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HEALTHLINE
April 2005
NEW DRUGS/FORMULARY INFO
Eszopiclone (Lunesta)
Eszopiclone has been approved for the treatment of insomnia in individuals who experience
difficulty falling asleep. The approval is based on data from a pivotal 6-month, double-blind,
placebo-controlled safety and efficacy study in 788 subjects. Eszopiclone has not been limited to
short-term use by the Food and Drug Administration. The recommended dosing to improve sleep
onset and/or maintenance is 2 to 3 mg in 18 – 64 year old persons and 2 mg for persons older
than 64 years. A dose of 1 mg may be adequate for older adults whose primary compliant is
difficulty falling asleep. OBRA requirements for hypnotics including administration, monitoring and
documentation should continue until otherwise clarified.
DRUG INDICATIONS / WARNINGS
Hydromorphone (Palladone)
Palladone is an extended-release formulation of hydromorphone that comes in 12, 16, 24, and 32
mg capsules. This drug should only be used in patients who are already receiving opioid therapy
and who require a total daily dose of at least 12 mg of oral hydromorphone or its equivalent. It
should never be prescribed in opioid-naïve persons. Patients considered opioid tolerant are those
who are taking at least 60 mg oral morphine/day, or at least 30 mg of oral oxycodone/day, or at
least 8 mg oral hydromorphone/day, or an equianalgesic dose of another opioid, for a week or
longer. Palladone capsules should be administered once every 24 hours.
The active ingredient in Palladone, hydromorphone, is currently a Scheduled II controlled
substance, which is the highest level of control for drugs with a recognized medical use. Based
on the risks associated with the drug, including the potential for abuse of Palladone, the FDA has
worked with the sponsor to develop a comprehensive risk management program. Use of
Palladone in non-opioid-tolerant patients may lead to FATAL RESPIRATORY DEPRESSION.
Overestimating the Palladone dose when converting patients from another opioid medication can
result in fatal overdose with the first dose. Due to the mean apparent 18-hour elimination half-life
of Palladone, patients who receive an overdose will require an extended period of monitoring and
treatment that may go beyond 18 hours. Even in the face of improvement, continued medical
monitoring is required because of the possibility of extended effects.
Palladone capsules must be swallowed whole and are not to be broken, chewed, opened,
dissolved or crushed. Taking broken, chewed, dissolved, or crushed Palladone capsules or
consuming it with alcohol can lead to the rapid release and absorption of a potentially fatal dose
of hydromorphone. Palladone may be taken without regard to food. Please see the package
insert for dosage conversion factors. The package insert and Medication Guide are available at:
http://www.fda.gov/cder/drug/infopage/palladone/default.htm
Hormone Replacement Therapy Associated with Increased Risk of Stroke
The use of estrogen and combined estrogen/progesterone (hormone replacement therapy [HRT])
appears to be associated with an increased risk of stroke, particularly ischemic stroke, according
to results from a recent meta-analysis. Patients receiving HRT were 29 percent more likely to
experience a stroke, particularly an ischemic stroke.
Additionally, among patients who did experience a stroke, researchers observed less favorable
outcomes among those receiving HRT; HRT patients were 56 percent more likely to have a
stroke resulting in death or disability. HRT use was not associated, however, with an increased
risk of hemorrhagic stroke or transient ischemic attack.
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HEALTHLINE
April 2005
"We have found that the use of HRT is associated with an increased risk of stroke, typically
ischemic in type and severe in nature. HRT cannot be recommended for the primary or
secondary prevention of stroke," the authors concluded.
Bath PM. Gray LJ. Association between hormone replacement therapy and subsequent stroke: a meta-analysis. BMJ
2005; 330(7487):342.
PATIENT CARE
Stroke
Stroke is a major manifestation of cerebrovascular disease, and refers to the sudden onset of a
focal neurologic deficit. When a stroke occurs, the neurologic manifestations produced are the
result of the location of the insult in the brain and the extent of ischemia, infarct, or hemorrhage.
Just as myocardial infarction has been termed ‘heart attack’, stroke has been termed ‘brain
attack.’ Stroke can produce reversible and irreversible impairments ranging from sensory deficits
to partial paralysis and weakness. However, certain symptoms are found frequently (Table 1).
Table 1: Signs and Symptoms of Stroke





Numbness or weakness of face, arm, or leg,
often on one side of the body
Confusion or trouble speaking or understanding speech
Trouble seeing in one or both eyes
Trouble walking, dizziness, loss of balance or coordination
Sudden severe headache with no known cause
The majority of strokes are caused by ischemia and infarction secondary to disease of the large,
small, and medium-sized arteries supplying the brain. Atherosclerosis is an ongoing process
affecting mainly large and medium-sized arteries, which can begin in childhood and progress
throughout a person’s lifetime. Unstable atherosclerotic plaques may rupture, leading to the
formation of a platelet-rich blood clot. The clot partially or completely blocks the artery and causes
acute ischemic symptoms as outlined in Table 1.
Transient Ischemic Attacks (TIAs) are episodes of temporary focal cerebral dysfunction of
vascular origin in which the onset is rapid, is of variable duration, and lasts from a few seconds up
to 24 hours. Between attacks, there may be no neurologic abnormality. TIAs have great
significance in that they herald an impending stroke.
It has been estimated that approximately 700,000 new or recurrent strokes occur each year in the
United States, and that 163,538 deaths occurred from stroke in 2001. Nearly one in every 15
deaths in the United States is attributable to stroke making it the third leading cause of death in
the US. Stroke has a 10-year cumulative death risk of 79%. However, there are approximately
4,800,000 stroke survivors alive today, and many are residing in nursing facilities with residual
impairment. These survivors often experience decreased quality of life following the event and
long-term disability.
The annual cost of stroke in the U.S. is estimated to be $53.6 billion. Hospital and nursing home
costs account for the bulk of the cost, totaling $26.5 billion. Prevalence of stroke increases with
age. Stroke is more prevalent in older men than women.
Table 2 outlines risk factors for stroke grouped into modifiable, non-modifiable, and treatable
factors.
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HEALTHLINE
April 2005
Table 2: Risk Factors for Stroke
Unmodifiable
Prior TIA/Stroke
Nonwhite Race
Family History
Male Sex
Increasing Age
Modifiable
Smoking
Obesity/Diet
Physical Inactivity
Alcohol consumption
Treatable
Heart Disease
Hyperlipidemia
Hypertension
Diabetes
Atrial Fibrillation
Prevention and Treatment of Stroke
Oral Antithrombotic Therapies
Several antithrombotic therapies have been studied and are used in clinical practice for the
prevention of stroke. These include warfarin, aspirin alone, aspirin in combination with extendedrelease dipyridamole (Aggrenox), clopidogrel (Plavix), and ticlopidine (Ticlid). Within this class are
the antiplatelets and the anticoagulants.
Antiplatelet Therapies
The proposed mechanism of action of the antiplatelet drugs is an alteration in blood platelet
aggregation, thus inhibiting the formation of clots in arterial vessels. These agents include
aspirin, clopidogrel (Plavix), extended-release dipyridamole-aspirin combination (Aggrenox), and
ticlopidine (Ticlid). Ticlopidine is associated with serious hematologic toxicity and is no longer
used.
The latest guidelines for stroke prevention state that, for patients with noncardioembolic (i.e.,
atherothrombotic, lacunar or cryptogenic) ischemic stoke or TIA, who have no contraindication to
an antiplatelet agent, aspirin 81-325 mg/day, aspirin 25 mg plus extended release dipyridamole
(Aggrenox) 200 mg twice daily or clopidogrel (Plavix) 75 mg daily are all acceptable options for
initial therapy. Aggrenox is more effective than aspirin alone for the prevention of stroke, and may
be more effective than Plavix, with a similar favorable adverse-effect profile. Plavix is
recommended for patients allergic to aspirin.
Table 3: Indications for Antiplatelet Agents
Aspirin
Ischemic Stroke
Transient Ischemic
Attack
Unstable Angina/ non
Q-wave MI
Myocardial Infarction
Peripheral Arterial
Disease
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Yes
Yes
Dipyridamole/Aspirin
Aggrenox
Yes
Yes
Clopidogrel
Plavix
Yes
No
Yes
No
Yes
Yes
No
No
No
Yes
Yes
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HEALTHLINE
April 2005
Anticoagulant Therapy
Warfarin is the drug of choice for patients at risk for a cardioembolic stroke, such as those with
atrial fibrillation (AF). Optimal anticoagulation with warfarin requires administration of the dose
that produces an international normalized ratio (INR) of 2 to 3. Anticoagulation above this range
of INR values dramatically increases the risk of serious bleeding. INRs below this therapeutic
range do not offer adequate protection against thromboembolic events. Long-term warfarin (INR
2-3) is recommended for patients with AF who are at high risk for stroke. These risk factors
include age >75 years, history of hypertension, previous stroke or TIA or systemic embolism,
prosthetic heart valve, rheumatic mitral valve disease or poor left ventricular systolic function.
Additional Treatment Strategies to Prevent Stroke:
In addition to the antithrombotic agents, identifying and treating risk factors for stroke is also
important. Risk factors such as obesity, tobacco use and lack of physical activity can be modified
by smoking cessation, improving the diet and increasing physical activity. Treatable risk factors
such as heart disease, diabetes, hyperlipidemia, and hypertension can be controlled with
appropriate drug therapy.
Stroke is devastating even with recovery. Prevention is always preferable to rehabilitation. Many
stroke risk factors overlap with those for MI, renal disease, or peripheral vascular disease.
Correction of modifiable stroke risk factors may help reduce morbidity and mortality of other
disease states. Benefit is derived from consistent management of risk factors. The longer these
risk factors stay controlled, the fewer cerebrovascular events will result. Elderly patients, even the
frail elderly can realize quality of life benefits from aggressive management of risk factors.
References
Albers, G.W., Ameranco, P. Easton, J.D., Sacco, R.L., Teal, P. Antithrombotics and thrombotic
therapy for ischemic stroke. Chest 126: 483-512S; 2004.
Bradberry C.J., Fagan S.C. Stroke. In: Dipiro J.T., Tabert R.L., Yee G.C., Matzke G.R., eds.
Pharmacotherapy, A Pathophysiologic Approach. McGraw-Hill Medical Publishing Division,
2002:375-394.
Geriatric Pharmaceutical Care Guidelines, The Omnicare Formulary. 2005:545-571.
Editorial Board
Karen Burton, R. Ph., GCP, FASCP
Mark Coggins, Pharm. D., GCP, FASCP
Kelly Hollenack, Pharm. D. CGP
Philip King, Pharm. D., GCP, FASCP
Susan Kleim, B.S., Pharm., GCP, FASCP
Terry O’Shea, Pharm. D., GCP, FASCP
Elmer Schmidt, Pharm. D., GCP, FASCP
Barbara J. Zarowitz, Pharm. D., GCP, FASCP
Copyright 2005
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Published by Omnicare, Inc.
distributed by PBM Plus, Inc.
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