suicidal tendencies. carbidopa and levodopa 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 the combination product, 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 the combination product may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer. falling asleep during activities of daily living and somnolence patients taking carbidopa and levodopa 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 should be advised to exercise caution while driving or operating machines during treatment with carbidopa and levodopa. patients who have already experienced somnolence or an episode of sudden sleep onset should not participate in these activities during treatment with carbidopa and levodopa. before initiating treatment with carbidopa and levodopa, advise patients about the potential to develop drowsiness and ask specifically about factors that may increase the risk for somnolence with carbidopa and levodopa such as the use of concomitant sedating medications and the presence of sleep disorders. consider discontinuing carbidopa and levodopa in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.). if treatment with carbidopa and levodopa 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. hyperpyrexia and confusion 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 and levodopa, or carbidopa and 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.g., pneumonia, systemic infection, etc.) is essential. 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: 1) intensive symptomatic treatment and medical monitoring and 2) treatment of any concomitant serious medical problems for which specific treatments are available. 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.

sed, dosage may be initiated with one tablet three or four times a day. however, this will not provide an adequate amount of carbidopa for many patients. dosage may be increased by one tablet every day or every other day until a total of eight tablets (2 tablets four times a day) is reached. how to transfer patients from levodopa levodopa must be discontinued at least twelve hours before starting this combination product. a daily dosage of carbidopa and levodopa should be chosen that will provide approximately 25% of the previous levodopa dosage. patients who are taking less than 1,500 mg of levodopa a day should be started on one tablet of carbidopa and levodopa 25 mg/100 mg three or four times a day. the suggested starting dosage for most patients taking more than 1,500 mg of levodopa is one tablet of carbidopa and levodopa 25 mg/250 mg three or four times a day. maintenance therapy should be individualized and adjusted according to the desired therapeutic response. at least 70 to 100 mg of carbidopa per day should be provided. when a greater proportion of carbidopa is required, one 25 mg/100 mg tablet may be substituted for each 10 mg/100 mg tablet. when more levodopa is required, each 25 mg/250 mg tablet should be substituted for a 25 mg/100 mg tablet or a 10 mg/100 mg tablet. if necessary, the dosage of carbidopa and levodopa 25 mg/250 mg may be increased by one-half or one tablet every day or every other day to a maximum of eight tablets a day. experience with total daily dosages of carbidopa greater than 200 mg is limited. because both therapeutic and adverse responses occur more rapidly with this combination product than with levodopa alone, patients should be monitored closely during the dose adjustment period. specifically, involuntary movements will occur more rapidly with carbidopa and levodopa than with levodopa. the occurrence of involuntary movements may require dosage reduction. blepharospasm may be a useful early sign of excess dosage in some patients. addition of other antiparkinsonian medications standard drugs for parkinson's disease, other than levodopa without a decarboxylase inhibitor, may be used concomitantly while carbidopa and levodopa is being administered, although dosage adjustments may be required. interruption of therapy sporadic cases of hyperpyrexia and confusion have been associated with dose reductions and withdrawal of carbidopa and levodopa. patients should be observed carefully if abrupt reduction or discontinuation of carbidopa and levodopa is required, especially if the patient is receiving neuroleptics (see warnings ). if general anesthesia is required, carbidopa and levodopa may be continued as long as the patient is permitted to take fluids and medication by mouth. if therapy is interrupted temporarily, the patient should be observed for symptoms resembling nms, and the usual daily dosage may be administered as soon as the patient is able to take oral medication.

inations, and paranoid ideation, bradykinetic episodes ("on-off" phenomenon), confusion, agitation, dizziness, somnolence, dream abnormalities including nightmares, insomnia, paresthesia, headache, depression with or without development of suicidal tendencies, dementia, pathological gambling, increased libido including hypersexuality, impulse control symptoms. convulsions also have occurred; however, a causal relationship with carbidopa and levodopa has not been established. respiratory dyspnea, upper respiratory infection. skin rash, increased sweating, alopecia, dark sweat. urogenital urinary tract infection, urinary frequency, dark urine. laboratory tests decreased hemoglobin and hematocrit; abnormalities in alkaline phosphatase, sgot (ast), sgpt (alt), ldh, bilirubin, bun, coombs test; elevated serum glucose; white blood cells, bacteria, and blood in the urine. other adverse reactions that have been reported with levodopa alone and with various carbidopa and levodopa formulations, and may occur with this combination product are: body as a whole abdominal pain and distress, fatigue. cardiovascular myocardial infarction. gastrointestinal gastrointestinal pain, dysphagia, sialorrhea, flatulence, bruxism, burning sensation of the tongue, heartburn, hiccups. metabolic edema, weight gain, weight loss. musculoskeletal leg pain. nervous system/psychiatric ataxia, extrapyramidal disorder, falling, anxiety, gait abnormalities, nervousness, decreased mental acuity, memory impairment, disorientation, euphoria, blepharospasm (which may be taken as an early sign of excess dosage; consideration of dosage reduction may be made at this time), trismus, increased tremor, numbness, muscle twitching, activation of latent horner's syndrome, peripheral neuropathy. respiratory pharyngeal pain, cough. skin malignant melanoma, flushing. special senses oculogyric crises, diplopia, blurred vision, dilated pupils. urogenital urinary retention, urinary incontinence, priapism. miscellaneous bizarre breathing patterns, faintness, hoarseness, malaise, hot flashes, sense of stimulation. laboratory tests decreased white blood cell count and serum potassium; increased serum creatinine and uric acid; protein and glucose in urine. to report suspected adverse events, contact avkare at 1-855-361-3993; email drugsafety@avkare.com or fda at 1-800-fda-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions.

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. it does not cross the blood-brain barrier and does not affect the metabolism of levodopa within the central nervous system. the incidence of levodopa-induced nausea and vomiting is less with the combination product than with levodopa. in many patients, this reduction in nausea and vomiting will permit more rapid dosage titration. since its decarboxylase inhibiting activity is limited to extracerebral tissues, administration of carbidopa with levodopa makes more levodopa available for transport to the brain. pharmacokinetics carbidopa reduces the amount of levodopa required to produce a given response by about 75% and, when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa, and decreases plasma and urinary dopamine and homovanillic acid. the plasma half-life of levodopa is about 50 minutes, without carbidopa. when carbidopa and levodopa are administered together, the half-life of levodopa is increased to about 1.5 hours. at steady state, the bioavailability of carbidopa from carbidopa and levodopa tablets is approximately 99% relative to the concomitant administration of carbidopa and levodopa. in clinical pharmacologic studies, simultaneous administration of carbidopa and levodopa produced greater urinary excretion of levodopa in proportion to the excretion of dopamine than administration of the two drugs at separate times. pyridoxine hydrochloride (vitamin b 6 ), in oral doses of 10 mg to 25 mg, may reverse the effects of levodopa by increasing the rate of aromatic amino acid decarboxylation. carbidopa inhibits this action of pyridoxine; therefore, carbidopa and levodopa can be given to patients receiving supplemental pyridoxine (vitamin b 6 ). special populations geriatric: a study in eight young healthy subjects (21 to 22 yr) and eight elderly healthy subjects (69 to 76 yr) showed that the absolute bioavailability of levodopa was similar between young and elderly subjects following oral administration of levodopa and carbidopa. however, the systemic exposure (auc) of levodopa was increased by 55% in elderly subjects compared to young subjects. based on another study in forty patients with parkinson’s disease, there was a correlation between age of patients and the increase of auc of levodopa following administration of levodopa and an inhibitor of peripheral dopa decarboxylase. auc of levodopa was increased by 28% in elderly patients (greater than or equal to 65 yr) compared to young patients (less than 65 yr). additionally, mean value of c max for levodopa was increased by 24% in elderly patients (greater than or equal to 65 yr) compared to young patients (less than 65 yr) (see precautions , geriatric use ). the auc of carbidopa was increased in elderly subjects (n=10, 65 to 76 yr) by 29% compared to young subjects (n=24, 23 to 64 yr) following iv administration of 50 mg levodopa with carbidopa (50 mg). this increase is not considered a clinically significant impact.

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