Professional Drug Information > Carbidopa and Levodopa

Carbidopa and Levodopa (Systemic)

Pharmacy Equivalent Name (PEN):

Co-Careldopa
VA CLASSIFICATION
Primary: CN500

Commonly used brand name(s): Apo-Levocarb; Atamet; Nu-Levocarb; Sinemet; Sinemet CR 25-100; Sinemet CR 50-200.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antidyskinetic—

Indications

General considerations
Levodopa is administered most commonly in combination with a peripheral decarboxylase inhibitor (PDI), such as carbidopa ^{{35} {42} {48} {68}}, to maximize the amount of levodopa available to enter the brain ^{40} and to lessen adverse effects (such as nausea, vomiting, and hypotension) caused by the peripheral decarboxylation of levodopa to dopamine ^{{34} {48} {68}}. Levodopa currently is a mainstay of therapy for symptomatic treatment of Parkinson's disease ^{{40} {48}}. However, complications to long-term levodopa therapy appear commonly ^{48}, and the majority of patients experience serious adverse effects including motor fluctuations ^{{05} {40} {47}}, dyskinesias ^{{40} {43} {46}}, and neuropsychiatric effects ^{{05} {47} {48}}. Fluctuations in response to levodopa therapy represent a significant problem in the long-term management of patients with Parkinson's disease ^{{40} {47}}. Later stage motor complications are related to the severity and duration of the underlying disease, as well as to treatment-related factors such as the dose of levodopa therapy ^{{05} {39}}.

Patients who develop response fluctuations to levodopa therapy appear to lack the capacity to buffer fluctuations in plasma levels of levodopa ^{48}. One theory to explain the mechanism of fluctuation is that chronic, sporadic stimulation of striatal postsynaptic dopaminergic receptors from exogenous levodopa administration results in changes downstream from the nigrostriatal dopamine system ^{{45} {48}}; residual dopaminergic neurons, attempting to compensate for loss of degenerated neurons, accelerate dopamine formation and rapidly release it, rather than retaining it in storage vesicles ^{45}. In addition, nondopaminergic neurons and other cells that possess significant decarboxylase activity become increasingly important sources of intrasynaptic dopamine ^{45}. Once synthesized in these cells, dopamine is immediately released ^{45}, resulting in intrasynaptic dopamine concentrations that reflect the marked swings in levodopa availability ^{45} and in the ensuing motor fluctuations.

Therapeutic responses to levodopa therapy include a short-duration response, in which improvement in motor disability lasts a few hours after the administration of a single dose of levodopa, and a long-duration response, in which antiparkinsonian effects may last for many hours or days following discontinuation of levodopa. ^{{46} {58}}

Controversies exist regarding the optimal time to initiate therapy with levodopa ^{{39} {48}} and the optimal use of other antiparkinsonian medications throughout the disease process ^{48}.

Accepted

Parkinsonism (treatment)—Carbidopa and levodopa combination is indicated in the treatment of idiopathic Parkinson's disease, postencephalitic parkinsonism, or symptomatic parkinsonism, which may follow injury to the nervous system by carbon monoxide intoxication or manganese intoxication, to permit achievement of symptomatic relief with a lower dosage of levodopa than with levodopa alone. Also, it permits a smoother and more rapid dosage titration, reduces nausea and vomiting, and allows concurrent administration of pyridoxine when necessary. ^{{03} {14} {67}}


Pharmacology/Pharmacokinetics

See also Levodopa (Systemic) .

Physicochemical characteristics:

Chemical group—
    Levodopa: Levorotatory isomer of dihydroxyphenylalanine (L-DOPA) ^{31}, which is the metabolic precursor of dopamine. ^{{31} {68}}
    Carbidopa: Hydrazine analog of levodopa ^{06}.
Molecular weight—
    Levodopa: 197.19 ^{65}
    Carbidopa: 244.25 ^{65}

Solubility
    Levodopa: 66 mg in 40 mL of water. ^{50}
    Carbidopa: Slightly soluble in water. ^{70}


Other properties
    In the presence of moisture, levodopa is oxidized by atmospheric oxygen and darkens. ^{50}

Mechanism of action/Effect:

Normal motor function depends on the synthesis and release of dopamine by neurons projecting from substantia nigra to corpus striatum. The progressive degeneration of these neurons ^{{41} {43} {45}} that occurs in Parkinson's disease disrupts the nigrostriatal pathway ^{42} and results in diminished levels of the intrasynaptic neurotransmitter dopamine ^{{43} {45}}. Striatal dopamine levels in symptomatic Parkinson's disease are decreased by 60 to 80% ^{{05} {43}}.

Levodopa—Striatal dopaminergic neurotransmission may be enhanced by exogenous supplementation of dopamine through administration of dopamine's precursor, levodopa. A small percentage of each levodopa dose crosses the blood-brain barrier and is decarboxylated to dopamine ^{68}. This newly formed dopamine then is available to stimulate dopaminergic receptors ^{68}, thus compensating for the depleted supply of endogenous dopamine ^{41}.

Carbidopa—Inhibits the peripheral decarboxylation of levodopa ^{{01} {03} {14}}, thus decreasing its conversion to dopamine in peripheral tissues. This results in higher plasma levels of levodopa and, consequently, an increased availability of levodopa for transport across the blood-brain barrier, where it undergoes decarboxylation to the neurotransmitter dopamine ^{{01} {03}}.


Other actions/effects:

Levodopa's metabolite, dopamine, stimulates beta-adrenergic cardiac receptors ^{06}, interacts with the chemoreceptor zone in the area postrema, located outside the blood-brain barrier ^{42}, and promotes release of pituitary growth hormone ^{57}.

Absorption:


Carbidopa:

Carbidopa is poorly absorbed; its oral bioavailability is 40 to 70% ^{46}.



Levodopa:

Levodopa is rapidly absorbed from the proximal small intestine by the large neutral amino acid (LNAA) transport carrier system ^{{34} {42}}. This transport system is a saturable, sodium-independent, facilitated mechanism for aromatic and branched chain amino acids ^{34}. The capacity of the transport system is limited ^{34}, and levodopa must compete for energy-dependent proximal small bowel absorption sites ^{{05} {46}}. Stomach and intestinal walls contain abundant levels of the L-aromatic amino acid decarboxylase (AAAD) enzyme, which degrades levodopa, and thus serves as a significant barrier to the absorption of intact levodopa ^{{34} {46}}; only about 30% of an orally administered dose reaches the circulation as intact levodopa ^{34}. However, comcomitant administration of a peripheral decarboxylase inhibitor, such as carbidopa, will enhance the absorption of levodopa ^{{05} {68} {46}}.

High gastric acidity, delayed stomach emptying time, and the presence of certain other amino acids, such as those that occur after digestion of a protein-containing meal, may prevent absorption of levodopa. ^{{05} {68} {34} {42} {46}} Intense exercise and other activity that diverts blood flow from the mesenteric circulation also may delay levodopa absorption. ^{{05} {34}}



Carbidopa and levodopa combination:

Tablets: Absorption is rapid and virtually complete in 2 to 3 hours. ^{{18} {67}}

Extended-release tablets: Absorption is gradual and continuous for 4 to 5 ^{{44} {67}} hours, although the majority of the dose is absorbed in 2 to 3 hours. ^{{17} {18} {67}}

Absorption may be impaired by a high-protein diet ^{67}.



Bioavailability of carbidopa and levodopa extended-release tablets:

Approximately 70 to 75% relative to the immediate-release tablets. ^{{17} {18} {19}}

Increased somewhat in the presence of food. ^{{17} {18} {67}}

Two half tablets approximately 20% more bioavailable than one intact tablet. ^{{18} {19} {67}}


Note: Liquid formulations of carbidopa and levodopa combination have been extemporaneously compounded in an attempt to minimize absorption problems ^{{44} {48} {69}}. The liquid preparation is absorbed slightly faster than carbidopa and levodopa tablets ^{44}, and antiparkinsonian effects may take effect more quickly than with the tablets. Thus, the liquid preparation may be useful in patients who are extremely sensitive to small changes in the dose of levodopa, such as those experiencing erratic motor control ^{48} (e.g., severe oscillations between “on” and “off” periods ^{42}). (See Side/Adverse Effects section and Preparation of dosage form section.)


Distribution:

Levodopa—Widely distributed to most body tissues, but not to the central nervous system (CNS) because of extensive metabolism in the periphery ^{06}. Levodopa crosses biological membranes, including the intestinal epithelium and the blood-brain barrier, by means of the LNAA transport system. ^{{03} {09} {34} {42} {46}} This system is the saturable, stereospecific, facilitated transport mechanism for large neutral amino acids, including those from dietary protein intake ^{{03} {09} {34} {41} {46}}. The transport rate across the blood-brain barrier is dependent upon the plasma concentration of levodopa and the concentration of competing amino acids. ^{03} The flux of amino acids across the blood-brain barrier is bidirectional; the net flux of unmetabolized levodopa is from the brain into the plasma as levodopa plasma concentrations fall. ^{34}

Carbidopa—Does not cross the blood-brain barrier ^{67}.

Biotransformation:

Levodopa—95% ^{46} of an administered oral dose of levodopa is pre-systemically ^{36} decarboxylated to dopamine by the L-aromatic amino acid decarboxylase (AAAD) enzyme ^{46} in the stomach, lumen of the intestine, kidney, and liver ^{05}. This converted portion of dopamine cannot cross the blood-brain barrier to exert its effects on the brain. ^{05} Dopamine remaining in the periphery is believed responsible for many levodopa adverse effects, including cardiac arrhythmias and gastrointestinal upset. ^{{68} {34}} Levodopa also may be methoxylated ^{40} by the hepatic catechol- O-methyltransferase (COMT) enzyme system to 3- O-methyldopa (3-OMD), which cannot be converted to central dopamine ^{05}. 3-OMD has a long half-life ^{05} and competes with levodopa for the same transport mechanism across the blood-brain barrier ^{{05} {40}}.

When the portion of the remaining intact levodopa does cross the blood-brain barrier, it is decarboxylated to dopamine, which is normally stored in presynaptic terminals of dopaminergic neurons in the striatum ^{{68} {36}}. After release into the synapse, dopamine is transported back into the dopaminergic terminals by the presynaptic uptake mechanism, or is further metabolized by monoamine oxidase (MAO) or COMT ^{68}. The actions of levodopa in the brain are affected by the rate and extent of cerebral conversion to dopamine, the rate of movement of the synthesized dopamine to the striatal receptors, and the rate of inactivation of newly synthesized dopamine. ^{05}

Carbidopa—Unlike levodopa, carbidopa is not a substrate for dopa decarboxylase ^{46}; it does inhibit the metabolism of levodopa in the gastrointestinal tract and plasma ^{71} by blocking dopa decarboxylase ^{46}, thus increasing the absorption and plasma concentrations of levodopa ^{{01} {03}}.

Half-life:

Levodopa: 0.75 to 1.5 hours. ^{{34} {44} {46} {64}}

3-O-methyldopa (3-OMD): 15 hours; accumulation will occur during chronic dosing. ^{34}

Carbidopa—1 to 2 hours. ^{15} When given in combination with levodopa, carbidopa increases levodopa's plasma half-life to about 1.5 hours. ^{{05} {68}}

Time to peak concentration:


Peak levodopa concentrations at steady state:


Carbidopa and levodopa tablets—

0.5 to 0.7 hours. ^{{18} {67}}



Carbidopa and levodopa extended-release tablets—

2.1 to 2.4 hours. ^{{18} {67}}


Note: Peak plasma concentrations of levodopa are increased when the extended-release tablets are administered with food. ^{17}
Plasma concentrations of levodopa fluctuate less with the extended-release tablets than with the immediate release tablets. ^{{18} {44} {67}}
Extended-release tablets have a delayed onset of action of two to three times that of the immediate-release tablets ^{44}.



Elimination:
    Levodopa—Renal, 70 to 80% of dose eliminated within 24 hours, largely as dopamine metabolites. ^{34} Homovanillic acid (HVA) is a major urinary metabolite, accounting for 13 to 42% of the ingested dose of levodopa in twenty-four hour urine samples. ^{31} Unchanged levodopa accounts for less than 1% of an administered dose. ^{68} Some of the eliminated metabolites may color the urine red ^{06}; oxidation that occurs when urine is exposed to air will cause it to darken ^{{06} {50}}.
    Fecal, 2% of dose. ^{34}
    Carbidopa—Renal; 30% of dose of carbidopa excreted unchanged in urine within 24 hours. When given in combination with levodopa, the amount of levodopa excreted unchanged in urine is increased by about 6%. ^{02}


Precautions to Consider

Carcinogenicity

In a two-year bioassay of carbidopa and levodopa, no evidence of carcinogenicity was found in rats that received doses of approximately two times the maximum daily human dose of carbidopa and four times the maximum daily human dose of levodopa ^{03}.

Pregnancy/Reproduction
Fertility—
No effects on fertility were found in reproduction studies done in rats receiving approximately two times the maximum daily human dose of carbidopa and four times the maximum daily human dose of levodopa ^{03}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done ^{03}. However, case studies have reported that levodopa crosses the placenta and is metabolized in the fetal tissues. ^{32}

Reproduction studies in rodents have shown that levodopa, when given in doses in excess of 200 mg per kg of body weight (mg/kg) per day ^{01}, depresses fetal and postnatal growth and viability. Also, studies in rabbits have shown that levodopa alone or in combination with carbidopa causes visceral and skeletal malformations. ^{{03} {14} {17} {67}}

FDA Pregnancy Category C. ^{{01} {03} {17}}

Breast-feeding

Levodopa is distributed into breast milk. Although problems in humans have not been documented, breast-feeding is not recommended because of the potential for side effects in the infant. ^{{03} {31}}

Also, levodopa may inhibit lactation. ^{{71} {72}}

Pediatrics

Appropriate studies on the relationship of age to the effects of carbidopa and levodopa have not been performed in children up to 18 years of age. ^{{01} {14}} Safety and efficacy have not been established. ^{{03} {14} {15} {67} {66}}


Geriatrics


Smaller doses may be required in geriatric patients since they may have reduced tolerance to the effects of levodopa ^{64}. Similarly, patients with Alzheimer's disease are more sensitive to usual doses of levodopa ^{64}.

Geriatric patients, especially those with osteoporosis, who respond to levodopa therapy should resume normal activity gradually and with caution because increased mobility may increase risk of fractures ^{15}.

Central nervous system (CNS) effects, such as anxiety, confusion, or nervousness, are more common in geriatric patients receiving anticholinergic antiparkinsonian medications in addition to levodopa. ^{05}


Dental

Involuntary movements of jaws may result in poor retention of full dentures; dosage reduction may be required. ^{02}

Surgical

If general anesthesia is required and the administration of carbidopa and levodopa combination is interrupted temporarily, the patient should be observed for symptoms of a neuroleptic malignant-like syndrome. ^{{03} {67}}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Amantadine^{26}{46} or
Benztropine^{04} or
Procyclidine^{59} or
Trihexyphenidyl^{60}    (concurrent use may result in increased efficacy of levodopa; however, concurrent use is not recommended if there is a history of psychosis)


» Anesthetics, hydrocarbon inhalation    (administration prior to anesthesia with these agents may result in cardiac arrhythmias because of increased endogenous dopamine concentration; carbidopa and levodopa combination should be discontinued 6 to 8 hours before the administration of these anesthetics, especially halothane ^{63})


Benzodiazepines^{29}{37}    (concurrent use may decrease the therapeutic effects of levodopa)


Bromocriptine^{05}    (may produce additive effects, allowing reduction in levodopa dosage)


» Cocaine    (concurrent use with levodopa may increase the risk of cardiac arrhythmias; if use of cocaine is necessary in patients receiving levodopa, it is recommended that cocaine be administered with caution, in reduced dosage, and in conjunction with electrocardiographic monitoring ^{{08} {11}})


Droperidol^{30} or
» Haloperidol^{{03}{14}{15}{27}{28}{67}} or
Loxapine^{28} or
Molindone or
Papaverine^{{03}{14}{15}{37}{67}} or
» Phenothiazines^{{03}{14}{15}{61}{62}{67}} or
» Thioxanthenes^{27}    (agents that block the dopamine receptors in the brain, such as traditional antipsychotics, may antagonize the effects of levodopa)


Foods, especially high-protein^{07}{46}{48}    (concurrent or previous ingestion of food may decrease the absorption of levodopa from the gastrointestinal tract, consequently delaying its effect ^{{14} {15}}; in addition, proteins in food may be degraded into amino acids that compete with levodopa for transport across the intestinal epithelium and the blood-brain barrier, resulting in a decreased or erratic response to levodopa; however, rather than cutting down on daily protein intake to avoid this effect, it has been recommended that the intake of proteins be distributed equally throughout the day ^{07}. Alternatively, some clinicians recommend a redistribution diet ^{48} for selected patients for a limited time during which all protein intake is in the evening meal, as patients would be minimally affected by any ensuing “off” period (see Side/Adverse Effects ); diets with austere restrictions in total daily protein intake (£ 10 grams) have been shown to reduce the magnitude of response fluctuations and may benefit some patients, but are often unpalatable and may result in a negative nitrogen balance if not carefully monitored ^{46}; a recommended dietary allowance of 0.8 gram of protein per kg of body weight a day is thought to be a sufficient and safe restriction that does not affect the levodopa dose-response relationship ^{44})


Hypotension-producing medications, other^{{03}{14} {15}{31}{67}} (see Appendix II )    (concurrent use with levodopa may result in an increased hypotensive effect)


Iron salts^{03}{37} or
Vitamin/mineral preparations containing iron salts^{03}    (iron salts may chelate with levodopa, resulting in decreased absorption and lower serum levels of levodopa, and thus reduce its efficacy)


Methyldopa^{63}    (concurrent use with levodopa may alter the antiparkinsonian effects of levodopa and may also produce additive toxic CNS effects such as psychosis)


Metoclopramide^{{03}{09}{35}{37}}    (metoclopramide may worsen Parkinson's disease through inhibition of CNS dopamine receptors; conversely, levodopa may antagonize the effects of metoclopramide by increasing the amount of available dopamine)


» Monoamine oxidase (MAO) inhibitors,^{{03}{14}{15}{17}{67}} including furazolidone, procarbazine, and selegiline    (although high doses [300 to 400 mg a day] of carbidopa in combination with levodopa may help suppress the hypertensive reactions caused by concurrent use with MAO inhibitors, it is recommended that MAO inhibitors be discontinued for at least 2 ^{{14} {15} {67}} weeks prior to initiation of carbidopa and levodopa combination therapy)


Rauwolfia alkaloids^{63}    (rauwolfia alkaloids cause dopamine depletion in the brain, decreasing the effects of levodopa; dosage adjustments of either or both medications may be necessary)


» Selegiline^{03} or
Tolcapone^{72}    (although sometimes used in conjunction with carbidopa and levodopa combination, selegiline or tolcapone may have additive effects; selegiline may enhance levodopa-induced dyskinesias, nausea, orthostatic hypotension, confusion, and hallucinations; levodopa dosage should be reduced within 2 to 3 days after the initiation of therapy with selegiline ^{{16} {25}}or tolcapone ^{72})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Catecholamines, plasma and urine^{03}{52} or
Metanephrines, plasma and urine^{03}{52}    (test results are unreliable)


Coombs' (antiglobulin) test^{{03}{14}{15}{17}}    (occasionally becomes positive after long-term levodopa therapy)


Glucose, urine    (tests using copper reduction methods may cause false-positive results ^{{17} {18}}; tests using glucose oxidase methods may cause false-negative results ^{{14} {15} {17} {18}})


Gonadorelin test^{53}    (levodopa may elevate serum gonadotropin concentrations)


Ketones, urine    (tests using dipstick or test tape methods may cause false-positive results ^{{03} {14} {15} {17} {18}})


Protein, urine    (use of the Lowery test may cause false-positive results)


Thyroid function determinations    (chronic use of levodopa may inhibit the TSH response to protirelin ^{51})


Uric acid, serum and urine    (tests may show high concentrations with colorimetric measurements, but not with uricase ^{31})

With physiology/laboratory values
Alanine aminotransferase (ALT [SGPT])^{{03}{14}{15}{17}{18}} and
Alkaline phosphatase^{{03}{14}{15}{17}{18}} and
Aspartate aminotransferase (AST [SGOT])^{{03}{14}{15}{17}{18}} and
Bilirubin^{{03}{14}{15}{17}{18}} and
Lactate dehydrogenase (LDH)^{{03}{14}{15}{17}{18}} and
Protein-bound iodine (PBI)^{14}{15}{17}    (serum concentrations may be increased)


Blood urea nitrogen (BUN)^{{03}{14}{15}{17}{18}}    (concentrations may be increased)


Hematocrit^{03} or
Hemoglobin^{03} or
White blood cell counts^{03}    (values may be decreased)


Note: Concentrations of BUN, creatinine, and uric acid, although elevated during carbidopa and levodopa therapy, are elevated to a lesser degree than when levodopa is used alone. ^{{03} {14}}


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Bronchial asthma, emphysema, and other severe pulmonary diseases^{{03}{14}{15}{17}{67}}    (respiratory effects of levodopa may aggravate condition)


» Cardiovascular disease, severe^{{03}{14}{15}{17}{67}}    (increased risk of cardiac arrhythmias)


Convulsive disorders, history of^{63}{67}    (use of levodopa may precipitate seizures)


Diabetes mellitus^{03}{63}    (use of levodopa may adversely affect control of glucose in blood)


Endocrine diseases^{{03}{14}{15}{17}{67}}    (use of levodopa may adversely affect hypothalamus or pituitary function)


» Glaucoma, angle-closure, or predisposition to^{{03}{14}{15}{17}{67}}    (mydriatic effect resulting in increased intraocular pressure may precipitate an acute attack of angle closure glaucoma)


Glaucoma, open-angle, chronic^{{03}{14}{15}{67}}    (mydriatic effect may cause a slight increase in intraocular pressure; glaucoma therapy may need to be adjusted ^{01})


Hepatic function impairment^{{03}{14}{15}{17}{67}}
» Melanoma, history of or suspected^{{03}{14}{15}{17}{67}}    (use of levodopa may activate a malignant melanoma)


Mental depression^{03}{31}{67} or
Psychosis^{{03}{14}{15}{17}{31}{67}}    (increased risk of developing suicidal tendencies and/or suicidal ideation; also, conditions may be aggravated by neuropsychiatric effects of levodopa)


» Myocardial infarction, history of, with residual atrial, nodal, or ventricular arrhythmias^{{03}{14}{17}{67}}    (use of levodopa may precipitate or aggravate condition)


» Peptic ulcer, history of^{{03}{14}{15}{17}{67}}    (increased risk of upper gastrointestinal hemorrhage)


» Renal function impairment^{{03}{14}{15}{17}{67}}    (use of levodopa may lead to urinary retention)


Sensitivity to carbidopa and/or levodopa^{14}{15}{17}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood cell counts^{{03}{14}{15}{17}{67}} and
Hemoglobin determinations^{{03}{14}{15}{67}} and
Hepatic function determinations^{{03}{14}{15}{17}{67}} and
Ophthalmologic examinations for glaucoma and monitoring of intraocular pressure in patients with open angle glaucoma^{03}{17}{67} and
Renal function determinations^{{03}{14}{15}{17}{67}}    (recommended at periodic intervals for patients on long-term levodopa therapy)


Cardiovascular monitoring ^{{03}{14}{15}{17}{67}}    (recommended at periodic intervals for patients on long-term therapy)






Side/Adverse Effects

Note: Carbidopa, in doses used to inhibit peripheral decarboxylation of levodopa, has no significant ability to produce side effects ^{06}. However, it allows certain CNS side effects of levodopa, such as dyskinesias and mental effects, to develop sooner and at lower levodopa doses because of the resultant greater efficiency per dose of levodopa. ^{{03} {14} {15}}
A syndrome resembling neuroleptic malignant syndrome, which includes intermittent dystonia alternating with substantial agitation, hyperthermia and mental changes, has been reported after the abrupt discontinuation of levodopa therapy. ^{{03} {10} {11} {14} {67}}
Although carbidopa and levodopa combination is the most commonly used antiparkinsonian medication ^{{35} {42} {48} {68}}, complications to long-term levodopa therapy appear commonly and include motor fluctutations, dyskinesias, and neuropsychiatric problems ^{{39} {48} {64}}. Fifty percent or more of patients who have received levodopa for 5 years experience motor fluctuations ^{{05} {39} {45} {46}}; after 10 years or more of treatment, up to 90% of patients may be affected ^{{39} {46} {48}}.
Periods of therapeutic response in terms of antiparkinsonian effects are termed “on” periods ^{{46} {48}}; ”off” periods are periods of suboptimal response where the patient experiences a worsening of parkinsonian symptoms ^{48}. Motor fluctuations include predictable “wearing off” periods ^{43}, unpredictable “off” periods ^{43}, and various abnormal involuntary movements ^{39}. End-of-dose deterioration ^{{45} {46}} or “wearing off” periods ^{43} (predictable periods of immobility or greater severity of other parkinsonian symptoms when medications wear off ^{39}) usually have a close temporal relationship to the timing of antiparkinsonian medication ^{39}. “On-off” fluctuations are sudden unpredictable shifts between “on” and “off” periods that are unrelated to the timing of antiparkinsonian medication ^{{39} {43}}; relatively small changes in circulating levodopa, and thus in striatal dopamine, can induce large shifts in dopaminergic transmission and ultimately in motor function ^{{43} {45}}.
Dyskinesias may include peak-dose (or square-wave) dyskinesias ^{{43} {46} {47}} (appearing during maximum effect), biphasic dyskinesias (appearing at beginning and end of dosing period) ^{{11} {46} {47}}, and focal or generalized dystonia ^{{40} {47}}. The severity of dyskinesias increases with time, as the distribution of abnormal movements spreads, and the degree of abnormal movements increases ^{05}. Dyskinesias are dose-dependent, and the dose threshold decreases as Parkinson's disease progresses ^{42}.
Random oscillations ^{40} include transient episodes of “freezing” or motor blocks ^{47}, where initiation or continuation of a motor act such as walking is arrested for a few seconds ^{39}. “Yo-yoing” is unpredictable ^{47} oscillations between choreic dyskinesia and Parkinsonian rigidity; patients may progress from severe dyskinesias to ridigity, or have an acceptable response to medication for part of the day (“ons”) and be intermittently disabled by periods of suboptimal response (“offs”) or dyskinesias ^{64}.
Neuropsychiatric effects ^{{05} {48} {64}} may occur in up to two-thirds of patients on long-term levodopa therapy ^{47} and may be related to the activation of dopamine receptors in nonstriatal regions of the brain, especially the cortical and limbic regions ^{{42} {64}}. These mental and behavioral changes include confusion, agitation, hallucinations, irritability, panic, paranoid delusions, mental depression, dementia, mania, and psychosis ^{{05} {47} {48} {64}}; euphoria, hypersexuality, or hypomania may occur during “on” periods ^{47}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention

Incidence more frequent
    
Agitation^{03}{31}{42}
    
anxiety^{03}{31}
    
ataxia^{03}{31} (clumsiness or unsteadiness)
    
bruxism^{03}{31} (clenching or grinding of teeth)
    
choreiform and/or dystonic movements^{{03}{14}{15}{31}{42}} (unusual and uncontrolled movements of the body, including the face, tongue, arms, hands, head, and upper body)
    
confusion^{16}{31}
    
delusions^{03}{31} (abnormal thinking: holding false beliefs that cannot be changed by fact)
    
dizziness^{03}{31}
    
dysphagia^{03}{31}{48} (difficulty swallowing)
    
euphoria^{03}{31} (false sense of well-being)
    
fatigue^{03}{31} (unusual tiredness or weakness)
    
feeling faint^{03}{31}
    
hallucinations^{03}{31}{42} (seeing, hearing, or feeling things that are not there)
    
increased hand tremor^{03}{31}
    
malaise^{03}{31} (general feeling of discomfort or illness)
    
nausea or vomiting^{{03}{14}{15}{17}{31}}
    
peripheral neuropathy^{03}{31} (numbness, burning, tingling, or prickling sensations)
    
sialorrhea^{03}{31} (excessive watering of mouth)
    
weakness^{31}

Note: Hallucinations are usually visual ^{{42} {48}} and, at early stages, non-threatening ^{42}.
Nausea and vomiting may occur frequently in early carbidopa and levodopa therapy, with tolerance being gradually achieved during continued use. The concurrent use of carbidopa with levodopa often reduces the frequency and severity of nausea and vomiting, although approximately 15% of patients continue to experience these side effects.


Incidence less frequent
    
Blepharospasm^{{03}{14}{15}{17}{31}} (increased blinking or spasms of eyelids)
    
blurred vision^{{01}{03}{17}{31}}
    
cardiac irregularities^{{03}{14}{15}{17}{31}} (fast, irregular, or pounding heart beat)
    
diplopia^{03}{31} (double vision)
    
hot flashes^{03}{31}
    
mydriasis^{03}{31} (dilated pupils)
    
neuropsychiatric effects, including paranoid ideation, psychotic episodes, and mental depression with or without suicidal tendencies^{{03}{14}{15}{17}{31}{48}} (mood or mental changes)
    
orthostatic hypotension^{{03}{14}{15}{17}{31}{48}} (dizziness or lightheadedness when getting up from a lying or sitting position)
    
palpitations^{03}{31} (fast or pounding heart beat)
    
skin rash^{03}{31}
    
trismus^{03}{31} (difficulty opening mouth)
    
unusual weight gain or loss^{03}{31}
    
urinary incontinence^{03}{31}{48} (loss of bladder control)
    
urinary retention^{{03}{14}{15}{17}{31}} (difficult urination)

Note: Cardiac arrhythmias, palpitations, and urinary retention may become less frequent when levodopa is administered concomitantly with a peripheral decarboxylase inhibitor, such as carbidopa. ^{05}


Incidence rare
    
Agranulocytosis^{03}{31} (chills; fever; sore throat; unusual tiredness or weakness)
    
duodenal ulcer^{{03}{14}{15}{17}{31}} (stomach pain)
    
edema^{03}{31} (swelling of face; swelling of feet or lower legs; unusual weight gain)
    
gastrointestinal bleeding^{03}{31} (bloody or black, tarry stools; severe stomach pain; vomiting of blood or material that looks like coffee grounds)
    
hemolytic anemia^{{03}{14}{15}{17}{31}} (back, leg, or stomach pain; fever; loss of appetite; pale skin; unusual tiredness or weakness)
    
hypertension^{{03}{14}{17}{31}} (high blood pressure)
    
oculogyric crisis^{03}{31} (inability to move eyes)
    
phlebitis^{03}{31} (pain, tenderness, or swelling of foot or leg)
    
priaprism^{03}{31} (prolonged, painful, inappropriate penile erection)
    
seizures (convulsions)


Note: A causal relationship between the use of levodopa or carbidopa and levodopa combination and seizures has not been established. ^{{03} {15} {17} {31}}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Abdominal pain^{03}{31}
    
anorexia^{03}{17}{31} (loss of appetite)
    
dryness of mouth^{03}{17}{31}
    
flatulence^{03} (passing gas)
    
nightmares^{03}{17}

Note:  Nightmares may become less frequent when levodopa is combined with carbidopa because of the reduced levodopa dose requirements and reduced conversion to peripheral dopamine ^{{02} {32}}.


Incidence less frequent
    
Constipation^{03}{17}
    
diarrhea^{03}{17}
    
flushing of skin^{03}{17}
    
headache^{03}{17}
    
hiccups^{03}{31}
    
increased sweating^{03}{31}{48}
    
insomnia^{03}{17} (trouble in sleeping)
    
muscle twitching^{03}{17}
    
unusual tiredness or weakness^{03}{17}

Note: Constipation may become less frequent when levodopa is combined with a peripheral decarboxylase inhibitor. ^{14}




Those not indicating need for medical attention
Incidence less frequent
    
Bitter taste^{31}
    
burning sensation of tongue^{03}{31}
    
darkening in color of urine, saliva, or sweat^{{03}{14}{15}{17}{18}}





Overdose
For information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
    
Blepharospasm^{03} (increased blinking or spasms of eyelids)—possible early sign of overdose^{03}{31}


Treatment of overdose
Since there is no specific antidote for acute overdose with carbidopa and levodopa, treatment is symptomatic and supportive, ^{{03} {14} {15} {17}} with possible utilization of the following



• To decrease absorption—Immediate gastric lavage. ^{{03} {14} {15} {17}}


• Monitoring—Electrocardiographic monitoring for development of arrhythmias ^{{03} {66}}.


• Specific treatment—

• Antiarrhythmic medication, if necessary. ^{{03} {14} {15} {17}}


• Pyridoxine is not effective in reversing the actions of carbidopa and levodopa combination. ^{{14} {17}}


• The value of dialysis in the treatment of overdose is not known. ^{{14} {15} {17} {66}}



• Supportive care—

• Judicious use of intravenous fluids. ^{66}


• Maintenance of airway. ^{66}


• Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Levodopa (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to carbidopa and/or levodopa

Pregnancy—No studies in humans; depressed growth and malformations in animal studies





Breast-feeding—Levodopa is distributed into breast milk; may inhibit lactation





Use in the elderly—Reduced tolerance to effects of levodopa; caution in resuming normal activity, especially in patients with osteoporosis; CNS effects more common with concurrent use of anticholinergic agents





Dental—Possible difficulty in retention of full dentures
Other medications, especially cocaine, haloperidol, hydrocarbon inhalation anesthetics, MAO inhibitors, phenothiazines, selegiline, and thioxanthenes; high-protein foods
Other medical problems, especially severe cardiovascular disease, glaucoma, melanoma (history of or suspected), mental depression, myocardial infarction with residual arrhythmias, peptic ulcer (history of), psychosis, severe pulmonary diseases, renal function impairment, or urinary retention

Proper use of this medication
» Taking with meals or snacks for the first few months until tolerance to gastrointestinal effects develops; later, taking on an empty stomach for maximal absorption

» Compliance with therapy; taking medication only as directed; not stopping medication unless ordered by physician

» Maximum effectiveness of medication may not occur for several weeks or months after therapy is initiated

» Proper dosing
Missed dose: Taking as soon as possible; skipping dose if next scheduled dose is within 2 hours; not doubling doses

» Proper storage

Precautions while using this medication
Caution if any kind of surgery (including dental surgery) or emergency treatment is required

For patients with diabetes—May interfere with urine tests for sugar and ketones

» Caution if drowsiness occurs

» Caution when getting up suddenly from lying or sitting position; dizziness and fainting may occur

» Caution in resuming normal physical activities when condition has improved, especially for geriatric patients


Side/adverse effects
Signs of potential side effects, especially agitation; anxiety; ataxia; bruxism; choreiform and/or dystonic movements; confusion; delusions; dizziness; dysphagia; euphoria; fatigue; feeling faint; hallucinations; increased hand tremor; malaise; nausea or vomiting; peripheral neuropathy; sialorrhea; weakness; blepharospasm; blurred vision; cardiac irregularities; diplopia; hot flashes; mydriasis; neuropsychiatric effects, including paranoid ideation, psychotic episodes, and mental depression with or without suicidal tendencies; orthostatic hypotension; palpitations; skin rash; trismus; unusual weight gain or loss; urinary incontinence; urinary retention; agranulocytosis; duodenal ulcer; edema; gastrointestinal bleeding; hemolytic anemia; hypertension; oculogyric crisis; phlebitis; priaprism; seizures

Occasional darkening of urine, saliva, or sweat may be alarming to patient although medically insignificant


General Dosing Information
Carbidopa and levodopa therapy must be individualized and dosage gradually titrated to the desired therapeutic level in order to minimize adverse effects. ^{{03} {14} {15} {31} {67}} An interval of at least 3 days is recommended between dosage adjustments of carbidopa and levodopa ^{67}. The therapeutic range of carbidopa and levodopa combination is narrower than that of levodopa, owing to its greater milligram potency ^{67}. Therefore, dosage adjustments should be made in small increments and the recommended dosage ranges generally should not be exceeded ^{67}. The treatment goal should be to achieve maximal benefit without inducing dyskinesias ^{67}. The appearance of involuntary movements may be a sign of levodopa toxicity, and may require dose reduction ^{67}.

End-of-dose deterioration ^{{45} {46}} or “wearing off” periods ^{43} usually have a close temporal relationship to the timing of levodopa administration ^{39}. These effects may be alleviated for a time by shortening the dosing interval ^{{41} {42}} and reducing the size of individual doses ^{41}. However, compliance may be poor if the dosage regimen becomes too complex ^{42}. Extended-release formulations of carbidopa and levodopa combination may be useful in the early stages of the wearing-off phenomenon, as they could typically add 60 to 90 minutes to the response duration compared with the immediate-release formulation ^{48}. Since the bioavailability of the extended-release formulation is less than that of the immediate-release form, a dose increase of 20 to 30% may be required ^{48}. Use of the extended-release form in the later stages of Parkinson's disease should be avoided, as it may induce prolonged dopaminergic side effects such as dyskinesia and psychosis ^{48}.

Benefits from initiation of levodopa therapy, although sometimes evident from the first dose, commonly increase over several weeks despite a fixed dosage regimen. Generally it takes 2 weeks for the final effects of a given change in levodopa treatment to “equilibrate” in the body so that the results of a dosage change can be assessed. ^{47}

Postencephalitic ^{{15} {67}} and geriatric ^{64} patients often require and tolerate lower dosage levels than other parkinsonism patients.

Patients who fail to respond to the carbidopa and levodopa combination may have an atypical parkinsonism. ^{48} Many patients with atypical parkinsonism still receive some benefit from small doses of levodopa. ^{48}

Levodopa must be discontinued at least 12 hours ^{66} before the carbidopa and levodopa combination dosage is begun. Levodopa may be discontinued in the evening and the carbidopa and levodopa combination started the following morning ^{67}.

The concurrent administration of carbidopa may permit the dose of levodopa to be reduced by up to 75% with no decrease in therapeutic results. ^{{03} {14} {15} {67}} Use of carbidopa and levodopa combination permits an earlier response to therapy than use of levodopa alone ^{67}, and also decreases the incidence of nausea, vomiting, and cardiac arrhythmias ^{67}. At least 75 to 100 mg of carbidopa per day ^{{05} {40} {67} {68}} is needed to block the peripheral decarboxylation of levodopa ^{{05} {40}}. A lesser amount of carbidopa renders the patient more likely to experience adverse reactions to levodopa, such as nausea and vomiting ^{05}. Rarely, doses of carbidopa as high as 300 mg a day are needed to functionally inhibit peripheral decarboxylase activity ^{48}.

When a patient is switched from the immediate-release form to the extended-release form of carbidopa and levodopa combination, dosage must be titrated carefully, and the patient should be kept on the new regimen for at least 3 to 5 days before further dosage changes are made. ^{44}

The absorption of the extended-release formulation of carbidopa and levodopa is sometimes considered to be unpredictable ^{68}. This is because levodopa absorption takes place over a limited length of the small intestine, and delivery to this region is controlled by the rate of gastric emptying and factors influencing gastric motility; these factors (e.g., too slow or too fast a release rate from the stomach or a rate of transit through the small intestine) can adversely affect the amount of levodopa absorbed from the extended-release dosage form. ^{46}

Other antiparkinsonian medications may be used concomitantly with or preceding carbidopa and levodopa therapy. Gradual dosage reduction of these medications is recommended during initiation of therapy with carbidopa and levodopa, and after optimum dosage is reached, to maintain proper control of the patient's condition. ^{{63} {67}}

When carbidopa and levodopa combination is to be discontinued, dosage should be tapered gradually to prevent the occurrence of a syndrome that resembles the neuroleptic malignant syndrome. Careful patient monitoring after withdrawal of carbidopa and levodopa will allow early diagnosis and treatment of neuroleptic malignant-like syndrome. ^{{10} {14}}

Diet/Nutrition
Carbidopa reduces the adverse effect of pyridoxine on levodopa ^{{05} {14}}. A daily carbidopa dose of 100 mg will eliminate the clinical significance of this interaction ^{05}.

Peripheral decarboxylation of levodopa to dopamine causes gastrointestinal side effects such as nausea and vomiting ^{05}, but concomitant administration with carbidopa will reduce this effect ^{{34} {48} {68}}. Levodopa may be given with meals or snacks for the first few months of therapy until tolerance to these side effects develops ^{05}. Later, levodopa should be given on an empty stomach for maximal absorption ^{05}; administering levodopa on an empty stomach facilitates absorption and reduces competition with dietary proteins ^{48}. Also, standardizing the administration of levodopa with regard to meal times will optimize the rate of gastric emptying ^{44}. Some clinicians consider administering the levodopa dose 1 hour before or after eating food to be a practical approach ^{48}.

High-protein diets should be avoided because protein degradation products compete with levodopa for transport across the intestinal epithelium and blood-brain barrier, resulting in a decreased or erratic response to levodopa ^{03}. Patients experiencing response fluctuations may be more susceptible to the interference that protein-containing meals have on the effectiveness of levodopa ^{46}. Strategies for reducing the competitive effects from dietary proteins include:    • Assuring that the intake of normal amounts of protein be distributed equally throughout the day ^{02}.
   • Introducing the redistribution diet, where protein intake is restricted to the evening meal only ^{48}.
   • Imposing austere restrictions on total daily protein intake (£ 10 grams) for limited times in selected patients ^{46}.
   • Adherence to a recommended dietary allowance of 0.8 gram of protein per kilogram of body weight per day which seems to be a sufficient and safe restriction that does not affect the levodopa dose-response relationship ^{44}.


Bioequivalence information
Because carbidopa and levodopa extended-release tablets are 25 to 30% systemically less bioavailable than Carbidopa and Levodopa Tablets USP (immediate-release), increased daily doses of the extended-release tablets may be required to achieve the same level of symptomatic relief. ^{{17} {18} {19}}

For treatment of adverse effects
Immediate relief of nausea and vomiting may sometimes be obtained by reducing the daily dose, giving smaller individual doses at more frequent intervals, or having patient take each dose with food. High-protein foods should be avoided since they may decrease levodopa's effect (See Drug interactions and/or related problems ). After tolerance to nausea and vomiting develops, carbidopa and levodopa combination should be taken on an empty stomach to maximize absorption and reduce competition with dietary proteins. In some patients, as much as 200 to 300 mg of carbidopa per day may be needed to eliminate levodopa-induced nausea ^{42}.


Oral Dosage Forms

CARBIDOPA AND LEVODOPA TABLETS USP

Usual adult dose
Antidyskinetic


For patients not being converted from levodopa therapy:
Oral, initially, 10 mg of carbidopa and 100 mg of levodopa three or four times a day or 25 mg of carbidopa and 100 mg of levodopa three times a day, the dosage per day being increased gradually at one- or two-day intervals as needed and tolerated. ^{{01} {03} {14} {23} {24}}


For patients being converted from levodopa therapy (levodopa must be discontinued for at least twelve hours prior to conversion to carbidopa and levodopa therapy) ^{{03} {67}}—
Patients who require less than 1.5 grams of levodopa per day—Oral, 10 mg of carbidopa and 100 mg of levodopa or 25 mg of carbidopa and 100 mg of levodopa three or four times a day initially, the dosage per day being increased gradually at one- or two-day intervals as needed and tolerated. ^{{03} {14}}

Patients who require more than 1.5 grams of levodopa per day—Oral, 25 mg of carbidopa and 250 mg of levodopa three or four times a day initially, the dosage per day being increased gradually at one- or two-day intervals as needed and tolerated. ^{{03} {14}}



Note: Postencephalitic patients may be more sensitive to the effects of the usual adult dose. ^{{15} {67}}
For patients being converted from levodopa therapy, the initial dose of carbidopa and levodopa per day should provide approximately 20 ^{67} to 25% ^{{03} {14} {23} {24}} of the total dosage of levodopa per day previously required.



Usual adult prescribing limits
200 mg of carbidopa and 2 grams of levodopa in combination daily. ^{{03} {14} {67}}

Note: Additional levodopa may be administered alone if it is required and tolerated.


Usual pediatric dose
Children up to 18 years of age—Safety and efficacy have not been established. ^{{03} {14} {15} {23} {24}}

Usual geriatric dose
See Usual adult dose .

Note: Geriatric patients may be more sensitive to the effects of the usual adult dose. ^{64}


Strength(s) usually available
U.S.—


10 mg of carbidopa and 100 mg of levodopa (Rx) [Sinemet (scored)][Generic]


25 mg of carbidopa and 100 mg of levodopa (Rx) [Atamet (scored)] [Sinemet (scored)][Generic]


25 mg of carbidopa and 250 mg of levodopa (Rx) [Atamet (scored)] [Sinemet (scored)][Generic]

Canada—


10 mg of carbidopa and 100 mg of levodopa (Rx) [Apo-Levocarb (scored)] [Nu-Levocarb] [Sinemet][Generic]


25 mg of carbidopa and 100 mg of levodopa (Rx) [Apo-Levocarb (scored)] [Nu-Levocarb] [Sinemet (scored)][Generic]


25 mg of carbidopa and 250 mg of levodopa (Rx) [Apo-Levocarb (scored)] [Nu-Levocarb] [Sinemet (scored)][Generic]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container.

Preparation of dosage form:
A liquid formulation of levodopa may be prepared extemporaneously for use in dosage titration in patients who are extremely sensitive to small changes in dose ^{{44} {48} {69}}. One formula uses ten crushed tablets of carbidopa 25 mg and levodopa 100 mg, and 1 gram of ascorbate, dissolved in one liter of water ^{69}. A fresh solution must be prepared daily. ^{{48} {69}}

Auxiliary labeling:
   • May darken urine, saliva, or sweat.


CARBIDOPA AND LEVODOPA EXTENDED-RELEASE TABLETS

Usual adult dose
Antidyskinetic


Initial dosage:


For patients not receiving levodopa therapy—


Mild to moderate disease—
Oral, initially, 50 mg of carbidopa and 200 mg of levodopa twice a day, at intervals of at least 6 hours. ^{{17} {66} {67}}




For patients currently treated with conventional carbidopa-levodopa preparations—
Dosage with the extended-release tablets should be substituted at an amount that provides approximately 10% more levodopa per day, although this may need to be increased to 30% more levodopa per day based on clinical response. ^{{17} {22} {66} {67}} The interval between doses of the extended-release tablets should be 4 to 8 hours during the waking day ^{{17} {22} {66} {67}}, although a few patients may require more frequent dosing ^{{20} {21}}.

Guidelines for initial conversion from Carbidopa and Levodopa Tablets USP (immediate-release) to carbidopa and levodopa extended-release tablets are as follows: ^{{17} {22} {66} {67}}

Total daily dose of levodopa (mg)	Suggested dosage regimen of carbidopa and levodopa extended-release tablets (based on levodopa content)
300–400	200 mg twice a day
500–600	300 mg twice a day or 200 mg three times a day
700–800	A total of 800 mg in 3 or more divided doses (e.g., 300 mg a.m., 300 mg early p.m., and 200 mg later p.m.)
900–1000	A total of 1000 mg in 3 or more divided doses (e.g., 400 mg a.m., 400 mg early p.m., and 200 mg later p.m.)

For patients currently treated with levodopa without a decarboxylase inhibitor—
Levodopa must be discontinued at least twelve hours before initiating therapy with carbidopa and levodopa extended-release tablets ^{{66} {67}}. The extended-release tablets should be substituted at a dosage of approximately 25% of the previous levodopa dosage. ^{{17} {22} {66} {67}}

Mild to moderate disease: Oral, initially, 50 mg of carbidopa and 200 mg of levodopa twice a day. ^{{17} {22} {66} {67}}




Maintenance dosing:
Depending upon therapeutic response, doses and dosing intervals may be increased or decreased following initiation of therapy ^{{17} {22} {66} {67}}. An interval of at least 3 days between dosage adjustments is recommended. Most patients have been adequately treated with 400 to 1600 mg of levodopa per day, administered as divided doses at intervals ranging from 4 to 8 hours. ^{{17} {22} {66} {67}} A few patients may require higher doses (12 or more tablets per day) and shorter intervals (less than 4 hours) ^{{17} {20} {21} {66} {67}}, but this is usually not recommended ^{66}.

When the extended-release tablets are given at less than 4-hour intervals, and/or if the divided doses are not equal, the smaller doses should be given at the end of the day. ^{{17} {22} {66} {67}}

Carbidopa and Levodopa Tablets USP (immediate-release) may be added to the dosage regimen in selected patients with advanced disease who need additional levodopa for a brief time during daytime hours. Usually one-half or one tablet of carbidopa 10 mg and levodopa 100 mg or carbidopa 25 mg and levodopa 100 mg is added. ^{{17} {22} {66}}


Note: Cutting or breaking an extended-release form of carbidopa and levodopa combination will cause a more rapid onset of action ^{{05} {44}}.



Usual adult prescribing limits
The equivalent of 2400 mg of levodopa ^{66}.

Usual pediatric dose
Children up to 18 years of age—Safety and efficacy have not been established. ^{{17} {22} {66} {67}}

Usual geriatric dose
See Usual adult dose .

Strength(s) usually available
U.S.—


25 mg of carbidopa and 100 mg of levodopa (Rx) [Sinemet CR 25-100]


50 mg of carbidopa and 200 mg of levodopa (Rx) [Sinemet CR 50-200 (scored)]

Canada—


25 mg of carbidopa and 100 mg of levodopa (Rx) [Sinemet CR 25-100]


50 mg of carbidopa and 200 mg of levodopa (Rx) [Sinemet CR 50-200 (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container.

Auxiliary labeling:
   • May darken urine, saliva, or sweat. ^{{17} {18}}
   • Do not chew or crush tablets. ^{17}

Revised: 06/15/1999

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62. Chlorpromazine hydrochloride oral concentrate package insert (Chlorpromazine Hydrochloride Intensol, Roxane—US), Rev 5/94, Rec 8/98.
    

63. Larodopa product monograph. In: CPS Compendium of pharmaceuticals and specialties. 24th ed. 1989. Ottawa: Canadian Pharmaceutical Association; 1989. p. 535-6.
    

64. Rowland LP, editor. Merritt's textbook of neurology. 9th ed. Baltimore: Williams and Wilkins; 1995. p. 713-30.
    

65. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 131, 416.
    

66. Sinemet CR product information (DuPont—US; Rev 11/97). In: PDR Physicians' desk reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Co Inc; 1999. p. 940-3.
    

67. Sinemet and Sinemet CR product information (DuPont Pharma—Canada). In: CPS Compendium of pharmaceuticals and specialties. 34th ed. 1999. Ottawa: Canadian Pharmacists Association; 1999. p. 1651-4.
    

68. Gilman AG, Hardman JG, Limbird LE, et al., editors. Goodman and Gilman's: the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1996. p. 506-13, 1562, 1754.
    

69. Pappert EJ, Goetz CG, Niederman F, et al. Liquid levodopa/carbidopa produces significant improvement in motor function without dyskinesia exacerbation. Neurology 1996; 47: 1493-5.
    

70. Reynolds JEF, editor. Martindale: the extrapharmacopeia. 31st ed. London: The Pharmaceutical Press; 1996. p. 1159.
    

71. Panel comment, 5/99.
    

72. Manufacturer comment, 6/9/99.
    

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