Although metoclopramide may increase the bioavailability of levodopa by increasing gastric emptying, metoclopramide may also adversely affect disease control by its dopamine receptor antagonistic properties. In order to reduce adverse reactions, it is necessary to individualize therapy. The addition of carbidopa with levodopa in the form of SINEMET reduces the peripheral effects nausea, vomiting due to decarboxylation of levodopa; however, carbidopa does not decrease the adverse reactions due to the central effects of levodopa.
Because carbidopa permits more levodopa to reach the brain and more dopamine to be formed, certain adverse central nervous system CNS effects, e. All patients should be observed carefully for the development of depression with concomitant suicidal tendencies. SINEMET should be administered cautiously to patients with severe cardiovascular or pulmonary disease, bronchial asthma , renal, hepatic or endocrine disease. As with levodopa, care should be exercised in administering SINEMET to patients with a history of myocardial infarction who have residual atrial , nodal, or ventricular arrhythmias.
In such patients, cardiac function should be monitored with particular care during the period of initial dosage adjustment, in a facility with provisions for intensive cardiac care. As with levodopa, treatment with SINEMET may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer. Patients taking SINEMET alone or with other dopaminergic drugs have reported suddenly falling asleep without prior warning of sleepiness while engaged in activities of daily living includes operation of motor vehicles.
Road traffic accidents attributed to sudden sleep onset have been reported. Although many patients reported somnolence while on dopaminergic medications, there have been reports of road traffic accidents attributed to sudden onset of sleep in which the patient did not perceive any warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Sudden onset of sleep has been reported to occur as long as one year after the initiation of treatment.
Falling asleep while engaged in activities of daily living usually occurs in patients experiencing preexisting somnolence, although some patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment. Prescribers should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.
Patients who have already experienced somnolence or an episode of sudden sleep onset should not participate in these activities during treatment with SINEMET. Before initiating treatment with SINEMET, advise patients about the potential to develop drowsiness and ask specifically about factors that may increase the risk for somnolence with SINEMET such as the use of concomitant sedating medications and the presence of sleep disorders.
Consider discontinuing SINEMET in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation e. If treatment with SINEMET continues, patients should be advised not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome NMS have been reported in association with dose reductions or withdrawal of certain antiparkinsonian agents such as levodopa, carbidopa levodopa, or carbidopa levodopa extended release. Therefore, patients should be observed carefully when the dosage of levodopa is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.
NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia. Neurological findings, including muscle rigidity, involuntary movements, altered consciousness, mental status changes; other disturbances, such as autonomic dysfunction, tachycardia , tachypnea , sweating, hyper- or hypotension ; laboratory findings, such as creatine phosphokinase elevation, leukocytosis , myoglobinuria, and increased serum myoglobin have been reported. The early diagnosis of this condition is important for the appropriate management of these patients.
Considering NMS as a possible diagnosis and ruling out other acute illnesses e. This may be especially complex if the clinical presentation includes both serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms EPS. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke , drug fever, and primary central nervous system CNS pathology. The management of NMS should include: Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene, are often used in the treatment of NMS; however, their effectiveness has not been demonstrated in controlled studies.
As with levodopa, periodic evaluations of hepatic, hematopoietic , cardiovascular, and renal function are recommended during extended therapy. Patients with chronic wide-angle glaucoma may be treated cautiously with SINEMET provided the intraocular pressure is well-controlled and the patient is monitored carefully for changes in intraocular pressure during therapy. The occurrence of dyskinesias may require dosage reduction.
Hallucinations and psychotic-like behavior have been reported with dopaminergic medications. In general, hallucinations present shortly after the initiation of therapy and may be responsive to dose reduction in levodopa. Hallucinations may be accompanied by confusion and to a lesser extent sleep disorder insomnia and excessive dreaming. This abnormal thinking and behavior may present with one or more symptoms, including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.
Ordinarily, patients with a major psychotic disorder should not be treated with SINEMET, because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of SINEMET. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued.
Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or the caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with SINEMET. Epidemiological studies have shown that patients with Parkinson's disease have a higher risk 2- to approximately 6-fold higher of developing melanoma than the general population.
Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear. For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using SINEMET for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals e.
Abnormalities in blood urea nitrogen BUN and positive Coombs test have also been reported. SINEMET may cause a false-positive reaction for urinary ketone bodies when a test tape is used for determination of ketonuria. This reaction will not be altered by boiling the urine specimen. Falsenegative tests may result with the use of glucose-oxidase methods of testing for glucosuria.
Cases of falsely diagnosed pheochromocytoma in patients on carbidopa levodopa therapy have been reported very rarely. Caution should be exercised when interpreting the plasma and urine levels of catecholamines and their metabolites in patients on levodopa or carbidopa levodopa therapy. In a two-year bioassay of SINEMET, no evidence of carcinogenicity was found in rats receiving doses of approximately two times the maximum daily human dose of carbidopa and four times the maximum daily human dose of levodopa.
In reproduction studies with SINEMET, no effects on fertility were found in rats receiving doses of approximately two times the maximum daily human dose of carbidopa and four times the maximum daily human dose of levodopa. There was a decrease in the number of live pups delivered by rats receiving approximately two times the maximum recommended human dose of carbidopa and approximately five times the maximum recommended human dose of levodopa during organogenesis.
There are no adequate or well-controlled studies in pregnant women. It has been reported from individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized. Carbidopa concentrations in fetal tissue appeared to be minimal. Use of SINEMET in women of childbearing potential requires that the anticipated benefits of the drug be weighed against possible hazards to mother and child.
Levodopa has been detected in human milk. Safety and effectiveness in pediatric patients have not been established. Use of the drug in patients below the age of 18 is not recommended. No overall meaningful differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals to adverse drug reactions such as hallucinations cannot be ruled out.
There is no specific dosing recommendation based upon clinical pharmacology data as SINEMET is titrated as tolerated for clinical effect. General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered judiciously and an adequate airway maintained. Electrocardiographic monitoring should be instituted and the patient carefully observed for the development of arrhythmias; if required, appropriate antiarrhythmic therapy should be given.
To date, no experience has been reported with dialysis ; hence, its value in overdosage is not known. A significant proportion of rats are expected to die after treatment with similar doses of carbidopa. The addition of carbidopa in a 1: SINEMET is contraindicated in patients with known hypersensitivity to any component of this drug, and in patients with narrow-angle glaucoma. Parkinson's disease is a progressive, neurodegenerative disorder of the extrapyramidal nervous system affecting the mobility and control of the skeletal muscular system.
Its characteristic features include resting tremor , rigidity, and bradykinetic movements. Symptomatic treatments, such as levodopa therapies, may permit the patient better mobility. Current evidence indicates that symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson's disease apparently because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain.
This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson's disease. When levodopa is administered orally, it is rapidly decarboxylated to dopamine in extracerebral tissues so that only a small portion of a given dose is transported unchanged to the central nervous system. For this reason, large doses of levodopa are required for adequate therapeutic effect, and these may often be accompanied by nausea and other adverse reactions, some of which are attributable to dopamine formed in extracerebral tissues.
Since levodopa competes with certain amino acids for transport across the gut wall, the absorption of levodopa may be impaired in some patients on a high protein diet. Carbidopa inhibits decarboxylation of peripheral levodopa. Although no clear predictive criteria for such successful withdrawal exist, evidence indicates that the recurrence of hyperprolactinemia is generally lower in patients with microadenomas than in those with macroadenomas.
Hyperprolactinemia is more likely to recur in patients with tumor remnant on pituitary MRI than it is in patients with no such remnant. In very large adenomas, regrowth of tumor is often seen after the withdrawal of medical treatment. In any case, if medical treatment is withdrawn, close clinical, biochemical, and radiologic monitoring is warranted to look for evidence of tumor recurrence. Most prolactinomas are medically responsive to dopamine agonist therapy.
A few of these patients have malignant prolactinomas. In those patients with DARPs having persistent hyperprolactinemia despite surgical debulking, with or without radiotherapy, temozolomide, a chemotherapeutic alkylating agent, has been recommended. Radiation treatment XRT has had a less prominent role in the treatment of prolactinomas. The major complication of this treatment is hypopituitarism, which occurs in Other complications include optic nerve damage and neurologic dysfunction see Complications.
Because of the excellent results produced by medical treatment, with or without surgery, XRT is seldom used. XRT is considered only in select cases, ie, when there is rapid tumor regrowth despite medical and surgical treatment. During pregnancy, a physiologic doubling occurs in the volume of a normal pituitary gland. Moreover, prolactin levels increase by fold during this period. When a woman with prolactinoma presents with infertility and is proceeding with medical treatment for hyperprolactinemia, the patient is advised to use mechanical barrier methods of contraception until her menstrual cycles resume and the first few cycles have occurred, so that accurate dating of pregnancy can be performed.
BEC is the preferred medical treatment in this situation because of its long safety record. The drug can be discontinued after the first skipped period; despite BEC's safety record, this precaution is taken to prevent unwanted fetal exposure to the agent. To date, however, increased rates of spontaneous abortion, ectopic pregnancy, or teratogenic effects have not been reported with BEC therapy.
Clinical experience with cabergoline-induced pregnancies in approximately patients suggests no excess risk of miscarriage or fetal malformation. Most women with microprolactinomas do not show significant increases in tumor size during pregnancy. The treatment of pregnant women with prolactinomas must be tailored to the individual patient. In women with microadenomas, as well as in the subgroup of women who have intrasellar macroadenomas without significant suprasellar or parasellar extension, BEC can usually be safely discontinued upon conception, and the patient can be monitored clinically for symptoms of tumor enlargement.
In women with larger macroadenomas, a definitive, individualized plan is made only after thorough discussions with the patient. Options include the following:. Transsphenoidal pituitary adenomectomy is the preferred surgical treatment in patients with microprolactinoma and in most patients with macroprolactinoma. A transcranial pituitary tumor resection is more hazardous, being associated with higher mortality and morbidity rates.
A combination of surgery followed by postoperative medical treatment with BEC or one of the other agents is used in patients with incomplete resolution of elevated PRL levels and in persons with residual tumors seen on follow-up imaging studies. This surgery is associated with low mortality and morbidity rates approximately 0. Complications include hypopituitarism, bleeding, cerebrospinal fluid rhinorrhea, and diabetes insipidus see Complications.
A retrospective study of male patients by Andereggen et al indicated that in men with prolactinomas, impaired bone density remains a problem even after medical DA agonist or surgical treatment. The two types of therapy each successfully controlled hyperprolactinemia and hypogonadism. For patients receiving medical treatment, attempts should be made to continue maintenance treatment at the lowest effective dose to maintain PRL in the normal range. If a decision is made to withdraw medical treatment, especially in microprolactinoma patients, PRL levels and radiologic imaging with MRI or CT scanning should be periodically performed to monitor for recurrence and growth of prolactinoma.
Medical treatment may be withdrawn cautiously after menopause in microprolactinoma patients, followed by biochemical and radiologic monitoring. Progress in the management of hyperprolactinemia. N Engl J Med. Effect of acute and chronic neuroleptic therapy on serum prolactin levels in men and women of different age groups. Diagnosis and treatment of hyperprolactinemia: J Clin Endocrinol Metab.
Operative treatment of prolactinomas: AIP mutation in pituitary adenomas in the 18th century and today. The natural history of untreated hyperprolactinemia: The role of cyclase activating CAP and cyclase inhibiting CIP parathormone fractions in the assessment of bone metabolism disturbances in women with hyperprolactinemia of various origin. Endocrinol Metab Clin North Am.
Hypopituitarism patterns among adult males with prolactinomas. Prevalence of pituitary adenomas: Prolactin-screening tumors and hypogonadism in 22 men. Recurrence of hyperprolactinemia following dopamine agonist withdrawal and possible predictive factors of recurrence in prolactinomas. Males with prolactinoma are at increased risk of incident cardiovascular disease.
Prolactinoma-associated headache and dopamine agonist treatment. Evidence for the partial dopamine-receptor agonist aripiprazole as a first-line treatment of psychosis in patients with iatrogenic or tumorogenic hyperprolactinemia. Serum prolactin levels in untreated primary hypothyroidism. Endocrine diagnosis of prolactin-secreting pituitary tumors. Secretory Tumors of the Pituitary Gland. Tirosh A, Shimon I. Current approach to treatments for prolactinomas.
Prolactinomas resistant to standard dopamine agonists respond to chronic cabergoline treatment. A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. Cabergoline Comparative Study Group. Update in pituitary Pharmacologic resistance in prolactinoma patients. Advances in the treatment of prolactinomas. Temozolomide in the management of dopamine agonist-resistant prolactinomas.
Follow-up of children born of bromocriptine-treated mothers. Transsphenoidal microsurgical therapy of prolactinomas: