Transcript New Drug Update - South Carolina Society of Health

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)
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Consultant:
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Merck (Diabetes, CV)
Tobacco’s Toll in South Carolina
as of 12/6/2006
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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
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Tobacco users maintain a minimum serum
nicotine concentration in order to
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Prevent withdrawal symptoms
Maintain pleasure/arousal
Modulate mood
Users self-titrate nicotine intake by
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Smoking more frequently
Smoking more intensely
Obstructing vents on low-nicotine brand cigarettes
Nicotine Pharmacodynamics:
Withdrawal Effects
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Depression
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Insomnia
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Irritability/frustration/anger
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Anxiety
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Difficulty concentrating
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Restlessness
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Increased appetite/weight gain
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Decreased heart rate
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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
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Chantix, marketed by Pfizer
Partial nicotinic receptor agonist
–
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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
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Binds with high affinity and selectivity at 42
neuronal nicotinic acetylcholine receptors
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Stimulates low-level agonist activity
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Competitively inhibits binding of nicotine
Clinical effects
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 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
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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
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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
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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
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Continue oral agent(s) at same
dosage (eventually reduce)
Add single, evening insulin dose (10U)
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Glargine insulin (basal insulin)
NPH insulin (bedtime)
70/30 insulin (evening)
Adjust dose by fasting SMBG (fasting)
Increase insulin dose weekly if needed
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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
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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)
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>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
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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
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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.
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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.
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Exanatide – Byetta
(Amylin and Lilly)
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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
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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)
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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
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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)
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New data suggests that it can be dosed
anywhere from 60 minutes prior to a meal or as
soon as just before a meal
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Diabet Med 2006;23:240-5
Exenatide – Byetta Injection
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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
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Recent preliminary data presented at the
ADA Annual Meeting 2006
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15 week, phase 2 trial in patients with Type 2
DM with a once a week SC injection
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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):
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Pharmacokinetics
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Tmax (median): 1 to 4 hours postdose
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Apparent t½ (mean): 12.4 hours
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Absolute bioavailability: approximately 87%
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High-fat meal had no effect on
pharmacokinetics; can be administered with or
without food
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Metabolism: approximately 79% excreted
unchanged in urine
JANUVIA™ (sitagliptin phosphate)
Indications and Usage
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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
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Contraindications
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Hypersensitivity to sitagliptin (SJS, TEN cases)
Warnings and Precautions
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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
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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
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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
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http://www.nice.org.uk/page.aspx?o=CG34&c=cardiovascular
Atenolol in HBP: Is It a Wise
Choice?
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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
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A more recent editorial by ASCOT Investigator Dr
Beevers states
“Surely, the era of beta blockers for hypertension is
over.”2
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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.
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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
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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
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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
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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
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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.
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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 )
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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)
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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
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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