New Drug Update 2008 C. Wayne Weart, Pharm D Professor of Pharmacy and Family Medicine South...

New Drug Update New Drug Update 20082008

C. Wayne Weart, Pharm DC. Wayne Weart, Pharm D

Professor of Pharmacy and Family Professor of Pharmacy and Family MedicineMedicine

South Carolina College of PharmacySouth Carolina College of Pharmacy

MUSC campusMUSC campus

Faculty DisclosuresFaculty Disclosures

Speakers Bureau: Speakers Bureau: Pfizer (CV, DM, Pain, Smoking Pfizer (CV, DM, Pain, Smoking

Cessation)Cessation) Novartis (CV)Novartis (CV) Merck (DM, Immunizations)Merck (DM, Immunizations) Sanofi-Aventis (DM)Sanofi-Aventis (DM)

Consultant: Consultant: Merck (Diabetes, CV)Merck (Diabetes, CV)

Tobacco’s Toll in South Tobacco’s Toll in South Carolina as of 12/6/2006Carolina as of 12/6/2006

Adults in SC who smoke 22.6% (729,500)Adults in SC who smoke 22.6% (729,500) Adults who die each year in SC from their own smoking Adults who die each year in SC from their own smoking

5,9005,900 Annual health care costs in SC directly caused by smoking Annual health care costs in SC directly caused by smoking

$1.09 Billion$1.09 Billion High school students in SC who smoke 19.1% and total High school students in SC who smoke 19.1% and total

youth smoking rate of 23.5%youth smoking rate of 23.5% Kids (under 18) who become new daily smokers each year Kids (under 18) who become new daily smokers each year

6,5006,500 Kids exposed to second hand smoke at home 240,000Kids exposed to second hand smoke at home 240,000 SC cigarette tax $0.07 (lowest in the US, range is from 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 $2.575 in NJ to $0.07 in SC) National average $1.07.3 per pack (last increase in SC was 1977)pack (last increase in SC was 1977)

Packs sold in SC 2006 - 410.4 million with a SC revenue of Packs sold in SC 2006 - 410.4 million with a SC revenue of $27.7 million and a CDC estimated health care cost per $27.7 million and a CDC estimated health care cost per pack sold in SC of $7.66pack sold in SC of $7.66

Typical retail cost per pack in SC $3.35 lowest in US vs. 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)$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

Depression Insomnia Irritability/frustration/anger Anxiety Difficulty concentrating Restlessness Increased appetite/weight gain Decreased heart rate Cravings*

Nicotine Pharmacodynamics: Withdrawal Effects

American Psychiatric Association. (1994). DSM-IV. Hughes et al. (1991). Arch Gen Psychiatry 48:52–59.

Hughes & Hatsukami. (1998). Tob Control 7:92–93.

Most symptoms peak 24–48 hr after quitting and subside within 2–4

weeks.

* Not considered a withdrawal symptom by DSM-IV criteria.

Nicotine Agonist—VARENICLINE

Chantix, marketed by PfizerChantix, marketed by Pfizer Partial nicotinic receptor agonistPartial nicotinic receptor agonist

– Approved by the FDA May 2006, to hit the market Approved by the FDA May 2006, to hit the market in the fall of 2006in the fall of 2006

– Much DTC marketing anticipated in 2007Much DTC marketing anticipated in 2007

Early trials (JAMA) show better results Early trials (JAMA) show better results than bupropionthan bupropion

Lessens withdrawal symptoms and Lessens withdrawal symptoms and inhibits the “buzz” from a smokeinhibits the “buzz” from a smoke

Main side effect is nauseaMain 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 Dose

Day 1 to day 3Day 1 to day 3 0.5 mg 0.5 mg qdqd

Day 4 to day 7Day 4 to day 7 0.5 mg 0.5 mg bidbid

Day 8 to end of treatment*Day 8 to end of treatment* 1 mg bid1 mg bid

Initial dose titration

* Up to 12 weeks

FDA MedWatch FDA MedWatch 11/20/200711/20/2007

11/20/2007] FDA informed healthcare professionals of 11/20/2007] FDA informed healthcare professionals of reports of suicidal thoughts and aggressive and erratic reports of suicidal thoughts and aggressive and erratic behavior in patient who have taken Chantix, a smoking behavior in patient who have taken Chantix, a smoking cessation product. There are also reports of patients cessation product. There are also reports of patients experiencing drowsiness that affected their ability to drive experiencing drowsiness that affected their ability to drive or operate machinery. FDA is currently reviewing these or operate machinery. FDA is currently reviewing these cases, along with other recent reports. A preliminary cases, along with other recent reports. A preliminary assessment reveals that many of the cases reflect new-assessment reveals that many of the cases reflect new-onset of depressed mood, suicidal ideation, and changes in onset of depressed mood, suicidal ideation, and changes in emotion and behavior within days to weeks of initiating emotion and behavior within days to weeks of initiating Chantix treatment. The role of Chantix in these cases is not Chantix treatment. The role of Chantix in these cases is not clear because smoking cessation, with or without clear because smoking cessation, with or without treatment, is associated with nicotine withdrawal treatment, is associated with nicotine withdrawal symptoms and has also been associated with the symptoms and has also been associated with the exacerbation of underlying psychiatric illness. exacerbation of underlying psychiatric illness.

Patients taking this product should report behavior or Patients taking this product should report behavior or mood changes to their doctor and use caution when driving mood changes to their doctor and use caution when driving or operating machinery until they know how quitting or operating machinery until they know how quitting smoking with Chantix may affect them. smoking with Chantix may affect them.

2008 ADA/EASD UpdateDiabetes 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 meta-analysis 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 Relative Contribution of FPG and PPG to Overall Hyperglycemia Depending on to Overall Hyperglycemia Depending on

A1C QuintilesA1C Quintiles

n=58 n=58 n=58 n=58n=58

Monnier L et al. Diabetes Care. 2003;26:881–885.

0

20

40

60

80

100

<7.3 7.3–8.4 8.5–9.2 9.3–10.2 >10.2

Postprandial glucose Fasting glucose

A1C

Co

ntr

ibu

tio

n,

%

-0.2

-0.1

-0.6

-1.0

-1.2

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

A1

C R

ed

uc

tio

n, %

Change in A1C from baseline

Higher A1C Baseline Level Correlates With Higher A1C Baseline Level Correlates With Larger A1C Larger A1C

Reduction With Pharmacologic InterventionReduction With Pharmacologic InterventionBaseline Baseline A1C%A1C% 6.06.0––6.96.9 7.07.0––7.97.9 8.08.0––8.98.9 9.09.0––9.99.9 10.010.0––

11.811.8Number of Number of patients patients enrolled in enrolled in clinical trialsclinical trials

n=410n=410 n=1,62n=1,6200

n=5,269n=5,269 n=1,22n=1,2288

n=266n=266

Adapted from Bloomgarden ZT et al. Diabetes Care. 2006;29:2137-2139.

European Assoc for the Study European Assoc for the Study of Diabetes (EASD) Consensus of Diabetes (EASD) Consensus

Report 9-06Report 9-06 Calls for urgent action to drastically Calls for urgent action to drastically

improve the management of DM, improve the management of DM, particularly urging the increased particularly urging the increased acceptance of insulinacceptance of insulin

All patients with Type 2 DM, if they live All patients with Type 2 DM, if they live long enough, will need insulinlong enough, will need insulin

Recent survey found that the major patient Recent survey found that the major patient barrier to achieving optimal blood sugar barrier to achieving optimal blood sugar control was patient resistance to insulincontrol was patient resistance to insulin

European Assoc for the Study European Assoc for the Study of Diabetes (EASD) Consensus of Diabetes (EASD) Consensus

Report 9-06Report 9-06 Clinical research shows that one half Clinical research shows that one half

of patients who are not at goal on of patients who are not at goal on oral medications are delaying at oral medications are delaying at least 4-6 years to add insulinleast 4-6 years to add insulin

The new non-injectable insulin could The new non-injectable insulin could be a way to increase patient be a way to increase patient acceptance and thus lead to better acceptance and thus lead to better outcomesoutcomes

Initiating Basal Insulin Initiating Basal Insulin TherapyTherapy

Continue oral agent(s) at same dosage Continue oral agent(s) at same dosage (eventually reduce)(eventually reduce)

Add single, evening insulin dose (10U) Add single, evening insulin dose (10U) Glargine insulin (basal insulin)Glargine insulin (basal insulin) NPH insulin (bedtime)NPH insulin (bedtime) 70/30 insulin (evening)70/30 insulin (evening)

Adjust dose by fasting SMBG (fasting) Adjust dose by fasting SMBG (fasting) Increase insulin dose weekly if neededIncrease insulin dose weekly if needed

Increase 2 U if FBG > 120 mg/dLIncrease 2 U if FBG > 120 mg/dL Increase 4 U if FBG > 140 mg/dLIncrease 4 U if FBG > 140 mg/dL Increase 6 U if FBG > 160 mg/dLIncrease 6 U if FBG > 160 mg/dL Increase 8 U if FBG > 180 mg/dLIncrease 8 U if FBG > 180 mg/dL

Insulin Titration Insulin Titration ScheduleSchedule

Initial dose calculation: (baseline FBG Initial dose calculation: (baseline FBG [mg/dL] – 50)/10[mg/dL] – 50)/10

Insulin dose individually titrated using Insulin dose individually titrated using predefined titration regimen with predefined titration regimen with fasting blood glucose (FBG) target fasting blood glucose (FBG) target 100 mg/dL (5.6 mmol/L)100 mg/dL (5.6 mmol/L) >100>100 2 units 2 units >120>120 4 units 4 units >140>140 6 units 6 units >160>160 8 units 8 units

Fritsche A et al, and the 4001 Study Group. Ann Intern Med. 2003:138:952

Mean A1C Levels During StudyMean A1C Levels During Study

* Decrease in A1C from baseline for Morning Glargine: P<0.001 vs Bedtime NPH and P=0.008 vs Bedtime Glargine

Time (wk)0 4 8 12 16 20 24

7.5

8.0

8.5

9.0

9.5

A1C

(%

)

7.8

8.1

8.3

*

Morning Glargine

Bedtime Glargine

Bedtime NPH

Fritsche A et al, and the 4001 Study Group. Ann Intern Med. 2003:138:952

Nocturnal and Symptomatic Nocturnal and Symptomatic HypoglycemiaHypoglycemia

Nocturnal Symptomatic

P<0.001

P<0.001

1723

38

0

10

20

30

40

50

60

Pa

tie

nts

(%

)

P=0.004

P=0.001

56

43

58

0

10

20

30

40

50

60

Pa

tie

nts

(%

)

MorningGlargine

BedtimeGlargine

BedtimeNPH

MorningGlargine

BedtimeGlargine

BedtimeNPH

Adapted from Fritsche A et al, and the 4001 Study Group. Ann Intern Med. 2003:138:952

Insulin Glulisine - Insulin Glulisine - ApidraApidra

A rapid acting human insulin analog A rapid acting human insulin analog with lysine for asparagine at B3 and with lysine for asparagine at B3 and glutamic acid for lysine at B29 from glutamic acid for lysine at B29 from Sanofi-AventisSanofi-Aventis

Appears to be similar to both insulin Appears to be similar to both insulin lispro and insulin aspartlispro and insulin aspart

Limited data on mixing (NPH can be Limited data on mixing (NPH can be mixed immediately before injection mixed immediately before injection and draw up glulisine firstand draw up glulisine first

Maybe less risk of line occlusion in Maybe less risk of line occlusion in pumps and less variation is response pumps and less variation is response with changes in BMI?with changes in BMI?

Insulin Detemir - Insulin Detemir - LevemirLevemir

A soluble, neutral insulin in which the A soluble, neutral insulin in which the B29 lysine residue has been covalently B29 lysine residue has been covalently bound to a 14 carbon fatty acid and it bound to a 14 carbon fatty acid and it binds extensively (~98%) to albumin and binds extensively (~98%) to albumin and has a bioavailability of ~ 60% from Novo-has a bioavailability of ~ 60% from Novo-Nordisk (increased dosage when Nordisk (increased dosage when changing insulins?)changing insulins?)

Peak levels occur in ~ 4-6 hrs and Peak levels occur in ~ 4-6 hrs and duration is up to ~ 20 hrs (dosed once or duration is up to ~ 20 hrs (dosed once or twice a day)twice a day)

Should not be mixed with other insulinsShould not be mixed with other insulins Maybe less glucose excursions and Maybe less glucose excursions and

weight gain?weight gain?

31

Time, min

IR In

sulin

, mU

/L nm

ol/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 1200

The Incretin Effect in Subjects Without and With Type 2 Diabetes

Control Subjects (n=8)

Patients With Type 2 Diabetes (n=14)

Time, min

IR In

sulin

, mU

/L nm

ol / L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 120 0

Oral glucose load

Intravenous (IV) glucose infusion

Incretin Effect

The incretin effect is diminished

in type 2 diabetes.

Adapted from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.Permission pending.

32

Role of Incretins in Glucose Homeostasis

DPP-4 = dipeptidyl-peptidase 41. 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.

Ingestion of food

Beta cellsAlpha cells

Release of gut hormones —

Incretins1,2

Pancreas2,3

Glucose-dependent Insulin from beta cells

(GLP-1 and GIP)Glucose uptake

by muscles2,4

Glucose production

by liver

Blood glucose

Glucose dependent Glucagon from

alpha cells(GLP-1)

GI tract

ActiveGLP-1 & GIP

DPP-4 enzyme

InactiveGIP

InactiveGLP-1

Exanatide – Byetta Exanatide – Byetta (Amylin and Lilly)(Amylin and Lilly)

An incretin or glucagon-like peptide 1 An incretin or glucagon-like peptide 1 (GLP-1) receptor agonist related to (GLP-1) receptor agonist related to Gila Monster saliva that is FDA Gila Monster saliva that is FDA approved to be added to sulfonylureas approved to be added to sulfonylureas and/or metforminand/or metformin

Increases glucose stimulated insulin Increases glucose stimulated insulin release, slows gastric emptying, release, slows gastric emptying, inhibits glucagon secretioninhibits glucagon secretion

After sub Q injection, T ½ ~ 2.4 hrsAfter sub Q injection, T ½ ~ 2.4 hrs

Exenatide - ByettaExenatide - Byetta Synthetic injectable GLP-1 that binds Synthetic injectable GLP-1 that binds

to and activates human GLP-1 to and activates human GLP-1 receptorsreceptors

Increases glucose dependent insulin Increases glucose dependent insulin synthesis and secretion in beta cellssynthesis and secretion in beta cells

Inhibits glucagon secretion from the Inhibits glucagon secretion from the alpha cells and thus hepatic glucose alpha cells and thus hepatic glucose productionproduction

Slows gastric motilitySlows gastric motility Promotes early satiety and potential Promotes early satiety and potential

weight lossweight loss

Exanatide – Byetta Exanatide – Byetta (Amylin and Lilly)(Amylin and Lilly)

Lowers A1c about 0.5 – 1.0%Lowers A1c about 0.5 – 1.0% Dose related nausea up to 44%, dose Dose related nausea up to 44%, dose

related hypoglycemia up to 38% with related hypoglycemia up to 38% with sulfonylureas, vomiting 13%, diarrhea 13%sulfonylureas, vomiting 13%, diarrhea 13%

Dose 5 mcg Sub Q BID and after 1 month Dose 5 mcg Sub Q BID and after 1 month can increase to 10 mcg Sub Q BID (reduce can increase to 10 mcg Sub Q BID (reduce dose of sulfonylurea by about 50% upon dose of sulfonylurea by about 50% upon starting therapy)starting therapy)

Cost ~$188.00/5 mcg pre-filled 60 dose Cost ~$188.00/5 mcg pre-filled 60 dose syringe, $215.00/10 mcg pre-filled 60 dose syringe, $215.00/10 mcg pre-filled 60 dose syringe (change room temp OK) syringe (change room temp OK)

Exenatide - ByettaExenatide - Byetta

FDA approved for patients with FDA approved for patients with Type 2 DM who are not controlled Type 2 DM who are not controlled on metformin and/or sulfonylurea on metformin and/or sulfonylurea and most recently TZDsand most recently TZDs

Dosed SC BID (T1/2 ~2.4 hours) Dosed SC BID (T1/2 ~2.4 hours) New data suggests that it can be New data suggests that it can be

dosed anywhere from 60 minutes dosed anywhere from 60 minutes prior to a meal or as soon as just prior to a meal or as soon as just before a mealbefore a meal

Diabet Med 2006;23:240-5Diabet Med 2006;23:240-5

Exenatide – Byetta Exenatide – Byetta InjectionInjection Adverse effects seen in 30 week trialsAdverse effects seen in 30 week trials

Adverse Effect Placebo ExenatideAdverse Effect Placebo ExenatideNauseaNausea 18% 44%18% 44%VomitingVomiting 4% 4% 13% 13%DiarrheaDiarrhea 6% 6% 13% 13%Feeling jitteryFeeling jittery 4% 4% 9% 9%DizzinessDizziness 6% 6% 9% 9%HeadacheHeadache 6% 6% 9% 9%DyspepsiaDyspepsia 3% 3% 6% 6%(Overall withdrawal rates due to adverse effects (Overall withdrawal rates due to adverse effects

were 3% placebo and 7% exenatide)were 3% placebo and 7% exenatide)Pancreatitis hasPancreatitis has been reported post approval in about 30 been reported post approval in about 30

patients. Patients should seek prompt medical care if they patients. Patients should seek prompt medical care if they experience unexplained, persistent, severe abdominal pain experience unexplained, persistent, severe abdominal pain which may or may not be accompanied by vomiting. If which may or may not be accompanied by vomiting. If pancreatitis is suspected, d/c Byetta. (FDA MedWatch pancreatitis is suspected, d/c Byetta. (FDA MedWatch 10/16/07)10/16/07)

Exenatide LAR Exenatide LAR InvestigationalInvestigational

Recent preliminary data presented Recent preliminary data presented at the ADA Annual Meeting 2006at the ADA Annual Meeting 2006 15 week, phase 2 trial in patients 15 week, phase 2 trial in patients

with Type 2 DM with a once a week with Type 2 DM with a once a week SC injectionSC injection

Results: (average baseline A1c 8.5%)Results: (average baseline A1c 8.5%) A1c decreased by ~2% vs. placeboA1c decreased by ~2% vs. placebo Fasting blood glucose decreased by ~ Fasting blood glucose decreased by ~

50mg/dl50mg/dl Weight loss ~ 9 pounds vs. baselineWeight loss ~ 9 pounds vs. baseline

Clinical Pharmacology of Clinical Pharmacology of JANUVIA™ (sitagliptin JANUVIA™ (sitagliptin

phosphate):phosphate): PharmacokineticsPharmacokinetics

TTmaxmax (median): (median): 1 to 4 hours postdose 1 to 4 hours postdose

Apparent tApparent t½½ (mean): 12.4 hours (mean): 12.4 hours

Absolute bioavailability: approximately 87% Absolute bioavailability: approximately 87% High-fat meal had no effect on High-fat meal had no effect on

pharmacokinetics; can be administered pharmacokinetics; can be administered with or without foodwith or without food

Metabolism: approximately 79% excreted Metabolism: approximately 79% excreted unchanged in urineunchanged in urine

JANUVIA™ (sitagliptin JANUVIA™ (sitagliptin phosphate)phosphate)

Indications and UsageIndications and Usage MonotherapyMonotherapy Adjunct to diet and exercise to improve glycemic Adjunct to diet and exercise to improve glycemic

control in patients with type 2 diabetes mellituscontrol in patients with type 2 diabetes mellitus Combination therapy (Janumet 50/500 & 50/1000 Combination therapy (Janumet 50/500 & 50/1000

BID)BID) To improve glycemic control in combination with To improve glycemic control in combination with

metformin, a PPARmetformin, a PPAR agonist (eg, thiazolidinediones) agonist (eg, thiazolidinediones) or a sulfonylurea when the single agent alone with or a sulfonylurea when the single agent alone with diet and exercise does not provide adequate glycemic diet and exercise does not provide adequate glycemic controlcontrol

Important limitations of useImportant limitations of use Sitagliptuin should not be used in patients with type Sitagliptuin should not be used in patients with type

1 diabetes or for the treatment of diabetic 1 diabetes or for the treatment of diabetic ketoacidosisketoacidosis

PPAR=peroxisome proliferator-activated receptor gamma.

Dosage and AdministrationDosage and AdministrationUsual Dosing for sitagliptin phosphate*Usual Dosing for sitagliptin phosphate*

The recommended dose of The recommended dose of JANUVIA is JANUVIA is 100 mg once daily100 mg once daily

Patients With Renal Insufficiency*Patients With Renal Insufficiency*,†,†

50 mg once daily50 mg once daily 25 mg once daily25 mg once daily

ModerateModerate Severe and ESRDSevere and ESRD‡‡

CrCl CrCl 30 to <50 mL/min30 to <50 mL/min(~Serum Cr levels [mg/dL](~Serum Cr levels [mg/dL]Men: >1.7–≤3.0; Women: Men: >1.7–≤3.0; Women:

>1.5–≤2.5)>1.5–≤2.5)

CrCl <30 mL/minCrCl <30 mL/min(~Serum Cr levels [mg/dL](~Serum Cr levels [mg/dL]Men: >3.0; Women: >2.5) Men: >3.0; Women: >2.5)

*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.

Section

2

Assessment of renal function is recommended prior to initiationof JANUVIA and periodically thereafter.

Contraindications/Warnings Contraindications/Warnings and Precautionsand Precautions

ContraindicationsContraindications Hypersensitivity to sitagliptin (SJS, TEN cases)Hypersensitivity to sitagliptin (SJS, TEN cases)

Warnings and PrecautionsWarnings and Precautions Use in patients with renal insufficiencyUse in patients with renal insufficiency::

A dosage adjustment is A dosage adjustment is recommended in patients with moderate or recommended in patients with moderate or severe renal insufficiency and in patients with severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal ESRD requiring hemodialysis or peritoneal dialysisdialysis

Use with medications known to cause Use with medications known to cause hypoglycemiahypoglycemia:: (IE sulfonylureas) (IE sulfonylureas) As monotherapy and as part of combination As monotherapy and as part of combination therapy with metformin or pioglitazone, rates therapy with metformin or pioglitazone, rates of hypoglycemia were similar to placebo. of hypoglycemia were similar to placebo.

Sections

4and5

New UK Guidelines for New UK Guidelines for HypertensionHypertension

NICE(Nat Inst for Health and Clinical NICE(Nat Inst for Health and Clinical Excellence)/BHS (British Hypertension Soc) Excellence)/BHS (British Hypertension Soc) Hypertension Guidelines issued 6/28/2006 omit beta Hypertension Guidelines issued 6/28/2006 omit beta blockers for routine use including first, second or blockers for routine use including first, second or third line for the treatment of patients with third line for the treatment of patients with uncomplicated hypertensionuncomplicated hypertension

In patients 55 y/o or over or black patients of any In patients 55 y/o or over or black patients of any age, the first choice for initial therapy should be age, the first choice for initial therapy should be either a thiazide type diuretic or CCBeither a thiazide type diuretic or CCB

In patients younger than 55, the first choice for In patients younger than 55, the first choice for initial therapy should be an ACEIinitial therapy should be an ACEI

If treatment with three drugs is required, the If treatment with three drugs is required, the combination of an ACEI, thiazide and CCB should combination of an ACEI, thiazide and CCB should be usedbe used http://www.nice.org.uk/page.aspx?http://www.nice.org.uk/page.aspx?

o=CG34&c=cardiovascularo=CG34&c=cardiovascular

AHA Perspective/ Hypertension Management and BP Goals

AHA Scientific Statement - HTN and CAD

<130/80, but consider <120/80HF of Ischemic Etiology

ACS - STEMI

ACS - UA and NSTEMI <130/80

CAD and Stable Angina

<130/80Diabetes, chronic renal disease, CAD, CAD equivalents, Framingham Risk Score >10%

<140/90

Primary Prevention

Target BP (mm Hg)Diagnosis

adapted from Rosendorff C, et al. Circulation 2007;115:published online

AHA Perspective/ Hypertension Management and BP Goals

AHA Scientific Statement - HTN and CAD

ß-B, and ACEI/ARB andAldosterone Antagonist and

Diuretic (thiazide or loop) andHydralazine/ISDN

HF of Ischemic Etiology

ACS - UA, NSTEMI, STEMI

ß -B, and ACEI/ARB and Thiazide Diuretic

Can add DHP CCB if neededCan use non-DHP CCB instead of

CAD and Stable Angina

ACEI/ARB, or CCB, or Thiazide Diuretic, or Combination

Primary/Secondary Prevention

Drug TreatmentDiagnosis

adapted from Rosendorff C, et al. Circulation 2007;115:published online

Atenolol in HBP: Is It a Atenolol in HBP: Is It a Wise Choice?Wise Choice?

The authors concludeThe authors conclude““Our results cast doubt on atenolol as a suitable Our results cast doubt on atenolol as a suitable drug for hypertensive patients. Moreover, they drug for hypertensive patients. Moreover, they challenge the use of atenolol as a reference challenge the use of atenolol as a reference drug in outcome trials in hypertension.”drug in outcome trials in hypertension.”11

A more recent editorial by ASCOT A more recent editorial by ASCOT Investigator Dr Beevers states Investigator Dr Beevers states ““Surely, the era of beta blockers for Surely, the era of beta blockers for hypertension is over.”hypertension is over.”22

Atenolol is also not a good once-a-day Atenolol is also not a good once-a-day agent as the agent as the TT1/21/2 is only about 6–7 hours 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 Beta-blockers for HypertensionHypertension

Cochrane Database of Systematic Reviews Cochrane Database of Systematic Reviews 2007, Issue 1, Art No.:CD0020032007, Issue 1, Art No.:CD002003 The available evidence does not support the use of beta-

blockers 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-types of beta-blockers.

Nebivolol Bystolic by Nebivolol Bystolic by Forest LabsForest Labs

Nebivolol is the newest Nebivolol is the newest cardioselective beta blocker that is cardioselective beta blocker that is also vasodilating but not by way of also vasodilating but not by way of also having alpha blocking activityalso having alpha blocking activity A recent study from Italy (Hypertension A recent study from Italy (Hypertension

2007;50:652-6) demonstrates that 2007;50:652-6) demonstrates that nebivolol stimulates nitric oxide nebivolol stimulates nitric oxide production in the heart and that this production in the heart and that this action is exerted by a signaling pathway action is exerted by a signaling pathway starting from the activation of beta 3-starting from the activation of beta 3-adrenergic receptors and leading to the adrenergic receptors and leading to the over-expression of inducible nitric oxide over-expression of inducible nitric oxide synthase.synthase.

Nebivolol BystolicNebivolol Bystolic INDICATIONS: Nebivolol is INDICATIONS: Nebivolol is

indicated for the treatment of indicated for the treatment of hypertension. Nebivolol may be hypertension. Nebivolol may be used alone or in combination used alone or in combination with other antihypertensive with other antihypertensive agents. BP effects are similar agents. BP effects are similar to other beta blockersto other beta blockers

It also is under evaluation for It also is under evaluation for use in the treatment of heart use in the treatment of heart failure. failure.

Nebivolol BystolicNebivolol Bystolic SENIORS Trial (European Heart Journal 2005, 26(3):215-25)SENIORS Trial (European Heart Journal 2005, 26(3):215-25) 2128 patients aged >/=70 years with a history of heart 2128 patients aged >/=70 years with a history of heart

failure (hospital admission for heart failure within the failure (hospital admission for heart failure within the previous year or known ejection fraction </=35%)previous year or known ejection fraction </=35%)

1067 to nebivolol (titrated from 1.25 mg once daily to 10 mg 1067 to nebivolol (titrated from 1.25 mg once daily to 10 mg once daily), and 1061 to placeboonce daily), and 1061 to placebo

The primary outcome was a composite of all cause mortality The primary outcome was a composite of all cause mortality or cardiovascular hospital admission (time to first event). or cardiovascular hospital admission (time to first event).

Mean duration of follow-up was 21 monthsMean duration of follow-up was 21 months Mean age was 76 years (SD 4.7), 37% were female, mean Mean age was 76 years (SD 4.7), 37% were female, mean

ejection fraction was 36% (with 35% having ejection fraction ejection fraction was 36% (with 35% having ejection fraction >35%), and 68% had a prior history of coronary heart >35%), and 68% had a prior history of coronary heart diseasedisease

The mean maintenance dose of nebivolol was 7.7 mg and of The mean maintenance dose of nebivolol was 7.7 mg and of placebo 8.5 mgplacebo 8.5 mg

The primary outcome occurred in 332 patients (31.1%) on The primary outcome occurred in 332 patients (31.1%) on nebivolol compared with 375 (35.3%) on placebo [hazard nebivolol compared with 375 (35.3%) on placebo [hazard ratio (HR) 0.86, 95% CI 0.74-0.99; P=0.039]. NNT 24ratio (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 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; 192 (18.1%) on placebo (HR 0.88, 95% CI 0.71-1.08; P=0.21). NNT 44P=0.21). NNT 44

Nebivolol BystolicNebivolol Bystolic A subsequent analysis of the SENIORS trial A subsequent analysis of the SENIORS trial

(Am Heart J 2007;154:109-15) showed that (Am Heart J 2007;154:109-15) showed that nebivolol reduced the risk of death or nebivolol reduced the risk of death or cardiovascular (CV) hospitalization in cardiovascular (CV) hospitalization in elderly patients with heart failure (HF) in a elderly patients with heart failure (HF) in a dose related manner. dose related manner. RESULTS: After adjustment, all-cause mortality RESULTS: After adjustment, all-cause mortality

or CV hospitalization was significantly reduced or CV hospitalization was significantly reduced in the 10 mg dose group compared with placebo in the 10 mg dose group compared with placebo (hazard ratio [HR] 0.75, 95% CI 0.63-0.90) (hazard ratio [HR] 0.75, 95% CI 0.63-0.90) which was similar to the medium dose group which was similar to the medium dose group (HR 0.73, 95% CI 0.52-1.02). (HR 0.73, 95% CI 0.52-1.02).

The low dose group had an apparently lower The low dose group had an apparently lower benefit (HR 0.88, 95% CI 0.64-1.20), whereas benefit (HR 0.88, 95% CI 0.64-1.20), whereas patients unable to tolerate any dose of nebivolol patients unable to tolerate any dose of nebivolol had an increased risk of death or CV had an increased risk of death or CV hospitalization (HR 1.95, 95% CI 1.38-2.75). hospitalization (HR 1.95, 95% CI 1.38-2.75).

Nebivolol BystolicNebivolol Bystolic

It is available as 2.5, 5, and 10 mg It is available as 2.5, 5, and 10 mg unscored tablets. Cost ~$60.00/30 unscored tablets. Cost ~$60.00/30 tabletstablets

Additional studies are needed to Additional studies are needed to address the long-term benefits of address the long-term benefits of nebivolol for hypertension, to compare nebivolol for hypertension, to compare nebivolol with other beta-adrenergic nebivolol with other beta-adrenergic blockers for heart failure, and to blockers for heart failure, and to investigate the clinical relevance of investigate the clinical relevance of nitric oxide-mediated vasodilation nitric oxide-mediated vasodilation

ALISKIRENALISKIRENTekturnaTekturna ( Novartis ) ( Novartis )

Aliskiren is a direct renin inhibitor, decreasing Aliskiren is a direct renin inhibitor, decreasing plasma renin activity and inhibiting the conversion plasma renin activity and inhibiting the conversion of angiotensinogen to angiotensinof angiotensinogen to angiotensin

Oral bioavailability is 2.6%. Oral bioavailability is 2.6%. The mean elimination half-life of aliskiren is 25 to The mean elimination half-life of aliskiren is 25 to

58 hours 58 hours INDICATIONS: Aliskiren is indicated for the INDICATIONS: Aliskiren is indicated for the

treatment of hypertension. It may be used alone or treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. in combination with other antihypertensive agents. (Use with maximal doses of angiotensin-converting (Use with maximal doses of angiotensin-converting enzyme (ACE) inhibitors has not been adequately enzyme (ACE) inhibitors has not been adequately studied)studied) Aliskiren has produced blood pressure reductions Aliskiren has produced blood pressure reductions

comparable with angiotensin receptor blockers and ACE comparable with angiotensin receptor blockers and ACE inhibitors. It has also shown increased blood pressure–inhibitors. It has also shown increased blood pressure–lowering effects in combination with these agents. lowering effects in combination with these agents.

Whether it has any effects on outcome measures such as Whether it has any effects on outcome measures such as heart attack, stroke, or nephropathy is yet to be determined heart attack, stroke, or nephropathy is yet to be determined

Clinical Pharmacology:Clinical Pharmacology:Mechanism of Action (cont’d)Mechanism of Action (cont’d)

ALISKIREN-ALISKIREN-TekturnaTekturna Pregnancy Category C for first trimester exposure Pregnancy Category C for first trimester exposure

and in Pregnancy Category D for second and third and in Pregnancy Category D for second and third trimester exposure (box warning). Drugs that act trimester exposure (box warning). Drugs that act directly on the renin-angiotensin system can cause directly on the renin-angiotensin system can cause fetal injury or death when used during the second or fetal injury or death when used during the second or third trimesters third trimesters

Hyperkalemia (serum potassium more than 5.5 Hyperkalemia (serum potassium more than 5.5 mEq/L) occurred infrequently with aliskiren mEq/L) occurred infrequently with aliskiren monotherapy (0.9% compared with 0.6% with monotherapy (0.9% compared with 0.6% with placebo). Increases in serum potassium were placebo). Increases in serum potassium were observed more frequently with use in combination observed more frequently with use in combination with ACE inhibitors in diabetic patients (5.5%)with ACE inhibitors in diabetic patients (5.5%)

Coadministration with furosemide was associated Coadministration with furosemide was associated with a 30% reduction in the furosemide AUC and a with a 30% reduction in the furosemide AUC and a 50% reduction in furosemide peak concentration. 50% reduction in furosemide peak concentration. The therapeutic effects of furosemide may be The therapeutic effects of furosemide may be reduced upon initiation of aliskiren therapy reduced upon initiation of aliskiren therapy

ALISKIREN - ALISKIREN - TekturnaTekturna The most common adverse reactions observed in The most common adverse reactions observed in

aliskiren studies included headache, dizziness, aliskiren studies included headache, dizziness, fatigue, and diarrheafatigue, and diarrhea diarrhea was much higher in patients treated with aliskiren diarrhea was much higher in patients treated with aliskiren

600 mg (9.5%) than in those treated with aliskiren 150 mg 600 mg (9.5%) than in those treated with aliskiren 150 mg (1.2%), 300 mg (2.3%), or placebo (1.2%) (1.2%), 300 mg (2.3%), or placebo (1.2%)

Significant adverse reactions occurring less Significant adverse reactions occurring less frequently included angioedema, edema, rash, frequently included angioedema, edema, rash, elevated uric acid, gout, and renal stones. elevated uric acid, gout, and renal stones.

Cough occurred slightly more frequently with Cough occurred slightly more frequently with aliskiren (1.1%) than with placebo (0.6%) aliskiren (1.1%) than with placebo (0.6%)

150 mg tabs $74/30 and 300 mg tabs $94/30150 mg tabs $74/30 and 300 mg tabs $94/30 Advantages over ACE inhibitors and angiotensin Advantages over ACE inhibitors and angiotensin

receptor blockers have not been established. Until receptor blockers have not been established. Until outcome data are available, use should be reserved outcome data are available, use should be reserved for those patients failing to respond adequately to for those patients failing to respond adequately to or tolerate agents from those drug classes. or tolerate agents from those drug classes.

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GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

Human Papillomavirus (HPV)

• >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

Nonenveloped double-stranded DNA virus1

*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.

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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. J Infect Dis. 1996;174:679–689. 5. Bauer HM, Ting Y, Greer CE, et al. JAMA. 1991;265:472–477.

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Estimated Annual Burden of HPV-Related Diagnoses in the United States

1 million new cases of genital warts3

1.4 million new cases of low-grade cervical dysplasia (CIN 1)2

330,000 new cases of high-grade cervical dysplasia (CIN 2/3)2

9,710 new cases of cervical cancer1

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. 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.


3,700 deaths estimated

in 20061

CIN = cervical intraepithelial neoplasia.

CIN = cervical intraepithelial neoplasia.

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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 aluminum-containing 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).

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• 35%35%––50% of all CIN 1, VIN 1, and VaIN 1 50% of all CIN 1, VIN 1, and VaIN 1 casescases 6, 11, 16, and 186, 11, 16, and 18

• 70% of cervical cancer, AIS, CIN 3, VIN 70% of cervical cancer, AIS, CIN 3, VIN 2/3, and VaIN 2/3 cases2/3, and VaIN 2/3 cases

• 50% of CIN 2 cases50% of CIN 2 cases

16 and 1816 and 18

Approximate Disease BurdenApproximate Disease BurdenHPV TypeHPV Type

Targeting a High Disease Burden With GARDASIL

• 90% of genital warts cases90% of genital warts cases

6, 11, 16, and 186, 11, 16, and 18

AIS = adenocarcinoma in situ.CIN = cervical intraepithelial neoplasia.VaIN = vaginal intraepithelial neoplasia.VIN = vulvar intraepithelial neoplasia.

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9 10 11 12 13 14 15 16 17 18 19 20 21 22 23Age at Enrollment (Years)

500

700

900

1,100

1,300

1,5001,600

Ser

um c

LIA

GM

T w

ith 9

5% C

I, m

MU

/mL

Efficacy ProgramImmunogenicity Bridge

Adolescent Females Young Adult Females

Per-protocol immunogenicity population (ages 9–26)*

Neutralizing Antibodies by Age at EnrollmentNeutralizing anti-HPV 6 GMTs at Month 7

*Inclusive of 5 study protocols; all GMTs measured using cLIA.

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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.


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Injection Site (1 to 5 days Postvaccination)Injection Site (1 to 5 days Postvaccination)

GARDASILGARDASIL®® (N=5,088)(N=5,088)

Placebo (Aluminum)Placebo (Aluminum)

(N=3,470)(N=3,470)

Placebo (Saline)Placebo (Saline)

(N=320)(N=320)

PainPain 83.9%83.9% 75.4%75.4% 48.6%48.6%

SwellingSwelling 25.4%25.4% 15.8%15.8% 7.3%7.3%

ErythemaErythema 24.6%24.6% 18.4%18.4% 12.1%12.1%

PruritusPruritus 3.1%3.1% 2.8%2.8% 0.6%0.6%

Systemic AEs (1 to 15 days Postvaccination)Systemic AEs (1 to 15 days Postvaccination)

GARDASILGARDASIL

(N=5,088)(N=5,088)

Placebo Placebo

(N=3,790)(N=3,790)

Fever Fever 10.3%10.3% 8.6%8.6%

NauseaNausea 4.2%4.2% 4.1%4.1%

DizzinessDizziness 2.8%2.8% 2.6%2.6%


Vaccine-Related Adverse Experiences

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.

• Few subjects (0.1%) discontinued due to AEs.

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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.

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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

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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

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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

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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 identifiedSource: NEJM 2005;352(22):2271-84.

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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

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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

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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

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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

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• 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 T-score 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.

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•

Outcome 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%

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• 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.

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• 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

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• 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).

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• 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

New Drug Update 2008 C. Wayne Weart, Pharm D Professor of Pharmacy and Family Medicine South...

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