LEVOMED

Levodopa is a prodrug of dopamine that is administered to patients with Parkinson's due to its ability to cross the blood-brain barrier Label.

Levodopa can be metabolised to dopamine on either side of the blood-brain barrier and so it is generally administered with a dopa decarboxylase inhibitor like carbidopa to prevent metabolism until after it has crossed the blood-brain barrier Label, 1.

Once past the blood-brain barrier, levodopa is metabolized to dopamine and supplements the low endogenous levels of dopamine to treat symptoms of Parkinson's Label.

The first developed drug product that was approved by the FDA was a levodopa and carbidopa combined product called Sinemet that was approved on May 2, 1975 1, 7.

Levodopa on its own is formulated as an oral inhalation powder indicated for intermittent treatment of off episodes in Parkinson's patients who are already being treated with carbidopa and levodopa Label.

Levodopa is most commonly formulated as an oral tablet with a peripheral dopa decarboxylase inhibitor indicated for treatment of Parkinson's disease, post-encephalitic parkinsonism, and symptomatic parkinsonism following carbon monoxide intoxication or manganese intoxication 8.

Levodopa is able to cross the blood-brain barrier while dopamine is not Label, 8.

The addition of a peripheral dopa decarboxylase inhibitor prevents the conversion of levodopa to dopamine in the periphery so that more levodopa can reach the blood-brain barrier Label, 8.

Once past the blood-brain barrier, levodopa is converted to dopamine by aromatic-L-amino-acid decarboxylase Label, 8.

D(1A) dopamine receptor Agonist D(1B) dopamine receptor Agonist D dopamine receptor Agonist + 2 more targets.

Oral inhaled levodopa reaches a peak concentration in 0.5 hours with a bioavailability than is 70% that of the immediate release levodopa tablets with a peripheral dopa decarboxylase inhibitor like carbidopa or benserazide Label, 1.

L for Oral inhaled levodopa

Levodopa is either converted to dopamine by aromatic-L-amino-acid decarboxylase or O-methylated to 3-O-methyldopa by catechol-O-methyltransferase Label, 2, 3. 3-O-methyldopa cannot be metabolized to dopamine 3.

Once levodopa is converted to dopamine, it is converted to sulfated or glucuronidated metabolites, epinephrine E, or homovanillic acid through various metabolic processes 2.

The primary metabolites are 3,4-dihydroxyphenylacetic acid (13-47%) and homovanillic acid (23-39%) 3, 5.

Hover over products below to view reaction partners Levodopa Dopamine Dopamine-3-O-glucuronide + Dopamine-4-O-glucuronide Dopamine-3-O-sulfate + Dopamine-4-O-sulfate 3,4-Dihydroxyphenylacetaldehyde (DOPAL) 3,4-dihydroxyphenylethanol (DOPET) 3,4-dihydroxyphenylacetic acid (DOPAC) Homovanillic acid Norepinephrine Epinephrine E 3-Methoxytyramine 3-methoxy-4-hydroxyacetaldehyde Homovanillic acid Levodopa Methylated Metabolite.

After 48 hours, 0.17% of an Oral administered dose is recovered in stool, 0.28% is exhaled, and 78.4% is recovered in urine 5.

hours for Oral inhaled levodopa Label.

Oral levodopa has a half life of 50 minutes but when combined with a peripheral dopa decarboxylase inhibitor, the half life is increased to 1.5 hours 8.

Intravenous administered levodopa is cleared at a rate of 14.2 mL/min/kg in elderly patients and 23.4 mL/min/kg in younger patients 4.

When given carbidopa, the clearance of levodopa was 5.8 mL/min/kg in elderyly patients and 9.3 mL/min/kg in younger patients 4.

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There is no readily available data for the use of levodopa in pregnancy Label.

Rabbits treated with levodopa and carbidopa produced smaller litters and their offspring developed visceral and skeletal deformities Label.

Levodopa may lower prolactin and interfere with lactation but there is limited human data to demonstrate this effect Label.

Levodopa is present in human breast milk and so the potential effects of nursing while taking levodopa should be considered before prescribing levodopa to nursing mothers Label.

There is currently a lack of data on the safety and effectiveness of using levodopa in pediatric patients Label.

Patients over 65 years of age are more likely to experience adverse effects associated with taking levodopa, however this generally is not sufficient to exclude this patient group from treatment Label.

When patients are receiving levodopa without a decarboxylase inhibitor, levodopa must be discontinued at least twelve hours before carbidopa and levodopa extended-release is started.

In order to reduce adverse reactions, it is necessary to individualize therapy.

ADMINISTRATION section before initiating therapy.

Carbidopa and levodopa extended-release should be substituted at a dosage that will provide approximately 25% of the previous levodopa dosage See DOSAGE AND ADMINISTRATION.

Carbidopa does not decrease adverse reactions due to central effects of levodopa.

By permitting more levodopa to reach the brain, particularly when nausea and vomiting is not a dose-limiting factor, certain adverse central nervous system (CNS) effects, e.g., dyskinesias, will occur at lower dosages and sooner during therapy with carbidopa and levodopa extended-release than with levodopa alone.

Patients receiving carbidopa and levodopa extended-release may develop increased dyskinesias compared to carbidopa and levodopa immediate-release.

Dyskinesias are a common side effect of carbidopa-levodopa treatment.

The occurrence of dyskinesias may require dosage reduction.

All patients should be observed carefully for the development of depression with concomitant suicidal tendencies.

Carbidopa and levodopa extended-release should be administered cautiously to patients with severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine disease.

As with levodopa, care should be exercised in administering carbidopa and levodopa extended-release to patients with a history of myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias.

In such patients, cardiac function should be monitored with particular care during the period of initial dosage adjustment, in a facility with provisions for intensive cardiac care.

As with levodopa, treatment with carbidopa and levodopa extended-release may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer.

Falling Asleep During Activities of Daily Living and Somnolence Patients taking carbidopa and levodopa extended-release alone or with other dopaminergic drugs have reported suddenly falling asleep without prior warning of sleepiness while engaged in activities of daily living (includes operation of motor vehicles).

Road traffic accidents attributed to sudden sleep onset have been reported.

Although many patients reported somnolence while on dopaminergic medications, there have been reports of road traffic accidents attributed to sudden onset of sleep in which the patient did not perceive any warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event.

Sudden onset of sleep has been reported to occur as long as one year after the initiation of treatment.

Falling asleep while engaged in activities of daily living usually occurs in patients experiencing preexisting somnolence, although some patients may not give such a history.

For this reason, prescribers should reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment.

Prescribers should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.

Patients should be advised to exercise caution while driving or operating machines during treatment with carbidopa and levodopa extended-release.

Patients who have already experienced somnolence or an episode of sudden sleep onset should not participate in these activities during treatment with carbidopa and levodopa extended-release.

Before initiating treatment with carbidopa and levodopa extended-release, advise patients about the potential to develop drowsiness and ask specifically about factors that may increase the risk for somnolence with carbidopa and levodopa extended-release such as the use of concomitant sedating medications and the presence of sleep disorders.

Consider discontinuing carbidopa and levodopa extended-release in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc).

If treatment with carbidopa and levodopa extended-release continues, patients should be advised not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent.

There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been reported in association with dose reductions or withdrawal of certain antiparkinsonian agents such as levodopa, carbidopa-levodopa and carbidopa and levodopa extended-release.

Therefore, patients should be observed carefully when the dosage of levodopa is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.

NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia.

Neurological findings, including muscle rigidity, involuntary movements, altered consciousness, mental status changes; other disturbances, such as autonomic dysfunction, tachycardia, tachypnea, sweating, hyper.

• or hypotension; laboratory findings, such as creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin have been reported.

The early diagnosis of this condition is important for the appropriate management of these patients.

NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic infection, etc). is essential.

This may be especially complex if the clinical presentation includes both serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).

Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.

The management of

NMS should include: 1) intensive symptomatic treatment and medical monitoring and 2) treatment of any concomitant serious medical problems for which specific treatments are available.

Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene, are often used in the treatment of NMS; however, their effectiveness has not been demonstrated in controlled studies.

Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with carbidopa and levodopa extended-release tablets.

These inhibitors must be discontinued at least two weeks prior to initiating therapy with carbidopa and levodopa extended-release.

Carbidopa and levodopa extended-release may be administered concomitantly with the manufacturer’s recommended dose of an MAO inhibitor with selectivity for MAO type B (e.g., selegiline HCl) .

Carbidopa and levodopa extended-release is contraindicated in patients with known hypersensitivity to any component of this drug and in patients with narrow-angle glaucoma.

Carbidopa and levodopa extended-release tablets contain carbidopa and levodopa in a 1:4 ratio as either the 50-200 tablet or the 25-100 tablet.

The daily dosage of carbidopa and levodopa extended-release tablets must be determined by careful titration.

Patients should be monitored closely during the dose adjustment period, particularly with regard to appearance or worsening of involuntary movements, dyskinesias or nausea.

Carbidopa and levodopa extended-release tablets should not be chewed or crushed.

Standard drugs for

Parkinson’s disease, other than levodopa without a decarboxylase inhibitor, may be used concomitantly while carbidopa and levodopa extended-release tablets are being administered, although their dosage may have to be adjusted.

Since carbidopa prevents the reversal of levodopa effects caused by pyridoxine, carbidopa and levodopa extended-release tablets can be given to patients receiving supplemental pyridoxine (vitamin B 6 ).

Initial Dosage Patients Currently Treated with Conventional Carbidopa-Levodopa Preparations Studies show that peripheral dopa-decarboxylase is saturated by the bioavailable carbidopa at doses of 70 mg a day and greater.

Because the bioavailabilities of carbidopa and levodopa in carbidopa and levodopa immediate-release tablets and carbidopa and levodopa extended-release tablets are different, appropriate adjustments should be made, as shown in Table 2.

Table 2: Approximate Bioavailabilities at Steady State This table is only a guide to bioavailabilities since other factors such as food, drugs, and inter-patient variabilities may affect the bioavailability of carbidopa and levodopa.

Tablet Amount of

Levodopa (mg) in Each Tablet Approximate Bioavailability Approximate Amount of Bioavailable Levodopa (mg) in Each Tablet Carbidopa and Levodopa Extended-Release Tablets 50 mg/200 mg 200 0.70-0.75 The extent of availability of levodopa from carbidopa and levodopa extended-release tablets was about 70-75% relative to intravenous levodopa or standard carbidopa and levodopa immediate-release tablets in the elderly. 140-150 Carbidopa and Levodopa Immediate-Release Tablets 25 mg/100 mg 100 0.99 The extent of availability of levodopa from carbidopa and levodopa immediate-release tablets was 99% relative to intravenous levodopa in the healthy elderly.

Dosage with carbidopa and levodopa 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 a dosage that provides up to 30% more levodopa per day depending on clinical response See DOSAGE AND ADMINISTRATION: Titration with Carbidopa and Levodopa Extended-Release Tablets.

The interval between doses of carbidopa and levodopa extended-release tablets should be 4-8 hours during the waking day.

A guideline for initiation of carbidopa and levodopa extended-release tablets is shown in Table 3.

Table 3: Guidelines for Initial Conversion from Carbidopa and Levodopa Immediate-Release Tablets to Carbidopa and Levodopa Extended-Release Tablets Carbidopa and Levodopa Immediate-Release Tablets Total Daily Dose For dosing ranges not shown in the table see DOSAGE AND ADMINISTRATION: Initial Dosage: Patients Currently Treated with Conventional Carbidopa and Levodopa Preparations.

Levodopa (mg) Carbidopa and Levodopa Extended-Release Tablets Suggested Dosage Regimen 300-400 200 mg b.i.d. 500-600 300 mg b.i.d. or 200 mg t.i.d. 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). Patients Currently Treated with Levodopa Without a Decarboxylase Inhibitor Levodopa must be discontinued at least twelve hours before therapy with carbidopa and levodopa extended-release tablets is started.

Carbidopa and levodopa extended-release tablets should be substituted at a dosage that will provide approximately 25% of the previous levodopa dosage.

In patients with mild to moderate disease, the initial dose is usually 1 tablet of 50 mg/200 mg carbidopa and levodopa extended-release tablets b.i.d.

In patients with mild to moderate disease, the initial recommended dose is 1 tablet of 50 mg/200 mg carbidopa and levodopa extended-release tablets b.i.d.

Initial dosage should not be given at intervals of less than 6 hours.

Titration with Carbidopa and Levodopa Extended-Release Tablets Following initiation of therapy, doses and dosing intervals may be increased or decreased depending upon therapeutic response.

Most patients have been adequately treated with doses of carbidopa and levodopa extended-release tablets that provide to 1600 mg of levodopa per day, administered as divided doses at intervals ranging from to 8 hours during the waking day. Higher doses of carbidopa and levodopa extended-release tablets (2400 mg or more of levodopa per day) and shorter intervals (less than 4 hours) have been used, but are not usually recommended.

When doses of carbidopa and levodopa extended-release tablets are given at intervals of less than 4 hours, and/or if the divided doses are not equal, it is recommended that the smaller doses be given at the end of the day. An interval of at least 3 days between dosage adjustments is recommended.

Parkinson’s disease is progressive, periodic clinical evaluations are recommended; adjustment of the dosage regimen of carbidopa and levodopa extended-release tablets may be required.

Anticholinergic agents, dopamine agonists, and amantadine can be given with carbidopa and levodopa extended-release tablets.

Dosage adjustment of carbidopa and levodopa extended-release tablets may be necessary when these agents are added.

A dose of carbidopa and levodopa immediate-release tablets 25/100 or 10/100 (one half or a whole tablet) can be added to the dosage regimen of carbidopa and levodopa extended-release tablets in selected patients with advanced disease who need additional immediate-release levodopa for a brief time during daytime hours.

Sporadic cases of hyperpyrexia and confusion have been associated with dose reductions and withdrawal of carbidopa and levodopa immediate-release tablets or carbidopa and levodopa extended-release tablets.

Patients should be observed carefully if abrupt reduction or discontinuation of carbidopa and levodopa extended-release tablets is required, especially if the patient is receiving neuroleptics See WARNINGS.

If general anesthesia is required, carbidopa and levodopa extended-release tablets may be continued as long as the patient is permitted to take oral medication.

If therapy is interrupted temporarily, the patient should be observed for symptoms resembling NMS, and the usual dosage should be administered as soon as the patient is able to take oral medication.

Tablets, USP are available containing 25 mg of carbidopa, USP and 100 mg of levodopa, USP or 50 mg of carbidopa, USP and 200 mg of levodopa, USP.

The 25 mg/100 mg tablets are purple, oval, unscored tablets debossed with MYLAN on one side of the tablet and on the other side of the tablet.

They are available as follows

NDC 48433-015-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each).

The 50 mg/200 mg tablets are purple, oval, scored tablets debossed with MYLAN on one side of the tablet and to the left of the score and to the right of the score on the other side of the tablet.

NDC 48433-016-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each).

Store at 20° to 25°C (68° to 77°F).

Protect from light.

Manufactured for

Morgantown, WV 26505 U.S.A.

No teratogenic effects were observed in a study in mice receiving up to 20 times the maximum recommended human dose of carbidopa and levodopa immediate-release.

There was a decrease in the number of live pups delivered by rats receiving approximately two times the maximum recommended human dose of carbidopa and approximately five times the maximum recommended human dose of levodopa during organogenesis.

Carbidopa and levodopa immediate-release caused both visceral and skeletal malformations in rabbits at all doses and ratios of carbidopa/levodopa tested, which ranged from 10 times/5 times the maximum recommended human dose of carbidopa/levodopa to 20 times/10 times the maximum recommended human dose of carbidopa/levodopa.

There are no adequate or well-controlled studies in pregnant women.

It has been reported from individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized.

Carbidopa concentrations in fetal tissue appeared to be minimal.

Use of carbidopa and levodopa extended-release in women of childbearing potential requires that the anticipated benefits of the drug be weighed against possible hazards to mother and child.

Levodopa has been detected in human milk.

Caution should be exercised when carbidopa and levodopa extended-release is administered to a nursing woman.

Safety and effectiveness in pediatric patients have not been established.

Use of the drug in patients below the age of is not recommended.

In the clinical efficacy trials for carbidopa and levodopa immediate-release, almost half of the patients were older than 65, but few were older than 75.

No overall meaningful differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals to adverse drug reactions such as hallucinations cannot be ruled out.

There is no specific dosing recommendation based upon clinical pharmacology data as carbidopa and levodopa immediate-release and carbidopa and levodopa extended-release are titrated as tolerated for clinical effect.