This study like all studies found in the archive are formatted to use a 65 character line. They display the tables best if they are printed using the Courier font which is non-proportional. In multiple part files, it is advisable to load them into a text or word processor and put the sections together. Some parts may have a dangling sentence that meshes with the next part. Also look through the pages and if a table crosses between pages, insert blank lines until the table is forced to the succeeding page. For the most part, references are intact and can be used for independent study. Posts of this kind, are not always easy reading and may not provide the value of information you need today. They are posted today, to give answers that you will seek in the tomorrows. This study is posted here for research purposes. 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 mortality. Neurology 1967;17:427-442. 6. Folstein MF, Folstein SF, McHugh PR. "Mini-Mental State". A Guide for grading the cognitive state of patients for the clinician. J Psychiatr Res, 1975;12:189-198. 7. Calne DB. Treatment of Parkinson's disease. N Engl J Med 1993;329:1021-1027. 8. Standaert DC, Stern MB. Update on the management of Parkinson's disease. 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Behavioral complications of drug treatment of Parkinson's disease. J Am Geriatr Soc 1991;39:708-716. 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 disease. Compr Ther 1992;18:20-24. 24.Koller WC, LeWitt PA, Sage JI et al. Role of the controlled-release formulation of carbidopa-levodopa in the treatment of Parkinson's disease: Discussion. Neurology 1992;42 (suppl 1):57-60. 25.LeWitt PA. Clinical studies with and pharmacokinetic considerations of sustained-release levodopa. Neurology 1992;42 (suppl 1):29-32. 26.Wilding IR, Davis SS, Melia CD et al. Gastrointestinal transit of Sinemet CR in healthy volunteers. Neurology 1989;39 (suppl 2):53-58. 27.Nutt JG, Woodward WR, Hammerstad JP et al. The "on-off" phenomenon in Parkinson's disease. Relation to levodopa absorption and transport. N Engl J Med 1984;310:483-488. 28.Koller WC. Controlled-release carbidopa-levodopa: Old drug-new drug. Neurology 1992;42 (suppl 1):4-5. 29.Gauthier S, Amyot D. Sustained release antiparkinson agents: Controlled release levodopa. Can J Neurol Sci 1992;19:153-155. John Cottingham "The parkinsn list brings Knowledge, Comfort, Hope, and Friendship to the parkinsonian world." [log in to unmask]