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Parkinsn Current Topics
Adverse
Reactions to Sinemet CR in the Elderly : Joseph et al.
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Posts of this kind, are not always
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This study is posted here for
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Adverse Reactions to Controlled
Release Levodopa/Carbidopa in Older Persons: Case Reports
Carol L. Joseph MD,*^ Jolene Siple,*j
Karen McWhorter, MN, CS,* and Richard Camicioli, MD*^
From the *Veterans Affairs Medical
Center, Portland Oregon; and ^Oregon Health Sciences University,
Portland, Oregon.
Address correspondence and reprint
requests to Carol L. Joseph, MD, VA Medical Center, Section of
Gerontology (111-NHCU-V), PO Box 1035, Portland, OR 97207.
J Am Geriatr Soc 1995;43( No.
1):47-50.
Levodopa/carbidopa (Sinemet)
combinations have been a mainstay in the treatment of Parkinson's
disease (PD) since their approval for general use in 1975. One
disadvantage of these combinations is the need for frequent
dosing to provide constant dopaminergic stimulation and minimize
motor fluctuations. In 1991 a controlled release form of
levodopa/carbidopa (Sinemet CR (Merck & Co., Rahway, NJ) 50
mg carbidopa/200 mg levodopa) was introduced, which offers
sustained peak plasma levodopa levels and less fluctuation in
plasma concentrations.[1] Potential benefits of this formulation
include less frequent dosing, diminished peak-dose dyskinesias,
and fewer episodes of wearing-off and other end-of-dose
phenomena. (Table 1)[2-4] The potential disadvantages include
mental status changes and worsening of certain dyskinesias. We
report experience with four frail, elderly patients who exhibited
hallucinations, confusion, and worsening dyskinesias after
changing from standard Sinemet to Sinemet CR.
METHODS
The patients in this series were all
inpatients on the Geriatric Evaluation and Management Service
(GEMS) of the Portland Veterans Affairs Medical Center.
Subsequent clinical observations were made either by the GEMS
unit (Patient 4) or Adult Day Health Care (ADHC) staff (Patients
1-3). In both programs, assessments and interventions are made by
interdisciplinary health care teams that include a geriatrician,
adult nurse practitioner, clinical nurse specialist and
consultant pharmacist. The teams routinely evaluate all patients
enrolled in the GEMS or ADHC: for treatable causes of mental
status decline such as metabolic abnormalities or infection In
addition, the staff of ADHC maintain close contact with patient's
family members and significant others for reports of mental or
functional decline. The severity of PD was assessed using the
Hoehn and Yahr score, a clinical measure of the severity of PD
with 1 being the least severe and 5 being the most severe.[5]
Since the bioavailability of both standard Sinemet and Sinemet CR
is affected by food, ADHC patients were instructed to keep the
relationship between their medications and meals consistent.
CASE REPORTS
Patient 1.
AA was an 82-year-old retired
Lieutenant Colonel who lived at home with his wife, PD was
diagnosed in 1987 and dementia 3 years later. He was admitted to
the GEMS for evaluation of cognitive and functional decline. At
that time his thyroid, hepatic, and renal functions were normal.
MiniMental State Examination (MMSE) score was 18. Although AA was
independent in ambulation, he exhibited on-off phenomena,
freezing, festinating gait, and postural instability, including
falls.[6] His antiparkinsonian pharmacotherapy included standard
Sinemet 25/100 1.5 tablets 5 times daily (750 mg levodopa/day)
and selegiline 5 mg/day in divided doses. No other psychotropic
or anticholinergic drugs were given during the observation
period. During hospitalization, standard Sinemet was replaced
with Sinemet CR 50/200 3 times daily, while selegiline was
continued at the same dose. After the change to Sinemet CR, AA's
gait improved, festination and on-off symptoms decreased, and no
changes in mentation were noted. At discharge, the Sinemet CR
dose was one tablet bid and 1.5 tablets at noon (700 mg
levodopa/day, a decrease of 7% in the total daily dose). One
month after discharge AA's wife reported that the patient was
having visual hallucinations in the evening hours. On several
occasions he described seeing a herd of wild horses in his
back-yard; at other times he became agitated and wandered about
as he tried to organize a troop of soldiers. With a decrease of
the evening Sinemet CR dose to one-half tablet (600 mg
levodopa/day) the hallucinations and agitation resolved. AA
continued to experience a moderate amount of gait difficulty, but
remained independent in ambulation with a walker.
Patient 2.
BB was an 81-year-old- retired
history teacher and school principal who lived at home with his
wife. He had a 5-year history of PD with normal MMSE score (29)
at the time of disease onset. BB was hospitalized on the GEMS
unit for evaluation of frequent falls, at which time he had
impaired cognition (MMSE score 24). Thyroid and hepatic function
were normal, the serum creatinine was elevated at 3.0 mg/dL,
which was consistent with previous values. Just before
hospitalization his standard Sinemet dose was one tablet of
25/250 3 times a day, with an additional one tablet of 10/100 at
bedtime (850 mg levodopa/day). BB was not taking any other
psychotropic or anticholinergic medications. During BB's
hospitalization, Sinemet CR was instituted at 1.5 tablets tid (900 mg levodopa/day) with a
resultant decrease in the frequency of falls. However, both
nursing staff and the patient's wife reported that BB was
confused during the nighttime. Subsequently, BB was discharged on
Sinemet CR 1.5 tabs tid with standard Sinemet 10/100 as an early
morning start-up dose (1000 mg levodopa/day, an 18% increase in
total daily dose) which further improved his gait. After hospital
discharge the patient experienced visual hallucinations in the
evenings. Replacing Sinemet (CR with standard Sinemet at BB's
prehospital dose resulted in cessation of the visual
hallucinations. BB's MMSE score also increased to 27 following
this change, and he continued to be ambulatory with a walker.
----------------------------------------------------------
Table 1. Sinemet CR Compared with
Standard Sinemet
Potential Advantages Potential
Disadvantages
-----------------------------------------------------------
Dosing frequency decreased Delayed
onset of action, lack of "kick in" is associated
Duration of action increased with regular release
Interdose interval increased
Fluctuations less predicable
Improved compliance Increased
dyskinesias,especially biphasic dyskinesia
Decreased dyskinesias Increased
hallucinations
More physiologic dopamine Increased
sleep disturbances replacement Daily "off' periods decreased
Increased "on" time Improved bed mobility and sleep
Improved early morning performance
-----------------------------------------------------------
Adapted from references 8,28,29.
___________________________________________________________
Patient 3.
CC was an 80-year-old retired
engineering clerk living at home with his wife. He had a 24-year
history of PD and documented dementia for 10 years. Prior to CC's
GEMS admission, he had been treated with stereotactic left
thalamatomy and several pharmacologic regimens, including
standard Sinemet, ethopropazine and bromocriptine. When CC was
hospitalized on the GEMS to evaluate weight loss and flank pain,
he could not stand without assistance. Other problems included a
history of depression and orthostatic hypotension. On admission
thyroid, hepatic, and renal function were normal. His standard
Sinemet dosage was 10/100, two tablets alternating with one
tablet, for a total of six tablets daily (600 mg levodopa/day)
and bromocriptine 10 mg tid. During the GEMS admission, standard
Sinemet was replaced with Sinemet CR one tablet tid (600 mg
lesodopa/ day). This dosage was increased over a period of 5 days
to 1.5 tablets in the morning and noon and one tablet in the
evening (800 mg levodopa/day, a 33% increase in total daily
dose). The bromocriptine dose was reduced to 5 mg tid. The
patient's rigidity decreased and his functional status improved.
Methylphenidate 10 mg bid was initiated for depression. No other
psychotropic or anticholinergic medications were administered
during the observation period. After discharge from inpatient
care, CC experienced choreoathetoid movements and hallucinations
in the evening. These problems were evaluated in the movement
disorder clinic and bromocriptine and methylphenidate were
discontinued. No further hallucinations were reported, and CC's
severe choreoathetoid movements decreased, although some
dyskinesias persisted. He continued to be ambulatory with a
walker and standby assistance.
Patient 4.
DD was an 84-year-old retired
carpenter who lived at home with his wife. He had had PD for 14
years, manifested by resting tremor, rigidity, and autonomic
dysfunction. DD also had a history of dementia (MMSE score 17)
and cerebrovascular event with right hemiparesis. The patient had
been treated with standard Sinemet for 11 years (since 1979). The
most recent Sinemet dose was 25/100, 1.5 tablets tid and total of
six tablets daily (400 mg levodopa/day).
The patient was not taking any other
psychotropic or anticholinergic medications. Motor fluctuations,
tongue/jaw, dyskinesias, and wearing-off prompted replacing DD's
standard Sinemet with Sinemet CR, three tablets/day (600 mg
levodopa/day). After this change, DD was more confused. Because
of continued motor slowing, DD's Sinemet CR dose was increased to
four tablets/day (800 mg levodopa/day, a 33% increase in total
daily dose). DD then began to experience visual hallucinations,
which resolved after decreasing Sinemet CR to three tablets per
day, although his confusion continued. DD was subsequently
admitted to the GEMS for rehabilitation following surgery for
prostate cancer. During this hospitalization, DD had nighttime
visual hallucinations associated with confusion and agitation.
Thyroid, hepatic, and renal function were normal. Sinemet CR was
decreased to one-half tablet twice a day (200 mg levodopa/day, a
decrease over his original Sinemet dose); however, the
hallucinations persisted. Sinemet CR was then replaced with
standard Sinemet 10/100, three tablets/day, which was further
reduced to two tablets/day (200 mg levodopa/day) resulting in a
decrease in nighttime agitation. DD continued to have resting
tremor and minimal rigidity, but was ambulatory, with a walker
and standby assistance.
DISCUSSION
Information about tbe patients is
summarized in Table 2. All four patients were elderly(aged 80
years or older), male, veterans, with some degree of cognitive
impairment. All of the patients in this series edespite a 50% reduction in his
original dose of standard Sinemet, suggesting that other factors
probably contributed to his confusion. Each of the four patients
in this series was evaluated for infections, metabolic
abnormalities, cerebrovascular events, and effects from other
pharmacologic agents without finding alternative explanations for
their visual hallucinations and dyskinesias. However, underlying
medical problems may have contributed to these symptoms.
experienced mental
status changes or increased dyskinesias after changing to the
controlled release form of Sinemet. Patients 1 and 2 had
resolution of these symptoms after decreasing or discontinuing
Sinemet CR. Patient 3, who continued on Sinemet CR, was observed
by family and staff to experience persistent dyskinesias, despite
adjustment of his other antiparkinsonian medication. Patient 4
experienced some improvement in mental status after Sinemet CR
was discontinued, yet remained confused
Differences in the dose and
bioavailability of levodopa in the two formulations may have
resulted in the symptoms experienced by our patients. The overall
bioavailability of levodopa from Sinemet CR is approximately 70%,
compared with nearly 100% with standard Sinemet.[1]
Theoretically, a 30% increase in total daily levodopa dose would
be necessary to obtain the same clinical effect from Sinemet CR
as standard Sinemet.[1,7,8] However in three of our four
patients, institution of Sinemet CR therapy at levels providing
18 to 33% increases in total daily levodopa doses relative to
standard Sinemet appeared to be accompanied by adverse reactions.
This finding may reflect the complexity of levodopa's
bioavailability, which is influenced by many factors, such as
dosing in relation to meals, the protein content of meals, other
medications, and gastric motility.[9]
Use of Sinemet CR may lead to
accumulation of levodopa in the circulation, even without dosage
increases.[8] Compared with standard Sinemet, the controlled
release preparation produces a narrower range of plasma levodopa
fluctuation with reduced peak levels and elevated trough
concentrations.[1] Successive doses of Sinemet CR may lead to
rising levodopa plasma concentrations, reflecting its longer
duration of effect and progressive elevation of interdose peak
and trough plasma levels.[10,11] Thus, peak plasma levels wonld
be expected after the last dose of a regimen. This mechanism may
have contributed to the occurrence of dyskinesias or mental
status changes seen in our patients in the evening hours.
Although Sinemet CR has not been reported to cause significantly
more mental status changes than standard Sinemet, hallucinations
and confusion have been listed as reasons for patient dropout in
clinical trials.[3,12-17]
It is possible that accumulation of
levodopa in the plasma from the controlled-release preparation
contributed to the increase in dyskinesias experienced by one of
our patients (Patient 3). Cedarbaum et al.[18] found that after
1.5 to 5 years, almost half of patients discontinued Sinemet CR
therapy because of progressive increases in dyskinesias. In one
clinical trial, patients with moderate to advanced PD who
tolerated a single dose of Sinemet CR without adverse effects
experienced a cumulative dyskinetic response after successive
doses.[16]
Patient characteristics combined with
pharmacologic properties may result in increased vulnerability to
the side effects of Sinemet CR. Factors previously identified
with an increased risk of hallucinations and confusion in
association with standard Sinemet therapy include older age,
preexisting dementia and more severe PD.[19-23] Pharmacologic
factors may include higher doses of levodopa with longer duration
of treatment and dosage regimens including mixed
anticholinergic-dopaminergic agents.[20-23] All of our patients
were more than 80 years old, had preexisting dementia, and had
taken standard Sinemet for more than 5 years. Other pharmacologic
agents or antiparkinsonian medications (selegiline, Patient 1;
bromocriptine and methylphenidate, Patient 3) may have played a
part in these observations. The effects of underlying medical
illness may explain why Patient 4 experienced visual
hallucinations during hospitalization, despite a dosage of
Sinemet CR he had tolerated previously.
Replacing standard Sinemet with
Sinemet CR may be desirable for many elderly patieiits with PD,
but employing strategies to minimize the occurrence of adverse
reactions during the transition is advisable. Although some
anthors suggest increasing total daily levodopa dosage when
changing from standard Sinemet to Sinemet CR, this approach may
be inappropriate for frail elderly patients. Instead, Sinemet CR
may he initiated at the same dose as standard Sinemet and
increased slowly over intervals of 3 to 5 days.[4] Alternatively,
one may wish to replace only the first morning dose of standard
Sinemet with Sinemet CR, observe the duration of its effect, and
gradually alter subsequent doses to achieve optimal response.[24]
Lowering the late afternoon or evening dose of Sinemet CR or
substituting standard Sinemet for these doses may diminish
cumulative effects.[11,16] Sinemet CR should not he taken more
frequently than every 4 hoors to prevent effects of levodopa
plasma concentration buildup.[25]
Patient education is important in
ensuring a smooth transition between standard Sinemet and Sinemet
CR. Patients and caregivers should be instructed not to
"double up" on their next dose of Sinetnet CR if the
previous dose was inadvertently missed.[4] Patients need to know
that the effects of Sinemet CR may be increased by administration
with food, while those of standard Sinemet may be decreased.
Administering Sinemer CR with food may increase the
bioavailability of levodopa as much as 50% and elevate peak
plasma levels by 25%.[1,26] Conversely, food may delay the
response to standard Sinemet by approximately 30 minutes and
decrease peak plasma levels by 27%.[27] Patients and caregivers
must also be instructed to report adverse reactions promptly.
Clinicians should be aware of the
potential for Sinemet CR preparations to cause mental status
changes and dyskinesias in elderly, frail patients with
preexisting cognitive impairment and should exercise caution in
substituting the controlled-release preparation for standard
Sinemet.
-----------------------------------------------------------
Table 2. Case Study Data
Patient 1 Patient 2 Patient 3 Patient
4
AA BB CC DD
Age years 82 81 80 84
MMSE[6] 18 24 17 17
Hoehn&Yahr[5] 4 4 4 4
Duration PD, years 6 5 24 14
Standard Sinemet* 750 850 800 600
Sinemet CR* 700 900(+10/100 800 800
once daily) Adverse effects hallucinate hallucinate dyskinesias
hallucinate
confusion
Other psychoactive medications
Selegiline Bromocuptine
Methylphenidate
-----------------------------------------------------------
* mg levodopa
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