Download Heart Failure:

HEALTHLINE
December 2005
FOCUS ON INSOMNIA
NEW DRUGS AND INDICATIONS
Herceptin Cuts Risk of Recurrence in Half for Women with Early-Stage Breast Cancer
Trastuzumab (Herceptin) is a targeted therapy for HER2-positive breast cancer recently shown to
reduce the risk of recurrence in patients with early-stage breast cancer by as much as 50 percent.
The HERA trial was designed to assess the drug's efficacy and safety profile in
5,081 women with surgically removed HER2-positive breast cancer who had completed at least
four cycles of neoadjuvant or adjuvant chemotherapy prior to randomization. The patients were
randomized to observation or one or two years of treatment with Herceptin. At one year of followup, 220 events (death, recurrence or new disease) occurred in the observation group compared
with 127 events in the Herceptin group. Overall survival was similar between the two groups.
The combined data from two other trials comparing adjuvant chemotherapy with or without
concurrent Herceptin treatment in women with surgically removed HER2-positive breast cancer
revealed similarly positive outcomes.
At three years, treatment with Herceptin was associated with a 33 percent reduction in the risk of
death. Additionally, women with estrogen receptor-positive and -negative tumors, benefited from
treatment with Herceptin.
Herceptin, is already approved for treating metastatic breast cancer in specific patient groups.
Romond EH et al Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. NEWM
2005;353:1673-84.
Burstein HJ. The distinctive nature of HER2-positive breast cancers. NEJM 2005;353:1652-4.
Piccart-Gebhart MJ et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. NEJM 353:1659-72.
Meta-Analysis Shows Statin Therapy Safely Reduces Risk of Heart Disease, Stroke
The use of statins was shown to reduce the five-year incidence of major coronary events,
coronary revascularization and stroke by approximately one-fifth per mmol/L (38 mg/dL) reduction
in LDL cholesterol, according to data from a meta-analysis of 14 randomized trials of statins.
The main goal of the study was to examine effects on different clinical outcomes per 1.0 mmol/L
(38 mg/dL) reduction in LDL cholesterol, including all-cause mortality, coronary heart disease
(CHD) mortality and non-CHD mortality. Other outcomes examined included effects on CHD
death, major coronary events, stroke, cancer and vascular events and procedures.
Overall, 8,186 deaths were recorded during a mean of five years, of which 3,832 were statin
patients and 4,354 were control patients. The difference between the groups represented a 12
percent proportional reduction in all-cause mortality per mmol/L (38 mg/dL) LDL cholesterol
reduction. There were 1,548 deaths due to CHD in the statin group compared with 1,960 deaths
due to CHD in the control group, representing a 19 percent proportional reduction. Reductions in
death from stroke, other vascular causes and nonvascular causes were not statistically
significant.
In addition, the data showed a 21 percent reduction in the risk of any major vascular event, with
the benefits of statin therapy reaching statistical significance within the first year and increasing in
later years. The overall risk reduction due to statin therapy translated into 48 fewer major vascular
events per 1,000 patients among those with pre-existing CHD at baseline compared with 25 per
1,000 among those without this history.
Copyright 2005
All Rights Reserved
Published by Omnicare, Inc.
distributed by PBM Plus, Inc.
Page - 1
HEALTHLINE
December 2005
WARNINGS AND ADVERSE EFFECTS
Duloxetine (Cymbalta) Should Not Be Prescribed for Patients with Liver Disease
Recent reports indicate that duloxetine (Cymbalta) may increase the risk for further liver damage
in patients with pre-existing liver conditions. The drug should not be used in patients with liver
disease or liver insufficiency because the drug may worsen existing conditions. Since its approval
in August 2004, several cases of hepatic injury have been reported, including hepatitis and
cholestatic jaundice. The manufacturer cautions against using the drug in persons with
substantial alcohol use. Clinical studies suggested that patients "with substantial alcohol use"
experienced liver damage when they consumed both alcohol and Cymbalta. Markers of liver
disease include hypoalbuminemia, prolonged prothrombin time (in the absence of warfarin
therapy), elevated liver function tests, in particular aspartate transaminase (AST).
Cymbalta was first approved to treat major depressive disorder; it is also approved to treat nerve
pain in patients with diabetes. Over 1 million patients have been prescribed Cymbalta. Health
care professionals should be aware of and discontinue Cymbalta if signs and symptoms of liver
damage occur, including pruritus, dark urine, jaundice, right upper quadrant tenderness and
unexplained flu-like symptoms. Because Cymbalta is an antidepressant that affects serotonin and
norepinephrine reuptake, the dose should be tapered down over a few days before
discontinuation and replacement therapy should be initiated. An alternate antidepressant or
analgesic should be prescribed, based on condition being treated. Please contact your Omnicare
consultant pharmacist for assistance.
Name Confusion – Toprol XL, Topamax, Tegretol or Tegretol-XR
AstraZeneca and FDA notified healthcare professionals of reports of medication dispensing or
prescribing errors between Toprol-XL (metoprolol succinate) extended release tablets, indicated
for the treatment of hypertension, long-term treatment of angina pectoris, and heart failure NYHA
Class II or III, and Topamax (topiramate), indicated for the treatment of epilepsy and migraine
prophylaxis. There have also been reports of medication errors involving confusion between
Toprol-XL and Tegretol or Tegretol-XR (carbamazepine), indicated for the treatment of complex
partial seizures, generalized tonic-clonic seizures, and trigeminal neuralgia. These reports include
instances where Toprol-XL was incorrectly administered to patients instead of Topamax,
Tegretol, or Tegretol-XR, and vice versa, some of them leading to adverse events. Extra caution
should be exercised when prescribing, dispensing, or administering drugs with similar sounding
names. Read the complete MedWatch 2005 Safety summary, including links to the Dear
Healthcare Professional and Dear Pharmacist letters, at:
http://www.fda.gov/medwatch/safety/2005/safety05.htm#Toprol
FOCUS ON INSOMNIA
About 33% of Americans report insomnia at some point during their life with higher prevalence in
females, in aging adults, and in those predisposed by underlying conditions or consumption of
alcohol and/or stimulants. Insomnia, the most common sleep problem, is defined as difficulty
falling asleep, maintaining sleep or non-restorative sleep. Sleep consists of non-rapid-eyemovement (NREM) and rapid-eye-movement (REM) phases. REM accounts for 20 – 25% of total
sleep time and lengthens with each subsequent sleep cycle/night.
NREM is further subdivided into 4 stages:
Stage 1 – transition between wakefulness and sleep, 3-8% of sleep time
Stage 2 – sleep officially begins, lasting 30 – 60 minutes, 45-55% of sleep time
Stage 3 – deep sleep (delta sleep), 3-8% of sleep time
Restorative Sleep
Stage 4 – deep sleep (delta sleep), 10-15% of sleep time
Copyright 2005
All Rights Reserved
Published by Omnicare, Inc.
distributed by PBM Plus, Inc.
Page - 2
HEALTHLINE
December 2005
Older persons are predisposed to insomnia as a result of a decrease in total sleep time,
decreased stage 3 and 4 sleep, an increase in time required to fall asleep and more nighttime
awakenings. Additionally, conditions common in the elderly are associated with quantifiable
changes in sleep quality due to neurochemical, medical and psychiatric alterations.
Table 1: Selected Causes of Sleep Disturbances in the Elderly
o the sleep-wake cycle is altered in patients with Alzheimer’s disease;
o patients with dementia manifest arousal disorders due to deficiencies in acetycholine;
o antidepressant medications, such as Zoloft, Lexapro, Paxil, that increase serotonin
circulation decrease restorative sleep;
o drugs used to treat Parkinson’s disease by increasing dopamine, increase wakefulness
and decrease restorative sleep;
o endogenous melatonin, which helps us fall asleep is known to decrease as we age;
o restless leg syndrome, which occurs in patients with chronic kidney disease, disturbs
sleep;
o medical conditions known to cause insomnia are prevalent in the elderly – pain, thyroid
disease, acid reflux, coronary artery disease, pulmonary conditions;
o many psychiatric conditions are associated with sleep disorders – schizophrenia,
depression, mania, post-traumatic stress disorder;
o therapy for hypertension, epilepsy, lipid disorders, chronic obstructive pulmonary disease,
and attention deficit hyperactivity disorder can cause insomnia;
o institutionalization and its associated noises, lights, and smells inherently disrupt sleep
comfort.
The consequences of disrupted non-restorative sleep can be staggering. Insomnia increases the
risk of mortality, poor work performance, accidents, psychological disturbances and social
problems. Older persons with insomnia are 1.6 – 2.0 times more likely to die prematurely than
those without insomnia.
Insomnia can be classified as transient (2-3 nights), short-term (< 1 month), and chronic (> 1
month). Most transient and short-term insomnias are due to factors such as inadequate sleep
fitness (discussed below), ingestion of substances known to interfere with sleep, environmental
factors (noise, strange surroundings) and physical or psychological stress. Chronic insomnia is
usually due to medical conditions or a primary sleep disorder. Persons complaining of
sleeplessness, trouble falling or staying asleep and sleepiness upon awakening should be
evaluated for a history of alcohol and drug use, caffeine intake, and underlying medical and
psychiatric conditions.
There are numerous subjective sleep scales and diaries used to help evaluate persons with sleep
disorders that ask patients to rate symptoms of insomnia such as sleep quality, sleep latency
(time to fall asleep), sleep duration, sleep disturbances, etc. Objective tests, like
polysomnography (PSG) are available in sleep centers and combine a measure of cardiac status,
with brain wave assessment, measures of eye movement, muscle tone, respiratory muscles and
limbs. The findings of PSG provide information regarding sleep-related breathing abnormalities,
periodic limb movement, total sleep time, time to sleep onset, time to restorative sleep, and
percentage of time spent in each of the sleep stages, and the number of awakenings and
arousals.
Nonpharmacological Treatment
Treatment of insomnia should start with addressing the cause and nonpharmacological therapies,
such as cognitive behavioral therapy. Good sleep hygiene involves keeping a regular sleep
Copyright 2005
All Rights Reserved
Published by Omnicare, Inc.
distributed by PBM Plus, Inc.
Page - 3
HEALTHLINE
December 2005
schedule (arising and going to bed at the same time every day). Drugs or substances that disturb
sleep (caffeine, alcohol, nicotine) should be avoided for up to 12 hours before bedtime. Patients
should be educated to avoid exercise within 3 hours of going to bed. Relaxation therapy can be
helpful as can other strategies that involve limiting time in bed to sleep time. Patients should not
eat, read, or watch television while in bed to help them associate falling asleep with going to bed.
Pharmacologic Treatment
Medications should be considered when nonpharmacological interventions fail to overcome
insomnia and when it causes decreased next day performance or leads to chronic behavioral,
mood, functional or cognitive impairments. Table 2 summarizes the effects of drugs on sleep
parameters.
Table 2. Effects of Drugs on Sleep Parameters
Drug
Nonprescription Drugs
Antihistamines
Melatonin
Valerian
Prescription Drugs
Tricyclic antidepressants
Trazodone (Desyrel)
Mirtazapine
Benzodiazepines
Zaleplon (Sonata)
Zolpidem (Ambien/CR)
Eszopiclone (Lunesta)
Ramelteon (Rozerem)
Time to Fall
Asleep
Total Sleep
Time
REM
Sleep
Sleep
Quality

 or 


 or  or 
 or 
NA



 or 















 or 
NA


 or 



NA
NA
NA






NA
A perfect sleep aid would provide patients with rapid and reliable sleep induction, maintain sleep
for 6 – 8 hours produce minimal changes in sleep architecture, leave no “hang-over” effect, and
result in no abuse, side effects or drug interactions. Unfortunately, as can be seen in Table 2,
drugs used as a sleep aid have a negative effect on total sleep time, or REM sleep and many
have abuse, drug interaction and side effect potentials. Therefore, patient-specific considerations
must be taken into account when trying to identify the best treatment.
Benzodiazepines (triazolam, temazepam, estazolam, quazepam and flurazepam) have positive
and negative effects on sleep patterns. They generally reduce the time to fall asleep, decrease
the number of nocturnal awakenings and increase total sleep time, but decrease the amount of
REM and restorative sleep. As well, benzodiazepines commonly produce adverse effects that
are problematic in older persons, such as drowsiness, fatigue, impaired cognition, ataxia, memory
impairment, respiratory depression, mood disorders and anxiety. Paradoxical excitation or
agitation can be seen in the elderly. Both short-acting and long-acting benzodiazepines have
been shown to increase the risk of falls and hip fracture and are considered Beers drugs,
requiring careful justification and gradual dose reduction attempts in accordance with federal
regulations. Tolerance develops to benzodiazepines, requiring dose escalation to achieve the
same effects. Patients who receive greater than 1 week of therapy may experience withdrawal
symptoms upon discontinuation as benzodiazepines are known to cause physical dependence.
As well, many drugs prolong the sedative side effects of benzodiazepines when they are used
Copyright 2005
All Rights Reserved
Published by Omnicare, Inc.
distributed by PBM Plus, Inc.
Page - 4
HEALTHLINE
December 2005
together. Benzodiazepines were excluded from coverage under Medicare Part D, but most state
Medicaid departments are expected to continue paying for these drugs.
Non-benzodiazepines that work at the benzodiazepine receptor include zolpidem (Ambien),
zaleplon (Sonata) and eszopiclone (Lunesta). Unlike the benzodiazepines, the nonbenzodiazepines preserve sleep architecture by not reducing REM and deep sleep. However,
they have the potential to cause many of the same CNS side effects as benzodiazepines. There
are fewer reports of tolerance, withdrawal, dependence and abuse associated with nonbenzodiazepines. There are no reports of significant next-day residual effects with Sonata dosed
within manufacturer guidelines. Ambien is associated with memory impairment for the first 1.5
hours after a 5 or 10 mg dose, but is no different from placebo at 6 hours post dose. Thus,
patients should go to bed immediately after taking a dose of Ambien and safeguard against taking
a second dose should they awaken through the night.
Eszopiclone (Lunesta) is the only non-benzodiazepine approved for long-term chronic use, up to
6 months. Several studies conducted in elderly and non-elderly subjects have shown reduced
time to fall asleep, increased sleep time and decreased awakenings without residual next-day
effects. Common side effects include unpleasant taste, headache, pain, nausea and pharyngitis.
There was no tolerance or rebound insomnia upon drug discontinuation. Eszopiclone dosing is
slightly lower in older persons; 2 mg for older persons who have difficulty staying asleep and 1
mg for older persons who have difficulty falling asleep. The half-life of the drug is longer (9 hours)
in older persons but no psychomotor impairment was reported as early as 6 hours after the dose.
Antidepressants can be helpful sleep aids in patients with depression but generally have long
half-lives resulting in next-day sedation. As well, tricyclic antidepressant medications have
anticholinergic properties and can cause orthostatic hypotension, dry mouth and eyes, urinary
retention, and constipation. In low doses, trazodone produces minimal anticholinergic properties
and can be taken at bedtime to alleviate symptoms of insomnia in those receiving SSRI
antidepressants (e.g. Zoloft, Paxil, Celexa, Lexapro).
Due to the adverse side effect profile, antihistamines, valerian root, and benzodiazepines are not
recommended to treat insomnia in the elderly. Melatonin, which decreases the time it takes to fall
asleep, can actually worsen insomnia.
For patients with transient or short-term insomnia, improved sleep hygiene may be sufficient to
correct the sleep problem. If not, short-term therapy (< 10 days) with Ambien, Sonata, or Lunesta
is preferred drug therapy. The bedtime dose should be skipped every 2 nd or 3rd night to reevaluate the need for continued therapy. Chronic drug therapy should be reserved for patients
with a chronic sleep disorder such as restless leg syndrome or REM sleep behavior disorder.
Jacobs GD et al. Cognitive behavior therapy and pharmacotherapy for insomnia: a randomized controlled trial and direct
comparison. Arch Intern Med 2004;164:1888-96.
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
All Rights Reserved
Published by Omnicare, Inc.
distributed by PBM Plus, Inc.
Page - 5