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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
 
----------------------------------------------------------
 
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,espec-
                                ially 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.
___________________________________________________________
 
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.
 
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.
 
DISCUSION
 
 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 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
 
-----------------------------------------------------------
 
 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
 
despite 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.
 
 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.
 
REFERENCES
 
 1. Yeh KC, August TF, Bush DF et al. Pharmacokinetics and
bioavailability of Sinemet CR: A summary of human studies.
Neurology 1989;39(suppl 2):25-338.
 
 2. LeWitt PA,Nelson MV, Berchou RC et al. Controlled-release
carbidopa/levodopa (Sinemet 50/200 CR4): Clinical and
pharmacokinetic studies. Neurology 1989;39(suppl 2):45-53.
 
 3. Hutton JT, Morris JL. Long acting carbidopa-levodopa in the
management of moderate and advanced Parkinson's disease.
Neurology 1992;42 (suppl 2)51-56.
 
 4. Rodnitzky RL. The use of Sinemet CR in the management of
mild to moderate Parkinson's disease. Neurology 1992; 42 (suppl
1): 44-50.
 
 5. Hoehn MM, Yahr MD. Parkinsonism: Onset, progression, and
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 6. Folstein MF, Folstein SF, McHugh PR. "Mini-Mental State". A
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 7. Calne DB. Treatment of Parkinson's disease. N Engl J Med
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 8. Standaert DC, Stern MB. Update on the management of
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 9.Carter JH, Nutt JG, Woodward WR et al. Amount and
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10.LeWitt PA. Treatment strategies for extension of levodopa
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11.Cedarbaum JM, Hoey M, McDowell FH. A double-blind crossover
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12.Goetz CG, Tanner CM, Gilley DW et al. Development and
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carbidopa/levodopa. Neurology 1989;39 (suppl 2):63-66.
 
13.Pfeiffer RF, Wilken KE, Glaeske CS et al. Sinemet CR in
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14.Mark MH, Sage JI. Long-term efficacy of controlled-release
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15.Rondot P, Ziegler M, Aymard N et al. Effect of
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16.Ahlskog JE, Meunter MD, McManis PG. Controlled-release
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17.Ulm G, Gerdes U, Haagen K. Experiences with Sinemet CR in the
Paracelsus-Elena-Klinik, Neurology 1989;39 (suppl 2):85-87.
 
18.Cedarbaum JM, Kutt H, McDowell FH. A pharmacokinetic and
pharmacodynamic comparison of Sinemet CR(50/200) and standard
Sinemet(25/100). Neurology 1989;39 (suppl 2):38-44.
 
19.Pederzoli M, Girotti F, Scigiliano G. L-dopa long-term
treatment in Parkinson's disease: Age-related side effects.
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20.Friedman JH. Review: The management of the levodopa
psychoses. Clin Neurophharmacol 1991;41:283-295.
 
21.Cummings JL. Behavioral complications of drug treatment of
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22.Banerjee AK, Falkai PG, Savidge M. Visual hallucinations in
the elderly associated with the use of levodopa. Postgrad Med J
1989;65:358-361.
 
23.Siemers E. Recent progress in the treatment of Parkinson's
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24.Koller WC, LeWitt PA, Sage JI et al. Role of the
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25.LeWitt PA. Clinical studies with and pharmacokinetic
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26.Wilding IR, Davis SS, Melia CD et al. Gastrointestinal
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27.Nutt JG, Woodward WR, Hammerstad JP et al. The "on-off"
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