Get advice for managing Multiple Sclerosis: Watch the video.

Levodopa (Systemic)


VA CLASSIFICATION
Primary: CN500

Commonly used brand name(s): Larodopa.

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



Category:


Antidyskinetic—

Indications

General considerations
Although levodopa is the most effective {09} {11} {41} {44} {46} {48} antiparkinsonian medication and remains a mainstay of therapy for symptomatic treatment of Parkinson's disease, complications to long-term levodopa therapy appear commonly {48}. The majority of patients receiving chronic levodopa therapy experience serious adverse effects {48}, including motor fluctuations {03} {40} {47}, dyskinesias {11} {40} {43} {46}, and neuropsychiatric effects {03} {11} {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 duration and dose of levodopa therapy {03} {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 response to levodopa therapy includes a short-duration response, in which improvement in motor disability lasts for 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 {48} and the optimal use of other antiparkinsonian medications throughout the disease process {48}.

Accepted

Parkinsonism (treatment)—Levodopa is indicated to alleviate symptoms and allow more normal body movements with improved muscle control in the treatment of idiopathic Parkinson's disease, postencephalitic parkinsonism, or symptomatic parkinsonism that may follow injury to the nervous system by carbon monoxide intoxication or manganese intoxication. It is also indicated in parkinsonism associated with cerebral arteriosclerosis. {01} {15} {31}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Levorotatory isomer of dihydroxyphenylalanine (L-DOPA), {31} which is the metabolic precursor of dopamine. {09} {31}
Molecular weight—
    197.19 {10} {31}

Solubility
    The solubility of levodopa in water is 66 mg in 40 mL. {50}


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%, {03} {43} 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. {09} This newly formed dopamine then is available to stimulate dopaminergic receptors, {09} thus compensating for the depleted supply of endogenous dopamine. {41}.


Other actions/effects:

Levodopa's metabolite, dopamine, stimulates beta-adrenergic cardiac receptors, {20} 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:

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. {03} {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} Absorption may be enhanced by concomitant administration of a peripheral decarboxylase inhibitor, such as carbidopa {03} {09} {46} or a catechol- O-methyltransferase (COMT) inhibitor, such as tolcapone. {59} {60} With long-term administration, levodopa absorption appears to become more efficient and complete. {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. {03} {09} {34} {42} {46} Intense exercise and other activity that diverts blood flow from the mesenteric circulation also may delay levodopa absorption. {03} {34}

Liquid formulations of levodopa have been extemporaneously compounded in an attempt to minimize absorption problems. The liquid preparation is absorbed slightly faster than levodopa tablets, {44} and antiparkinsonian effects may take effect more quickly than with levodopa 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 is widely distributed to most body tissues, but not to the central nervous system (CNS) because of extensive metabolism in the periphery. {20} 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}

Biotransformation:

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. {03} This converted portion of dopamine cannot cross the blood-brain barrier to exert its effects on the brain. {03} Dopamine remaining in the periphery is believed responsible for many levodopa adverse effects, including cardiac arrhythmias and gastrointestinal upset. {09} {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. {03} 3-OMD has a long half-life {03} and competes with levodopa for the same transport mechanism across the blood-brain barrier. {03} {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. {09} {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. {09} The effects 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. {03}

Half-life:

Levodopa: 0.75 to 1.5 hours. {11} {34} {44} {46}

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

Onset of action:

Significant improvement may occur in 2 to 3 weeks. Some patients may require up to 6 months of continuous levodopa therapy to obtain optimal therapeutic benefit. {01} {31}

Time to peak concentration:

0.5 to 2 hours. {03} {09} {11} {46}

Elimination:
    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. {09} Some of the eliminated metabolites may color the urine red; {20} oxidation that occurs when urine is exposed to air will cause it to darken. {20} {50}
    Fecal, 2% of dose. {34}


Precautions to Consider

Pregnancy/Reproduction

Pregnancy—
Adequate and well-controlled studies in humans have not been done. {15} {31} 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. {15} {31}

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. {15} {31}

Also, levodopa may inhibit lactation. {59} {61}

Pediatrics

Appropriate studies on the relationship of age to the effects of levodopa have not been performed in children up to 12 years of age. {01} {15} Safety and efficacy have not been established. {15} {31}


Geriatrics


Smaller doses may be required in geriatric patients since they may have a reduced tolerance to the effects of levodopa {11}. Similarly, patients with Alzheimer's disease are more sensitive to usual doses of levodopa {11}.

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. {16}

Central nervous system (CNS) effects, such as anxiety, confusion, or nervousness, occur more frequently in geriatric patients receiving anticholinergic antiparkinsonian medications in addition to levodopa. {03}

Geriatric patients, especially those with pre-existing coronary disease, are more susceptible to levodopa's cardiac effects, such as arrhythmias. These cardiac effects are minimized or eliminated when levodopa is combined with carbidopa. {13}


Dental

Involuntary movements of jaws may result in poor retention of full dentures; dosage reduction may be required. {13}

Surgical

If general anesthesia is required and the administration of levodopa is interrupted temporarily, the patient should be observed for symptoms of a neuroleptic malignant-like syndrome {32}.

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{24}{46} or
Benztropine{21} or
Procyclidine{22} or
Trihexyphenidyl{23}    (concurrent use may result in increased efficacy of levodopa; however, concurrent use is not recommended if there is a history of psychosis {03})


» Anesthetics, hydrocarbon inhalation{14}    (concurrent administration may result in cardiac arrhythmias because of increased endogenous dopamine concentration; levodopa should be discontinued 6 to 8 hours before administration of anesthetics, especially halothane)


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


Bromocriptine{03}    (may produce additive effects, allowing reduction in levodopa dosage)


» Cocaine{08}{09}    (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)


Droperidol{30} or
» Haloperidol{27}{28} or
Loxapine{28} or
Molindone or
Papaverine{37} or
» Phenothiazines{25}{26} or
» Thioxanthenes{27}    (agents that block the dopamine receptors in the brain, such as traditional antipyschotic agents, may antagonize the effects of levodopa)


Foods, especially high-protein{46}{48}    (concurrent or previous ingestion of food may decrease the absorption of levodopa from the gastrointestinal tract, consequently delaying its effect; 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; alternatively, some clinicians recommend a redistribution diet {48} for some 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” periods (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 dosage-response relationship {44})


Hypotension-producing medications, other{15}{16}{31} (see Appendix II )    (concurrent use with levodopa may result in an increased hypotensive effect)


Iron salts{32}{37} or
Vitamin/mineral preparations containing iron salts{32}    (iron salts may chelate with levodopa, resulting in decreased absorption and lower serum levels of levodopa, and thus reduce its efficacy)


Methyldopa{16}    (concurrent use with levodopa may alter the antiparkinsonian effects of levodopa and may also produce additive toxic CNS effects such as psychosis)


Metoclopramide{19}{33}{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{09}{15}{16}{31} , including furazolidone, procarbazine, and selegiline    (concurrent use with levodopa is not recommended as the combination may result in a hypertensive crisis; it is recommended that MAO inhibitors be discontinued for at least 2 weeks prior to initiation of levodopa therapy)


» Pyridoxine (vitamin B 6){09}{15}{16}{31}{34}{37}{46} or
» Vitamin preparations containing pyridoxine{31}{46}    (pyridoxine is a cofactor for dopa-decarboxylase, the enzyme responsible for the decarboxylation of levodopa; peripheral metabolism of levodopa is enhanced in the presence of pyridoxine, which results in decreased concentrations of levodopa available to compete for transport across the blood-brain barrier; concurrent use with levodopa is not recommended)


Rauwolfia alkaloids{16}    (rauwolfia alkaloids cause dopamine depletion in the brain, decreasing the effects of levodopa; dosage adjustments of either or both medications may be necessary)


» Selegiline{17}{18} or
Tolcapone{59}{60}    (although sometimes used in conjunction with levodopa or 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 or tolcapone)


Sympathomimetic agents{09}{16}    (concurrent use with levodopa may increase the possibility of cardiac arrhythmias, especially in patients with pre-existing conduction disturbances; dosage reduction of the sympathomimetic agent is recommended; the administration of carbidopa with levodopa reduces the tendency of sympathomimetic agents to cause dopamine-induced cardiac arrhythmias)



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, urine{52} or
Metanephrines{52}    (test results are unreliable)


Coombs' (antiglobulin) test{15}{31}    (occasionally becomes positive after long-term levodopa therapy)


Glucose, urine    (tests using copper reduction methods may cause false-positive results; tests using glucose oxidase methods may cause false-negative results {54} {55} {56})


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


Ketones, urine    (tests using dipstick methods may cause false-positive results {52})


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 {15} {31})

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]){15}{31} and
Alkaline phosphatase{15}{31} and
Aspartate aminotransferase (AST [SGOT]){15}{31} and
Bilirubin{15}{31} and
Lactate dehydrogenase (LDH){15}{31} and
Protein-bound iodine (PBI){15}{31}    (serum concentrations may be increased)


Blood urea nitrogen (BUN){15}{31}    (concentrations may be increased)


Hematocrit{31} and
Hemoglobin{31} and
White blood cell counts{31}    (values may be decreased)


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{15}{16}{31}    (respiratory effects of levodopa may aggravate condition)


» Cardiovascular disease, severe{15}{16}{31}    (increased risk of cardiac arrhythmias)


Convulsive disorders, history of{16}    (use of levodopa may precipitate seizures)


Diabetes mellitus{16}    (use of levodopa may adversely affect control of glucose in blood)


Endocrine diseases{15}{16}{31}    (use of levodopa may adversely affect hypothalamus or pituitary function)


» Glaucoma, angle-closure, or predisposition to{15}{31}    (mydriatic effect resulting in increased intraocular pressure may precipitate an acute attack of angle-closure glaucoma)


Glaucoma, open-angle, chronic{15}{31}    (mydriatic effect may cause a slight increase in intraocular pressure; glaucoma therapy may need to be adjusted {01})


Hepatic function impairment{15}{16}{31}
» Melanoma, history of or suspected{15}    (use of levodopa may activate a malignant melanoma {32})


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


» Myocardial infarction, history of, with residual atrial, nodal, or ventricular arrhythmias{15}{16}{31}    (use of levodopa may precipitate or aggravate condition)


» Peptic ulcer, history of{15}{31}    (increased risk of upper gastrointestinal hemorrhage)


» Renal function impairment{15} {16}{31}    (use of levodopa may lead to urinary retention)


Sensitivity to levodopa{15}{31}

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{15}{16}{31} and
Hemoglobin determinations{15}{16}{31} and
Hepatic function determinations{15}{16}{31} and
Ophthalmologic examinations for glaucoma and monitoring of intraocular pressure in patients with open-angle glaucoma{31} and
Renal function determinations{15}{16}{31}    (recommended at periodic intervals for patients on long-term levodopa therapy)


Cardiovascular monitoring{15}{16}{31}     (recommended at periodic intervals for patients on long-term therapy)




Side/Adverse Effects

Note: A syndrome resembling neuroleptic malignant syndrome, which includes intermittent dystonia alternating with substantial agitation, hyperthermia, and mental changes, has been reported after the abrupt {12} {13} discontinuation of levodopa therapy. {05}
Although levodopa is the most effective antiparkinsonian medication to date {09} {11} {41} {44} {46} {48}, complications to long-term levodopa therapy appear commonly and include motor fluctutations, dyskinesias, and neuropsychiatric problems {11} {39} {48}. Fifty percent or more of patients who have received levodopa for 5 years experience motor fluctuations {03} {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 dyskinesias generally spread to a wider distribution of, and increase the degree of, abnormal movements {03}. 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 rigidity, 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 {11}.
Neuropsychiatric effects {03} {11} {48} 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 {11} {42}. These mental and behavioral changes include confusion, agitation, hallucinations, irritability, panic, paranoid delusions, mental depression, dementia, mania, and psychosis {03} {11} {47} {48}; 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 {31} {42}
    
anxiety {15} {16} {31}
    
ataxia {31} (clumsiness or unsteadiness)
    
bruxism {31} (clenching or grinding of teeth)
    
choreiform and/or dystonic movements {15} {16} {31} {42} (unusual and uncontrolled movements of the body, including the face, tongue, arms, hands, head, and upper body)
    
confusion {15} {16} {31}
    
delusions {31} (abnormal thinking: holding false beliefs that cannot be changed by fact)
    
dizziness {31}
    
dysphagia {31} {48} (difficulty swallowing)—may occur in up to 40% of patients {48}
    
euphoria {31} (false sense of well-being)
    
fatigue {31} (unusual tiredness or weakness)
    
feeling faint {31}
    
hallucinations {31} {42} (seeing, hearing, or feeling things that are not there)
    
increased hand tremor {31}
    
malaise {31} (general feeling of discomfort or illness)
    
nausea or vomiting {15} {16} {31}
    
numbness {31}
    
sialorrhea {31} (excessive watering of mouth)
    
weakness {31}

Note: Nausea or vomiting occurs in nearly 80% of patients in early therapy {03}; after several weeks, many patients develop tolerance to these effects {42}.
Hallucinations are usually visual {42} {48} and, at early stages, non-threatening {42}.


Incidence less frequent
    
Blepharospasm {15} {16} {31} (increased blinking or spasms of eyelids)
    
blurred vision
    
cardiac irregularities {15} {16} {31} (fast, irregular, or pounding heart beat)
    
diplopia {31} (double vision)
    
hot flashes {31}
    
mydriasis {31} (dilated pupils)
    
neuropsychiatric effects, including paranoid ideation, psychotic episodes, and mental depression with or without suicidal tendencies {15} {16} {31} {48} (mood or mental changes)
    
orthostatic hypotension {31} {48} (dizziness or lightheadedness when getting up from a lying or sitting position)
    
palpitations {31} (fast or pounding heart beat)
    
skin rash {31}
    
trismus {31} (difficulty opening mouth)
    
unusual weight gain or loss {31}
    
urinary incontinence {31} {48} (loss of bladder control)
    
urinary retention {15} {16} {31} (difficult urination)

Note: Orthostatic hypotension occurs in about 30% of patients at the initiation of levodopa therapy {20}; tolerance may develop, and the severity of hypotension may decrease. {03}
Cardiac arrhythmias {03}, palpitations {03}, and urinary retention {03} may become less frequent when levodopa is administered concomitantly with a peripheral decarboxylase inhibitor, such as carbidopa.


Incidence rare
    
Agranulocytosis {31} (chills; fever; sore throat; unusual tiredness or weakness)
    
duodenal ulcer {15} {16} {31} (stomach pain)
    
edema {31} (swelling of face; swelling of feet or lower legs; unusual weight gain)
    
gastrointestinal bleeding {31} ( bloody or black, tarry stools; severe stomach pain; vomiting of blood or material that looks like coffee grounds)
    
hemolytic anemia {15} {31} (back, leg, or stomach pain; fever; loss of appetite; pale skin; unusual tiredness or weakness)
    
hypertension {15} {16} {31} (high blood pressure)
    
oculogyric crisis {31} (inability to move eyes)
    
phlebitis {31} (pain, tenderness, or swelling of foot or leg )
    
priaprism {31} (prolonged, painful, inappropriate penile erection)
    
seizures {31}

Note: A causal relationship between levodopa therapy and seizures has not been established. {15} {31}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Abdominal pain {31}
    
anorexia {15} {16} {31} (loss of appetite){03}{15}{16}{31}
    
dryness of mouth {15} {16} {31}
    
flatulence (passing gas)
    
nightmares {15} {16}

Note:  Nightmares may become less frequent when levodopa is combined with carbidopa because of the reduced dose requirements and unavailability of peripheral dopamine {13} {14}.


Incidence less frequent
    
Constipation {15} {16} {48}
    
diarrhea {15} {16} {31}
    
flushing of skin {15} {16} {31}
    
headache {15} {16} {31}
    
hiccups {31}
    
increased sweating {31} {48}
    
insomnia {15}{16}{31}(trouble in sleeping)
    
muscle twitching {15} {16} {31}
    
unusual tiredness or weakness {15} {16} {31}

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 {31}
    
darkening in color of urine, saliva, or sweat {15} {16} {31}





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
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)–not necessarily inclusive:
    
Blepharospasm (increased blinking or spasms of eyelids)—possible early sign of overdose{31}


Treatment of overdose
Since there is no specific antidote for acute overdose with levodopa, treatment is symptomatic and supportive {15} {16}, with possible utilization of the following:



• To decrease absorption—Immediate gastric lavage. {15} {16}The value of dialysis in the treatment of overdose is not known. {15} {16}


• Monitoring—Electrocardiographic monitoring for development of arrhythmias. {62}


• Specific treatment—

• Antiarrhythmic medication, if necessary. {15} {16}


• Pyridoxine in oral doses of 10 to 25 mg has been reported to reverse toxic and therapeutic effects of levodopa; however, in the treatment of acute overdosage, its usefulness has not been established. {15} {16}



• Supportive care—

• Judicious use of intravenous fluids. {62}


• Maintenance of airway. {62}


• 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 levodopa

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





Breast-feeding—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





Dental—Possible difficulty in retention of full dentures
Other medications, especially cocaine, haloperidol, hydrocarbon inhalation anesthetics, MAO inhibitors, phenothiazines, pyridoxine and vitamin preparations containing pyridoxine, 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

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

» Avoiding foods or vitamin products containing pyridoxine (vitamin B 6); diminished levodopa effect when used with pyridoxine

» 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; numbness; 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
Levodopa therapy must be individualized and the dosage gradually titrated to the desired therapeutic level in order to reduce the high incidence of adverse reactions. {15} {16} {31}

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}.

Although sometimes evident from the first dose, the benefit from initiation of levodopa therapy commonly increases over several weeks despite a fixed dosage regimen. In general, 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 and geriatric patients {11} often require and tolerate lower dosage levels than other parkinsonism patients {13}.

The concurrent administration of a peripheral decarboxylase inhibitor such as carbidopa may permit the dose of levodopa to be reduced by up to 75% and yet achieve equal therapeutic results {32}. Carbidopa also reduces the adverse effect of pyridoxine on levodopa {32}. Similarly, concomitant administration of a COMT inhibitor such as tolcapone also may permit the dose of levodopa to be reduced. {59} {61}

Other antiparkinsonian medications may be used concomitantly with or preceding levodopa therapy. Gradual dosage reduction of these medications is recommended during initiation of therapy with levodopa and after optimum dosage is reached to maintain proper control of the patient's condition. {16}

When levodopa is to be discontinued, dosage should be tapered gradually to prevent the occurrence of a syndrome that resembles the neuroleptic malignant syndrome {09} {11}, with rhabdonecrosis, myoglobinuria, and renal failure {38}. Careful patient monitoring after withdrawal of levodopa will allow early diagnosis and treatment of neuroleptic malignant-like syndrome. {05} {13}

Diet/Nutrition
Peripheral decarboxylation of levodopa to dopamine causes gastrointestinal side effects (such as nausea and vomiting) in up to 80% of patients in early therapy. {03} Levodopa may be given with meals or snacks for the first few months of therapy until tolerance to these side effects develops {03}. Later, levodopa should be given on an empty stomach for maximal absorption {03}; 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 the blood-brain barrier, resulting in a decreased or erratic response to levodopa. 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 {13}.


• 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}.


In addition, pyridoxine (vitamin B 6) reverses the effects of levodopa {31} {46}. Vitamin products containing pyridoxine should be avoided; intake of foods containing large amounts of pyridoxine (such as bananas, egg yolks, lima beans, meats, peanuts, and whole grain cereals {49}) may need to be limited.

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, giving smaller doses concurrently with a peripheral decarboxylase inhibitor such as carbidopa, or having patient take food shortly after each dose; {16} however, high-protein foods should be avoided since they may decrease levodopa's effect by competing for transport across the blood-brain barrier (see Absorption; Drug interactions and/or related problems ).

Orthostatic hypotension may be alleviated by the use of nonpharmacologic measures such as elastic hosiery {03} {42}, and an increase in sodium {03} {42} {48} and fluid {42} intake. Some patients may require pharmacologic treatment with agents such as fludrocortisone {03} {48} or an alpha-adrenergic agonist. {42} {48} However, concomitant use of a peripheral decarboxylase inhibitor, such as carbidopa, reduces the incidence of this side effect {13}.

Although drug holidays from levodopa therapy have been used to prevent some of the complications of long-term therapy and to enhance the efficacy of levodopa when therapy is reinstated {02}, such holidays are no longer considered justifiable {39} {41} {47}, as they may be associated with significant morbidity and life-threatening symptoms such as the neuroleptic malignant syndrome. {39}


Oral Dosage Forms

LEVODOPA TABLETS USP

Usual adult and adolescent dose
Antidyskinetic
Oral, initially 250 mg two to four times a day; the daily dosage may be increased by an additional 100 to 750 mg at three- to seven-day intervals as tolerated, until the desired response is obtained. {15} {31}


Note: Postencephalitic patients may be more sensitive to the effects of the usual adult dose. {13}


Usual adult prescribing limits
8 grams daily. {15} {31}

Usual pediatric dose
Children up to 12 years of age: Safety and efficacy have not been established. {15}

Children 12 years of age and over: See Usual adult and adolescent dose.

Usual geriatric dose
See Usual adult and adolescent dose .

Note: Geriatric patients and patients with Alzheimer's disease may be more sensitive to the effects of the usual adult dose. {11}


Strength(s) usually available
U.S.—


100 mg (Rx) [Larodopa]


250 mg (Rx) [Larodopa]


500 mg (Rx) [Larodopa]

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, 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 the dose of levodopa {48}. (See Carbidopa and Levodopa monograph. )

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



Revised: 06/15/1999



References
  1. Larodopa package insert (Roche—US), Rev 1/86, Rec 12/87.
  1. Mayeux R, Stern Y, Mulvey K, et al. Reappraisal of temporary levodopa withdrawal (“Drug holiday”) in Parkinson's disease. N Eng J Med 1985 Sep 19; 313(12): 724-8.
  1. Goetz CG. Parkinson's Disease and other parkinsonian syndromes. In: Klawans HL, Goetz CG, and Tanner CM, editors. Textbook of clinical neuropharmacology and therapeutics. 2nd ed. New York: Raven Press; 1992. p. 91-116.
  1. Friedman JH, Feinberg SS, Feldman RG. A neuroleptic malignantlike syndrome due to levodopa therapy withdrawal. JAMA 1985; 254: 2792-5.
  1. Kosten TR, Kleber HD. Sudden death in cocaine abusers: relation to neuroleptic malignant syndrome [letter]. Lancet 1987 May 23: 1198.
  1. Levenson JL. Neuroleptic malignant syndrome. Am J Psychiatry 1985 Oct; 142(10): 1137-45.
  1. Harpe C, Stoudemire A. Aetiology and treatment of neuroleptic malignant syndrome. Medical Toxicol 1987; 2: 166-76.
  1. Gay GR. Clinical management of acute and chronic cocaine poisoning. Ann Emerg Med 1982 Oct; 11(10): 562-72
  1. 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.
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 416.
  1. Rowland LP, editor. Merritt's textbook of neurology. 9th ed. Baltimore: Williams and Wilkins; 1995. p. 713-30.
  1. Gibb WRG, Griffith DNW. Levodopa withdrawal syndrome identical to neuroleptic malignant syndrome. Postgrad Med J 1986 Jan; 62: 59-60.
  1. Panel comments 3/88.
  1. Dukes MNG, editor. Meyler's side effects of drugs: an encyclopedia of adverse reactions and interactions. 9th ed. Amsterdam: Elsevier; 1980. p. 165-73.
  1. Larodopa (Roche—US) product monograph. In: PDR Physicians Desk Reference. 44th ed. 1990. Oradell, NJ: Medical Economics Co; 1990. pp. 1796-7.
  1. Larodopa (Roche—Canada) product monograph. In: CPS Compendium of pharmaceuticals and specialties. 24th ed. 1989. Ottawa: Canadian Pharmaceutical Association; 1989. p. 535-6.
  1. LeWitt PA. New perspectives in the treatment of Parkinson's disease. Clin Neuropharmacol 1986; 9 Suppl 1: S37-S54.
  1. Rinne UK. R-(—)-Deprenyl as an adjuvant to levodopa in the treatment of Parkinson's disease. J Neural Transm 1987; 25 Suppl: 149-55.
  1. Sirota R, Kimmel P, Trichtinger M, et al. Metoclopramide-induced parkinsonism in hemodialysis patients. Arch Int Med 1986; 146: 2070-1.
  1. Delgado, JN, Isaacson EI, Cosgrove FP. Therapy of Parkinson's disease. PharmIndex 1983 (Feb): 11-15.
  1. Benztropine Mesylate package insert (Cogentin, MSD—US), Rev 5/89, Rec 9/89.
  1. Procyclidine Hydrochloride package insert (Kemadrin, Wellcome—US), Rev 6/85, Rec 11/88.
  1. Trihexyphenidyl Hydrochloride package insert (Artane, Lederle—US), Rev 4/87, Rec 12/88.
  1. Amantadine package insert, (Symmetrel, Dupont—US), Rev 1/88, Rec 10/88.
  1. Perphenazine injection package insert and perphenazine package labels (Trilafon, Schering—Canada), Rec 12/95.
  1. Chlorpromazine hydrochloride oral concentrate package insert (Chlorpromazine Hydrochloride Intensol, Roxane—US), Rev 5/94, Rec 8/98.
  1. Watsky EJ, Salzman C. Psychotropic drug interactions. Hosp Community Psychiatry 1991 Mar; 42(3): 247-56.
  1. Shinn AF, Shrewsbury RP. EDI, Evaluation of drug interactions. 3rd ed. St Louis: Mosby; l985.
  1. Hansten PD, Horn JR. Drug interactions. 5th ed. Philadelphia: Lea & Febiger; 1985.
  1. Droperidol product monograph (Inapsine, Janssen Pharmaceutica—Canada), Rev 10/95, Rec 9/97.
  1. Larodopa package insert (Roche—US), Rev 8/97.
  1. Sinemet package insert (DuPont—US), Rev 6/96.
  1. Metoclopramide package insert (Reglan, A. H. Robins—US), Rev 2/94, Rec 5/10/96.
  1. Nutt JG, Fellman JH. Pharmacokinetics of levodopa. Clin Neuropharmacol 1984; 7(1): 35-9.
  1. Mena MA, Muradas V, Bezan E, et al. Pharmacokinetics of L-DOPA in patients with Parkinson's disease. Adv Neurol 1986; 45: 481-6.
  1. Harder S, Baas H, Rietbrock S. Concentration-Effect relationship of levodopa in patients with Parkinson's disease. Clin Pharmacokinet 1995; 29(4): 243-56.
  1. Tatro DS, editor. Drug interaction facts. St. Louis: Facts and Comparisons; 1998. pp. 644-56.
  1. Rakel RE, editor. Conn's current therapy 1999. Philadelphia: W.B. Saunders Company; 1999. pp. 955-9.
  1. Lang AE, Lozano AM. Parkinson's disease. Second of two parts. N Engl J Med 1998 Oct; 339(16): 1130-43.
  1. Juncos, JL. Levodopa: pharmacology, pharmacokinetics, and pharmacodynamics. Neurol Clin 1992 May; 10(2): 487-509.
  1. Speight TM, Holford NHG, editors. Avery's drug treatment. 4th ed. Auckland: ADIS International Limited; 1997. p. 1372-8.
  1. Koller WC, Rueda MG. Mechanism of action of dopaminergic agents in Parkinson's disease. Neurology 1998 Jun; 50 Suppl 6: S11-S14.
  1. Chase TN, Oh JD, Blanchet PJ. Neostriatal mechanisms in Parkinson's disease. Neurology 1998 Aug; 51 Suppl 2: S30-S35.
  1. Contin M, Riva R, Albani F, et al. Pharmacokinetic optimisation in the treatment of Parkinson's disease. Clin Pharmacokinet 1996 Jun; 30(6): 463-81.
  1. Chase TN. Levodopa therapy: consequences of the nonphysiologic replacement of dopamine. Neurology 1998 May; 50 Suppl 5: S17-S25.
  1. Cedarbaum JM. Clinical pharmacokinetics of anti-Parkinsonian drugs. Clin Pharmacokinet 1987; 13: 141-78.
  1. Quinn NP. Classification of fluctuations in patients with Parkinson's disease. Neurology 1998 Aug; 51 Suppl 2: S25-S29.
  1. Olanow CW, Koller WC, editors. An algorithm (decision tree) for the management of Parkinson's disease: treatment guidelines. Neurology 1998 Mar; 50 Suppl 3: S1-S57.
  1. Paige DM, editor. Manual of clinical nutrition. 1st ed. Pleasantville, NJ: Nutrition Publications, Inc., 1983; 33: 20–2.
  1. Budavari S, editor. The Merck index: an encyclopedia of chemicals, drugs and biologicals. 12th ed. Rahway, NJ: Merck Research Laboratories; 1996. p. 5490-1.
  1. Relefact TRH package insert (Hoechst-Roussel—US), Rev 6/86.
  1. Jacobs DS, Demott WR, Grady HJ, et al. Laboratory test handbook. 4th ed. Hudson (Cleveland): Lexi-Comp Inc; 1996. p. 104-5, 639-40.
  1. Factrel package insert (Wyeth-Ayerst—US), Rev 7/25/97, Rec 1/26/98.
  1. Gossel TA. Diabetes home testing—urine glucose and ketones. US Pharm 1987; 12(4): 52-62.
  1. McCall AL, Mullin CJ. Home blood glucose monitoring—keystone for modern diabetes care. Med Clin North Am 1987; 71(4): 763-87.
  1. Glucose oxidase urine glucose test (Tes-tape, Lilly—US), Rev 1986.
  1. Wallach J. Interpretation of diagnostic tests: a synopsis of laboratory medicine. 4th ed. Boston: Little, Brown and Company; 1986. p. 505.
  1. Zappia M, Oliveri RL, Montesanti R, et al. Loss of long-duration response to levodopa over time in PD: implications for wearing-off. Neurology 1999; 52(1): 763-7.
  1. Manufacturer comment, 6/9/99.
  1. Tasmar package insert (Tocapone, Roche—US), Rev 1/98, Rec 2/98.
  1. Panel comment, 5/17/99.
  1. Reviewer's consensus on monograph revision of 6/99.
Hide
(web3)