basal Insulin Therapy Continue oral agent(s) at same dosage (eventually reduce) Add single, evening insulin dose (10U) Glargine insulin (basal insulin) NPH insulin (bedtime) 70/30 insulin (evening) Adjust dose by fasting SMBG (fasting) Increase insulin dose weekly if needed Increase 2 U if FBG > 120 mg/dL Increase 4 U if FBG > 140 mg/dL Increase 6 U if FBG > 160 mg/dL Increase 8 U if FBG > 180 mg/dL Insulin Titration Schedule Initial dose calculation: (baseline FBG [mg/dL] – 50)/10 Insulin dose individually titrated using predefined titration regimen with fasting blood glucose (FBG) target 100 mg/dL (5.6 mmol/L) >100 >120 >140 >160 2 units 4 units 6 units 8 units Fritsche A et al, and the 4001 Study Group. Ann Intern Med. 2003:138:952 Mean A1C Levels During Study 9.5 Morning Glargine Bedtime Glargine Bedtime NPH A1C (%) 9.0 8.5 8.3 8.1 8.0 7.8 * 7.5 0 4 8 12 16 20 24 Time (wk) * Decrease in A1C from baseline for Morning Glargine: P<0.001 vs Bedtime NPH and P=0.008 vs Bedtime Glargine Fritsche A et al, and the 4001 Study Group. Ann Intern Med. 2003:138:952 Nocturnal and Symptomatic Hypoglycemia Nocturnal Symptomatic P=0.001 P<0.001 P=0.004 60 60 50 50 38 40 30 20 23 17 10 Patients (%) Patients (%) P<0.001 58 56 43 40 30 20 10 0 Morning Glargine Bedtime Glargine Bedtime NPH 0 Morning Glargine Bedtime Glargine Adapted from Fritsche A et al, and the 4001 Study Group. Ann Intern Med. 2003:138:952 Bedtime NPH Insulin Glulisine - Apidra A rapid acting human insulin analog with lysine for asparagine at B3 and glutamic acid for lysine at B29 from Sanofi-Aventis Appears to be similar to both insulin lispro and insulin aspart Limited data on mixing (NPH can be mixed immediately before injection and draw up glulisine first Maybe less risk of line occlusion in pumps and less variation is response with changes in BMI? Insulin Detemir - Levemir A soluble, neutral insulin in which the B29 lysine residue has been covalently bound to a 14 carbon fatty acid and it binds extensively (~98%) to albumin and has a bioavailability of ~ 60% from Novo-Nordisk (increased dosage when changing insulins?) Peak levels occur in ~ 4-6 hrs and duration is up to ~ 20 hrs (dosed once or twice a day) Should not be mixed with other insulins Maybe less glucose excursions and weight gain? The Incretin Effect in Subjects Without and With Type 2 Diabetes Control Subjects (n=8) 0.6 Incretin Effect 80 60 0.4 20 0.1 0 0 0 60 120 180 Time, min 60 0.5 0.4 0.3 40 nmol/L 0.2 nmol / L 0.3 40 0.6 The incretin effect is diminished in type 2 diabetes. 0.5 IR Insulin, mU/L 80 IR Insulin, mU/L Patients With Type 2 Diabetes (n=14) 0.2 20 0.1 0 0 0 60 120 180 Time, min Oral glucose load Intravenous (IV) glucose infusion Adapted from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag. Permission pending. 31 Role of Incretins in Glucose Homeostasis Ingestion of food Pancreas2,3 GI tract Glucose-dependent Insulin from beta cells (GLP-1 and GIP) Release of gut hormones — Incretins1,2 Active GLP-1 & GIP Glucose uptake by muscles2,4 Blood glucose Beta cells Alpha cells DPP-4 Glucose dependent enzyme Glucagon from Glucose production by liver alpha cells (GLP-1) Inactive Inactive GLP-1 GIP DPP-4 = dipeptidyl-peptidase 4 1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913. 2. Ahrén B. Curr Diab Rep. 2003;2:365–372. 3. Drucker DJ. Diabetes Care. 2003;26:2929–2940. 4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441. 32 Exanatide – Byetta (Amylin and Lilly) An incretin or glucagon-like peptide 1 (GLP-1) receptor agonist related to Gila Monster saliva that is FDA approved to be added to sulfonylureas and/or metformin Increases glucose stimulated insulin release, slows gastric emptying, inhibits glucagon secretion After sub Q injection, T ½ ~ 2.4 hrs Exenatide - Byetta Synthetic injectable GLP-1 that binds to and activates human GLP-1 receptors Increases glucose dependent insulin synthesis and secretion in beta cells Inhibits glucagon secretion from the alpha cells and thus hepatic glucose production Slows gastric motility Promotes early satiety and potential weight loss Exanatide – Byetta (Amylin and Lilly) Lowers A1c about 0.5 – 1.0% Dose related nausea up to 44%, dose related hypoglycemia up to 38% with sulfonylureas, vomiting 13%, diarrhea 13% Dose 5 mcg Sub Q BID and after 1 month can increase to 10 mcg Sub Q BID (reduce dose of sulfonylurea by about 50% upon starting therapy) Cost ~$188.00/5 mcg pre-filled 60 dose syringe, $215.00/10 mcg pre-filled 60 dose syringe (change room temp OK) Exenatide - Byetta FDA approved for patients with Type 2 DM who are not controlled on metformin and/or sulfonylurea and most recently TZDs Dosed SC BID (T1/2 ~2.4 hours) New data suggests that it can be dosed anywhere from 60 minutes prior to a meal or as soon as just before a meal Diabet Med 2006;23:240-5 Exenatide – Byetta Injection Adverse effects seen in 30 week trials Adverse Effect Placebo Exenatide Nausea 18% 44% Vomiting 4% 13% Diarrhea 6% 13% Feeling jittery 4% 9% Dizziness 6% 9% Headache 6% 9% Dyspepsia 3% 6% (Overall withdrawal rates due to adverse effects were 3% placebo and 7% exenatide) Pancreatitis has been reported post approval in about 30 patients. Patients should seek prompt medical care if they experience unexplained, persistent, severe abdominal pain which may or may not be accompanied by vomiting. If pancreatitis is suspected, d/c Byetta. (FDA MedWatch 10/16/07) Exenatide LAR Investigational Recent preliminary data presented at the ADA Annual Meeting 2006 15 week, phase 2 trial in patients with Type 2 DM with a once a week SC injection Results: (average baseline A1c 8.5%) A1c decreased by ~2% vs. placebo Fasting blood glucose decreased by ~ 50mg/dl Weight loss ~ 9 pounds vs. baseline Clinical Pharmacology of JANUVIA™ (sitagliptin phosphate): Pharmacokinetics Tmax (median): 1 to 4 hours postdose Apparent t½ (mean): 12.4 hours Absolute bioavailability: approximately 87% High-fat meal had no effect on pharmacokinetics; can be administered with or without food Metabolism: approximately 79% excreted unchanged in urine JANUVIA™ (sitagliptin phosphate) Indications and Usage Monotherapy Adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus Combination therapy (Janumet 50/500 & 50/1000 BID) To improve glycemic control in combination with metformin, a PPAR agonist (eg, thiazolidinediones) or a sulfonylurea when the single agent alone with diet and exercise does not provide adequate glycemic control Important limitations of use Sitagliptuin should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis PPAR=peroxisome proliferator-activated receptor gamma. S e c t i o n 2 Dosage and Administration Usual Dosing for sitagliptin phosphate* The recommended dose of JANUVIA is 100 mg once daily Patients With Renal Insufficiency*,† 50 mg once daily 25 mg once daily Moderate Severe and ESRD‡ CrCl 30 to <50 mL/min (~Serum Cr levels [mg/dL] Men: >1.7–≤3.0; Women: >1.5–≤2.5) CrCl <30 mL/min (~Serum Cr levels [mg/dL] Men: >3.0; Women: >2.5) Assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. *JANUVIA can be taken with or without food. †Patients with mild renal insufficiency—100 mg once daily. ‡ESRD = end-stage renal disease requiring hemodialysis or peritoneal dialysis. Contraindications/Warnings and Precautions Contraindications Hypersensitivity to sitagliptin (SJS, TEN cases) Warnings and Precautions Use in patients with renal insufficiency: A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis Use with medications known to cause hypoglycemia: (IE sulfonylureas) As monotherapy and as part of combination therapy with metformin or pioglitazone, rates of hypoglycemia were similar to placebo. New UK Guidelines for Hypertension NICE(Nat Inst for Health and Clinical Excellence)/BHS (British Hypertension Soc) Hypertension Guidelines issued 6/28/2006 omit beta blockers for routine use including first, second or third line for the treatment of patients with uncomplicated hypertension In patients 55 y/o or over or black patients of any age, the first choice for initial therapy should be either a thiazide type diuretic or CCB In patients younger than 55, the first choice for initial therapy should be an ACEI If treatment with three drugs is required, the combination of an ACEI, thiazide and CCB should be used http://www.nice.org.uk/page.aspx?o=CG34&c=cardiovascular Atenolol in HBP: Is It a Wise Choice? The authors conclude “Our results cast doubt on atenolol as a suitable drug for hypertensive patients. Moreover, they challenge the use of atenolol as a reference drug in outcome trials in hypertension.”1 A more recent editorial by ASCOT Investigator Dr Beevers states “Surely, the era of beta blockers for hypertension is over.”2 Atenolol is also not a good once-a-day agent as the T1/2 is only about 6–7 hours 1. Carlberg B, et al. Lancet. 2004;364:1684-9. 2. Beevers DG. Lancet. 2005;366:1510-2. Beta-blockers for Hypertension Cochrane Database of Systematic Reviews 2007, Issue 1, Art No.:CD002003 The available evidence does not support the use of betablockers as first-line drugs in the treatment of hypertension. 13 randomized, controlled trials in more than 91,000 patients This conclusion is based on the relatively weak effect of beta-blockers to reduce stroke and the absence of an effect on coronary heart disease when compared to placebo or no treatment. More importantly, it is based on the trend towards worse outcomes in comparison with calcium channel blockers, renin-angiotensin system inhibitors, and thiazide diuretics. Most of the evidence for these conclusions comes from trials where atenolol was the beta-blocker used (75% of beta-blocker participants in this review). However, it is not known at present whether beta-blockers have differential effects on younger and elderly patients or whether there are differences between the different sub- Nebivolol Bystolic by Forest Labs Nebivolol is the newest cardioselective beta blocker that is also vasodilating but not by way of also having alpha blocking activity A recent study from Italy (Hypertension 2007;50:652-6) demonstrates that nebivolol stimulates nitric oxide production in the heart and that this action is exerted by a signaling pathway starting from the activation of beta 3-adrenergic receptors and leading to the over-expression of inducible nitric oxide synthase. Nebivolol Bystolic INDICATIONS: Nebivolol is indicated for the treatment of hypertension. Nebivolol may be used alone or in combination with other antihypertensive agents. BP effects are similar to other beta blockers It also is under evaluation for use in the treatment of heart failure. Nebivolol Bystolic SENIORS Trial (European Heart Journal 2005, 26(3):215-25) 2128 patients aged >/=70 years with a history of heart failure (hospital admission for heart failure within the previous year or known ejection fraction </=35%) 1067 to nebivolol (titrated from 1.25 mg once daily to 10 mg once daily), and 1061 to placebo The primary outcome was a composite of all cause mortality or cardiovascular hospital admission (time to first event). Mean duration of follow-up was 21 months Mean age was 76 years (SD 4.7), 37% were female, mean ejection fraction was 36% (with 35% having ejection fraction >35%), and 68% had a prior history of coronary heart disease The mean maintenance dose of nebivolol was 7.7 mg and of placebo 8.5 mg The primary outcome occurred in 332 patients (31.1%) on nebivolol compared with 375 (35.3%) on placebo [hazard ratio (HR) 0.86, 95% CI 0.74-0.99; P=0.039]. NNT 24 Death (all causes) occurred in 169 (15.8%) on nebivolol and 192 (18.1%) on placebo (HR 0.88, 95% CI 0.71-1.08; P=0.21). NNT 44 Nebivolol Bystolic A subsequent analysis of the SENIORS trial (Am Heart J 2007;154:109-15) showed that nebivolol reduced the risk of death or cardiovascular (CV) hospitalization in elderly patients with heart failure (HF) in a dose related manner. RESULTS: After adjustment, all-cause mortality or CV hospitalization was significantly reduced in the 10 mg dose group compared with placebo (hazard ratio [HR] 0.75, 95% CI 0.63-0.90) which was similar to the medium dose group (HR 0.73, 95% CI 0.521.02). The low dose group had an apparently lower benefit (HR 0.88, 95% CI 0.64-1.20), whereas patients unable to tolerate any dose of nebivolol had an increased risk of death or CV hospitalization (HR 1.95, 95% CI 1.38-2.75). Nebivolol Bystolic It is available as 2.5, 5, and 10 mg unscored tablets. Cost ~$60.00/30 tablets Additional studies are needed to address the long-term benefits of nebivolol for hypertension, to compare nebivolol with other beta-adrenergic blockers for heart failure, and to investigate the clinical relevance of nitric oxide-mediated vasodilation ALISKIREN Tekturna ( Novartis ) Aliskiren is a direct renin inhibitor, decreasing plasma renin activity and inhibiting the conversion of angiotensinogen to angiotensin Oral bioavailability is 2.6%. The mean elimination half-life of aliskiren is 25 to 58 hours INDICATIONS: Aliskiren is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. (Use with maximal doses of angiotensin-converting enzyme (ACE) inhibitors has not been adequately studied) Aliskiren has produced blood pressure reductions comparable with angiotensin receptor blockers and ACE inhibitors. It has also shown increased blood pressure–lowering effects in combination with these agents. Whether it has any effects on outcome measures such as heart attack, stroke, or nephropathy is yet to be determined Clinical Pharmacology: Mechanism of Action (cont’d) ALISKIREN-Tekturna Pregnancy Category C for first trimester exposure and in Pregnancy Category D for second and third trimester exposure (box warning). Drugs that act directly on the renin-angiotensin system can cause fetal injury or death when used during the second or third trimesters Hyperkalemia (serum potassium more than 5.5 mEq/L) occurred infrequently with aliskiren monotherapy (0.9% compared with 0.6% with placebo). Increases in serum potassium were observed more frequently with use in combination with ACE inhibitors in diabetic patients (5.5%) Coadministration with furosemide was associated with a 30% reduction in the furosemide AUC and a 50% reduction in furosemide peak concentration. The therapeutic effects of furosemide may be reduced upon initiation of aliskiren therapy ALISKIREN - Tekturna The most common adverse reactions observed in aliskiren studies included headache, dizziness, fatigue, and diarrhea diarrhea was much higher in patients treated with aliskiren 600 mg (9.5%) than in those treated with aliskiren 150 mg (1.2%), 300 mg (2.3%), or placebo (1.2%) Significant adverse reactions occurring less frequently included angioedema, edema, rash, elevated uric acid, gout, and renal stones. Cough occurred slightly more frequently with aliskiren (1.1%) than with placebo (0.6%) 150 mg tabs $74/30 and 300 mg tabs $94/30 Advantages over ACE inhibitors and angiotensin receptor blockers have not been established. Until outcome data are available, use should be reserved for those patients failing to respond adequately to or tolerate agents from those drug classes. GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Human Papillomavirus (HPV) Nonenveloped double-stranded DNA virus1 • >100 types identified2 • 30–40 anogenital2,3 — — 15–20 oncogenic*,2,3 types, including 16, 18, 31, 33, 35, 39, 45, 51, 52, 584 HPV 16 (54%) and HPV 18 (13%) account for the majority of worldwide cervical cancers.5 Nononcogenic† types include: 6, 11, 40, 42, 43, 44, 544 HPV 6 and 11 are most often associated with external anogenital warts.3 *High risk; †Low risk 1. Howley PM. In: Fields BN, Knipe DM, Howley PM, eds. Fields Virology. 4th ed. Philadelphia, Pa: Lippincott-Raven; 2001:2197–2229. Reprinted with the permission of Lippincott-Raven. 2. Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127:930–934. 3. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis. 2002;35(suppl 2):S210–S224. 4. Muñoz N, Bosch FX, de Sanjosé S, et al. N Engl J Med. 2003;348:518–527. 5. Clifford GM, Smith JS, Aguado T, Franceschi S. Br J Cancer. 2003:89;101–105. 57 GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] US HPV Anogenital Infection Statistics • By 50 years of age, at least 80% of women will have acquired genital HPV infection.1 • Estimated new infections per year: 6.2 million1 • Estimated active infections (prevalence): 20 million2 • In sexually active individuals 15–24 years of age, ~9.2 million are currently infected.3 — An estimated 74% of new HPV infections occur in this age group.3 — In studies of women <25 years of age, prevalence rates ranged from 28% to 46%.4,5 1. Centers for Disease Control and Prevention. Rockville, Md: CDC National Prevention Information Network; 2004. 2. Cates W Jr, and the American Social Health Association Panel. Sex Transm Dis. 1999;26(suppl):S2–S7. 3. Weinstock H, Berman S, Cates W Jr. Perspect Sex Reprod Health. 2004;36:6–10. 4. Burk RD, Ho GYF, Beardsley L, Lempa M, Peters M, Bierman R. 58 J Infect Dis. 1996;174:679–689. 5. Bauer HM, Ting Y, Greer CE, et al. JAMA. 1991;265:472–477. GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Estimated Annual Burden of HPVRelated Diagnoses in the United States 9,710 new cases of cervical cancer1 3,700 deaths estimated in 20061 330,000 new cases of high-grade cervical dysplasia (CIN 2/3)2 CIN = cervical intraepithelial neoplasia. 1.4 million new cases of low-grade cervical dysplasia (CIN 1)2 1 million new cases of genital warts3 CIN = cervical intraepithelial neoplasia. 1. American Cancer Society. Cancer Facts and Figures 2006. Atlanta, Ga: American Cancer Society; 2006:4. 2. Schiffman M, Solomon D. Findings to date from the ASCUS-LSIL Triage Study (ALTS). Arch Pathol Lab Med. 2003;127:946–949. 59 3. Fleischer AB, Parrish CA, Glenn R, Feldman SR. Condylomata acuminata (genital warts):Patient demographics and treating physicians. Sex Transm Dis. 2001;28:643–647. GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] GARDASIL: The First Cervical Cancer Vaccine in the United States • Quadrivalent HPV 6/11/16/18 L1 virus-like particle (VLP) vaccine • VLPs are produced in Saccharomyces cerevisiae. — The L1 proteins self-assemble into VLPs. — Purified VLPs are adsorbed on aluminumcontaining adjuvant. — The adjuvant is amorphous aluminum hydroxyphosphate sulfate (225 μg per dose). • Each 0.5-mL dose contains HPV Types 6/11/16/18 (20/40/40/20 μg L1 protein, respectively). 60 GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Targeting a High Disease Burden With GARDASIL HPV Type 16 and 18 Approximate Disease Burden • 70% of cervical cancer, AIS, CIN 3, VIN 2/3, and VaIN 2/3 cases • 50% of CIN 2 cases and 18 18 6, 11, 16, and • 35%–50% of all CIN 1, VIN 1, and VaIN 1 cases • 90% of genital warts cases AIS = adenocarcinoma in situ. CIN = cervical intraepithelial neoplasia. VaIN = vaginal intraepithelial neoplasia. VIN = vulvar intraepithelial neoplasia. 61 GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Neutralizing Antibodies by Age at Enrollment Neutralizing anti-HPV 6 GMTs at Month 7 Serum cLIA GMT with 95% CI, mMU/mL Per-protocol immunogenicity population (ages 9–26)* Immunogenicity Bridge 1,600 1,500 1,300 Efficacy Program 1,100 900 700 500 Young Adult Females Adolescent Females 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Age at Enrollment (Years) *Inclusive of 5 study protocols; all GMTs measured using cLIA. 62 GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Select Information About GARDASIL • GARDASIL is a vaccine indicated in girls and women 9 to 26 years of age for the prevention of cervical cancer, precancerous or dysplastic lesions, and genital warts caused by HPV Types 6, 11, 16, and 18. • Individuals who were already infected with 1 or more vaccine-related HPV types prior to vaccination were protected from disease caused by the remaining vaccine HPV types. • GARDASIL is contraindicated in individuals who are hypersensitive to the active substances or to any of the excipients of the vaccine. • Vaccination with GARDASIL does not substitute for routine cervical cancer screening, and women who receive GARDASIL should continue to undergo screening per standard of care. 63 GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Vaccine-Related Adverse Experiences Injection Site (1 to 5 days Postvaccination) GARDASIL® (N=5,088) Placebo (Aluminum) Placebo (Saline) (N=3,470) (N=320) Pain 83.9% 75.4% 48.6% Swelling 25.4% 15.8% 7.3% Erythema 24.6% 18.4% 12.1% Pruritus 3.1% 2.8% 0.6% Systemic AEs (1 to 15 days Postvaccination) GARDASIL Placebo (N=5,088) (N=3,790) Fever 10.3% 8.6% Nausea 4.2% 4.1% Dizziness 2.8% 2.6% • Few subjects (0.1%) discontinued due to AEs. The vaccine-related adverse experiences that were observed among recipients of GARDASIL were at a frequency of at least 1.0% and also at a greater frequency than that observed among placebo recipients. 64 GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Overall Conclusions for GARDASIL • Highly effective in preventing cervical cancer, CIN 2/3, AIS, and other anogenital diseases including genital warts caused by HPV 6, 11, 16, and 18 in 16- to 26-year-old women naïve to the relevant HPV types • Individuals with current or past infection with 1 vaccine-related HPV types prior to vaccination were protected from disease caused by the remaining vaccine HPV types • Successful immunogenicity bridge between female adolescents and young adult women — Antibody response in 9- to 15-year-old females is higher, compared with response observed in young adult women (16–26 years old) • Duration of efficacy is demonstrated between 2 and 4 years • Favorable tolerability profile Cost $150.00/vial drugstore.com AIS = adenocarcinoma in situ. CIN = cervical intraepithelial neoplasia. 65 Herpes Zoster (Shingles) • Caused by reactivation of varicella zoster virus • Can occur years or decades after illness with chickenpox • Generally associated with normal aging and with anything that causes reduced immunocompetence • Lifetime risk of up to 30% in the United States • Estimated 500,000 to 1 million cases of zoster diagnosed annually in the U.S 66 Complications of Herpes Zoster • Postherpetic neuralgia (can persist for weeks or months after rash resolves) • Ophthalmic zoster (involvement of the ophthalmic division of the trigeminal nerve and the eye) • Dissemination with generalized skin eruptions and involvement of the central nervous system, lung, liver, and pancreas 67 Herpes Zoster Vaccine (Zostavax) • Contains live attenuated varicella virus in an amount that is approximately 14 times greater than that in regular varicella vaccine • Approved for persons 60 years and older • Administered by the subcutaneous route 68 Herpes Zoster Vaccine Trial (Shingles Prevention Study) • More than 38,500 patients included • Compared with the placebo group the vaccinated group had — 51% fewer episodes of zoster overall 64% efficacy age 60-69 yrs 41% efficacy age 70-79 yrs 18% efficacy age >/= 80 yrs — Less severe disease — 66% less postherpetic neuralgia • No significant safety issues identified Source: NEJM 2005;352(22):2271-84. 69 ACIP Recommendations* for Zoster Vaccine* • Single dose of zoster vaccine for adults 60 years of age and older whether or not they report a prior episode of shingles • Persons with a chronic medical condition may be vaccinated unless a contraindication or precaution exists for their condition * Recommendations, October 2007 70 Screening for Zoster Vaccine Eligibility • Screening for a history of varicella disease is NOT necessary or recommended to administer zoster vaccine to a person 60 years of age or older • Persons born in the U.S. before 1980 can be assumed to be immune regardless of their recollection of chickenpox • A trial is underway to evaluate the efficacy and safety in patients 50-60 yrs of age 71 Zoster Vaccine Storage and Handing • • • • Must be stored at 5o F (-15o C) or colder AT ALL TIMES Protect from light Administer within 30 minutes of reconstitution Cost $193.00 per vial drugstore.com 72 Reclast (zoledronic acid) Injection • Reclast is a bisphosphonate indicated for: · Treatment of osteoporosis in postmenopausal women Treatment of Paget’s disease of bone in men and women 73 Reclast (zoledronic acid) Injection • A randomized, double-blind, placebo -controlled, multinational study of 7736 women aged 65-89 years (mean age of 73) with either: a femoral neck BMD Tscore less than or equal to -1.5 and at least two mild or one moderate existing vertebral fracture(s); or a femoral neck BMD T-score less than or equal to -2.5 with or without evidence of an existing vertebral fracture(s). • The two primary efficacy variables were the incidence of vertebral fractures at 3 years and the incidence of hip fractures over a median duration of 3 years. 74 Reclast (zoledronic acid) Injection • utcome O Reclast Placebo ARR RRR (%) (%) At least 1 new vertebral fracture @ 0-1 yr 1.5% 3.7% 2.2% 60% At least 1 new vertebral fracture @ 0-2 yrs 2.2% 7.7% 5.1% 71% At least 1 new vertebral fracture @ 0-3 yrs 3.3% 10.9% 7.6% 70% 75 Reclast (zoledronic acid) Injection • Reclast demonstrated a 1.1% absolute reduction and 41% relative reduction in the risk of hip fractures over a median duration of follow-up of 3 years. The hip fracture event rate was 1.4% for Reclast -treated patients compared to 2.5% for placebo -treated patients. 76 Reclast (zoledronic acid) Injection • A randomized, double-blind, placebo-controlled trial, 1065 patients were assigned to receive yearly intravenous zoledronic acid (at a dose of 5 mg), and 1062 patients were assigned to receive placebo. The infusions were first administered within 90 days after surgical repair of a hip fracture. All patients (mean age, 74.5 years) received supplemental vitamin D and calcium. The median follow-up was 1.9 years. The primary end point was a new clinical fracture. — N Engl J Med 357:1799, November 1, 2007 77 Reclast (zoledronic acid) Injection • Results The rates of any new clinical fracture were 8.6% in the zoledronic acid group and 13.9% in the placebo group, a 35% risk reduction with zoledronic acid (P=0.001); the respective rates of a new clinical vertebral fracture were 1.7% and 3.8% (P=0.02), and the respective rates of new nonvertebral fractures were 7.6% and 10.7% (P=0.03). In the safety analysis, 101 of 1054 patients in the zoledronic acid group (9.6%) and 141 of 1057 patients in the placebo group (13.3%) died, a reduction of 28% in deaths from any cause in the zoledronic acid group (P=0.01). 78 Reclast (zoledronic acid) Injection • The most common adverse reactions (>10%) were pyrexia, myalgia, headache, arthralgia, and pain in extremity • Treatment of postmenopausal osteoporosis: a single 5 mg infusion once a year given intravenously over no less than 15 minutes • Cost is about $1200.00 79