Rytary

Anti-Parkinson Agents, Dopamine Precursors

Many products may be taken with or without food. Follow the directions of the product prescribed.
A change in a patient's diet to foods that are high in protein may delay or impair the oral absorption of levodopa and may reduce efficacy. The Parkinson's Foundation states that most patients have no problem taking medications with meals, but some experience less benefit if they take carbidopa/levodopa with a stomach full of protein (including meats, cheeses and other dairy products). When this occurs, it is recommended to only take carbidopa/levodopa along with non-protein foods. For patients with more advanced PD, it is best to take levodopa-containing medications 30 to 60 minutes before eating a meal to limit food interference. If nausea occurs, the products may be taken with a small non-protein snack, such as fruit or a cracker, to help.
Do not administer at the same time as a multivitamin containing iron or iron supplements as these may reduce levodopa absorption.
Advise patients that dark coloration (red, brown, or black) may appear in saliva, urine, or sweat. The color change is not harmful, but garments may become discolored.

Immediate-release tablets (e.g., Sinemet):
Administer at regular intervals as prescribed to provide therapeutic coverage and lessen "wearing off" time.
 
Immediate-release tablets, functionally scored (Dhivy):
Tablets have 3 functional scores to facilitate dose adjustment, with each segment containing 6.25 mg of carbidopa and 25 mg of levodopa.
Administer at regular intervals as prescribed.
 
Extended-release tablets (e.g., Sinemet CR):
Do not crush or chew; administer intact.
Dosing intervals range from 4 to 8 hours while awake and are individualized to the patient.
 
Extended-release capsules (Rytary):
Administer whole. Do not chew, divide or crush the capsules.
May give with or without food. However, a high-fat, high-calorie meal may delay the absorption of levodopa and the onset of action by 2 to 3 hours. For this reason, consideration should be given to taking the first dose of the day about 1 to 2 hours before eating.
For patients who have difficulty swallowing intact capsules: May administer by carefully twisting apart both halves of the capsule, sprinkling the entire contents of both halves on a small amount of applesauce (1 to 2 tablespoons). Have the patient consume immediately. Do not store the drug/food mixture for future administration.
 
Orally disintegrating tablets (ODT, e.g., Parcopa):
Gently remove ODT from packaging with dry hands just prior to use.
Place tablet in mouth on top of the patient's tongue and allow to dissolve. It will dissolve in seconds. Instruct the patient to swallow with the saliva.
Do not need to administer with water or other liquids.
Administer at regular intervals as prescribed to provide therapeutic coverage and lessen "wearing off" time.

Extemporaneous compounding instructions for liquid formulation:
NOTE: The extemporaneous preparation of carbidopa; levodopa is not approved by the FDA.
Do not use metal containers for compounding or storage.
Ingredients:
Mix 10 immediate-release tablets (only) of either carbidopa-levodopa 10 mg/100 mg OR 25 mg/100 mg (equivalent to 1,000 mg levodopa)
2.5 mL ascorbic acid crystals (approximately 2 grams)
1,000 mL distilled water (distilled water is preferred, but tap water may be used)
Rotate or shake container gently until tablets dissolve (no need to crush tablets).
Final concentrations:
carbidopa 0.1 mg/mL-levodopa 1 mg/mL (using carbidopa-levodopa 10 mg/100 mg tablets)
carbidopa 0.25 mg/mL-levodopa 1 mg/mL (using carbidopa-levodopa 25 mg/100 mg tablets)
Both solutions will contain ascorbic acid 2 mg/mL
Storage: Store in the refrigerator for 24 to 48 hours. Discard any unused solution after that time. The presence of black particles indicates that the levodopa has broken down; solutions containing these precipitates should be discarded.

Intrajejunal Route
Health care providers and the patient and/or caregiver should be fully experienced/trained in the use of the Duopa cassette, the programming, care, and maintenance of the CADD-Legacy 1400 Portable Infusion Pump used for enteral delivery, use of the PEG-J tube, and other aspects of proper and safe administration of the product.
 
Carbidopa and Levodopa enteral suspension (Duopa):
Administer into the jejunum via a percutaneous endoscopic gastrostomy with jejunal tube (PEG-J); the PEG-J tube is the procedure is performed by a gastroenterologist or other healthcare provider experienced in PEG-J tube placement.
The daily enteral suspension dose is delivered as a 16-hour infusion through a PEG-J for long-term administration. See below for recommended tubing sets for PEG-J administration.
The daily DUOPA dose infusion has 3 parts:
a morning dose
a continuous rate dose
extra doses
At the end of the daily 16-hour administration period for the enteral suspension, the PEG-J should be disconnected from the pump and flushed with room temperature potable water with a syringe as directed. Do NOT use hot water as this may burn the patient's intestine.
After the daily 16-hour enteral infusion, the patient will take their usual night-time dose of oral carbidopa-levodopa tablets as prescribed.
For short-term, temporary administration prior to the PEG-J tube placement only, treatment may be initiated by a nasojejunal tube with observation of the patient’s clinical response. See below for the recommended tubing sets for nasojejunal administration.
 
Duopa Cassettes:
The cassettes should be stored in a refrigerator by the pharmacy or the patient until the time of use. Store between 36 degrees to 46 degrees F (2 to 8 degrees C). Do not freeze. Protect from light and keep in the original carton.
Use Duopa at room temperature. Take one cassette out of the refrigerator and out of the carton 20 minutes prior to use; failure to use the product at room temperature may result in the patient not receiving the right amount of medication.
Do not use a cassette that appears damaged or empty. Each cassette contains approximately 100 mL of enteral suspension.
The cassettes are for single-use only and should not be used for longer than 16 hours, even if some drug product remains.
An opened cassette should not be re-used.
The medication is dispensed from the Duopa medication cassette reservoir and it is specifically designed to be connected to the CADD-Legacy 1400 programmable infusion pump. Do not use any other infusion pump for delivery.
Priming of the pump should be done by the health care provider. The prescribed dose of Duopa will be programmed into the patient's pump by the healthcare provider. The dose should only be changed by the healthcare provider or in the presence of the health care provider.
 
Recommended Tubing Sets for Long-Term PEG-J Administration:
- AbbVie PEG 15 and 20 Fr AbbVie J by AbbVie, Inc.
- EndoVive Standard PEG Kit – Pull Method and EndoVive Two-Port Through the PEG Jejunal Feeding Tube Kit by Boston Scientific Corp.
Recommended Tubing Sets for Short-Term Naso-Jejunal Administration:
- AbbVie NJ by AbbVie, Inc.
- NJFT-10 by Wilson-Cook Medical, Inc.
- Kangaroo Naso-Jejunal Feeding Tube and Kangaroo by Covidien
 
Enteral infusion interruption or discontinuation:
Avoid sudden discontinuation or rapid dose reduction of carbidopa; levodopa. The enteral dose should be tapered or the patient switched to immediate-release dosage forms for oral use.
The patient should keep a supply of immediate-release tablets on hand in case the enteral infusion is interrupted or halted.
If the patient anticipates disconnecting the pump for a short period of time (less than 2 hours such as to swim, shower, or short medical procedure), no supplemental oral medication is needed, but the patient may be advised to take an extra-dose of Duopa before disconnecting. Instruct the patient to stop the continuous rate, turn off the pump, clamp the cassette tube, disconnect the tubing, and replace the red cap on the cassette tube. The Duopa cassette can remain attached to the pump until the tubing is reconnected.
If a prolonged (e.g., more than 2 hours) interruption of therapy occurs, advise the patient to contact their healthcare provider and to take oral carbidopa-levodopa until the patient is able to resume the Duopa enteral infusion.
 
Pharmacy Thawing and Storage instructions for Duopa:
The Duopa product will arrive to the pharmacy frozen and the cartons should be stored in the freezer, until ready to thaw, at -20 degrees C (-4 degrees F).
Assign a 12-week “Use By” date based on the time the cartons are put into the refrigerator to thaw.
Fully thaw the enteral suspension in the refrigerator prior to dispensing, between 36 degrees to 46 degrees F (2 to 8 degrees C). Do not re-freeze.
In order to ensure controlled thawing, take the cartons containing the seven individual cassettes out of the transport box and separate the cartons from each other.
Thawing may take up to 96 hours when the cartons are taken out of the transport box.
Once the product has thawed, the individual cartons may be packed in a closer configuration within the refrigerator.
Any unused medication will expire after the 12-week "Use By" date.

akinesia / Delayed / Incidence not known
seizures / Delayed / Incidence not known
peptic ulcer / Delayed / Incidence not known
bezoar / Delayed / Incidence not known
GI perforation / Delayed / Incidence not known
GI bleeding / Delayed / Incidence not known
GI obstruction / Delayed / Incidence not known
intussusception / Delayed / Incidence not known
myocardial infarction / Delayed / Incidence not known
neuroleptic malignant syndrome-like symptoms / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
hemolytic anemia / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
suicidal ideation / Delayed / Incidence not known
skin cancer / Delayed / Incidence not known

orthostatic hypotension / Delayed / 0-73.0
constipation / Delayed / 0.2-22.0
erythema / Early / 19.0-19.0
dyskinesia / Delayed / 2.0-16.5
depression / Delayed / 1.3-11.0
confusion / Early / 2.3-8.0
peripheral neuropathy / Delayed / 0-5.0
hallucinations / Early / 3.0-5.0
psychosis / Early / 1.0-5.0
dystonic reaction / Delayed / 0.8-1.8
dyspnea / Early / 0.4-1.6
chest pain (unspecified) / Early / 0.8-1.0
involuntary movements / Delayed / 10.0
trismus / Delayed / Incidence not known
sudden sleep onset / Delayed / Incidence not known
memory impairment / Delayed / Incidence not known
ataxia / Delayed / Incidence not known
dysphagia / Delayed / Incidence not known
teeth grinding (bruxism) / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
hyperbilirubinemia / Delayed / Incidence not known
hypotension / Rapid / Incidence not known
hypertension / Early / Incidence not known
phlebitis / Rapid / Incidence not known
palpitations / Early / Incidence not known
priapism / Early / Incidence not known
urinary incontinence / Early / Incidence not known
urinary retention / Early / Incidence not known
pyuria / Delayed / Incidence not known
leukopenia / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
impulse control symptoms / Delayed / Incidence not known
bullous rash / Early / Incidence not known
hot flashes / Early / Incidence not known
euphoria / Early / Incidence not known
edema / Delayed / Incidence not known
peripheral edema / Delayed / Incidence not known
blepharospasm / Early / Incidence not known
blurred vision / Early / Incidence not known

nausea / Early / 3.0-30.0
dizziness / Early / 2.3-19.0
headache / Early / 1.0-17.0
infection / Delayed / 1.0-8.0
anxiety / Delayed / 0-8.0
xerostomia / Early / 1.1-7.0
insomnia / Early / 1.0-6.0
dyspepsia / Early / 0.6-5.0
vomiting / Early / 1.8-5.0
diarrhea / Early / 0.6-5.0
rash / Early / 0-5.0
back pain / Delayed / 0.6-1.6
anorexia / Delayed / 1.1-1.2
paresthesias / Delayed / 0.8-1.1
muscle cramps / Delayed / 0.8-1.0
urine discoloration / Early / 10.0
drowsiness / Early / Incidence not known
nightmares / Early / Incidence not known
tremor / Early / Incidence not known
pyrosis (heartburn) / Early / Incidence not known
dysgeusia / Early / Incidence not known
hypersalivation / Early / Incidence not known
weight loss / Delayed / Incidence not known
weight gain / Delayed / Incidence not known
abdominal pain / Early / Incidence not known
hiccups / Early / Incidence not known
flatulence / Early / Incidence not known
syncope / Early / Incidence not known
increased urinary frequency / Early / Incidence not known
fever / Early / Incidence not known
purpura / Delayed / Incidence not known
libido increase / Delayed / Incidence not known
urticaria / Rapid / Incidence not known
alopecia / Delayed / Incidence not known
hyperhidrosis / Delayed / Incidence not known
flushing / Rapid / Incidence not known
pruritus / Rapid / Incidence not known
cough / Delayed / Incidence not known
paranoia / Early / Incidence not known
agitation / Early / Incidence not known
malaise / Early / Incidence not known
hoarseness / Early / Incidence not known
asthenia / Delayed / Incidence not known
fatigue / Early / Incidence not known
diplopia / Early / Incidence not known
mydriasis / Early / Incidence not known
vitamin B6 deficiency / Delayed / Incidence not known

Atamet, Dhivy, Duopa, Parcopa, Rytary, SINEMET, SINEMET CR

Rx

Combination product of dopamine precursor (levodopa) with a decarboxylase inhibitor (carbidopa)
Used for idiopathic Parkinson's disease, post-encephalitic parkinsonism, and symptomatic parkinsonism following injury to the nervous system; various formulations help with individualization of dosing
An enteral suspension treats motor fluctuations in those with advanced Parkinson's disease

Prior to initiating the enteral suspension on Day 1, convert patients from all other forms of levodopa to oral immediate-release carbidopa; levodopa (1:4 ratio). Patients should remain on a stable dose of their concomitant medications taken for the treatment of Parkinson's disease before initiation of the carbidopa; levodopa suspension via enteral pump. Ensure patients take their oral Parkinson's disease medications the morning of the PEG-J procedure. The daily enteral suspension dose can be titrated as needed, based on response and tolerability after Day 1 and until a stable daily dose is maintained. Adjustments to concomitant Parkinson's disease medications may be needed. Once no further adjustments are required to the morning dose, continuous dose, or extra dose, this dosing regimen should be administered daily over 16 hours. Additional dose adjustments may be necessary over time based on the level of activity of the patient and disease progression. The maximum recommended daily dose of Duopa enteral suspension is 2,000 mg of the levodopa component (i.e., 1 cassette per day) administered over 16 hours. At the end of each daily 16-hour infusion, the patient will disconnect the pump from the PEG-J and take their night-time dose of oral immediate-release carbidopa-levodopa. DAY 1 MORNING DOSING: Determine the total amount of levodopa in milligrams (mg) in the first dose of oral immediate-release carbidopa; levodopa that was taken by the patient on the previous day. Convert the oral levodopa dose from milligrams (mg) to milliliters (mL) by multiplying the oral dose by 0.8 and then dividing by 20 mg/mL. This calculation will provide the morning dose of carbidopa; levodopa suspension in mL. Add 3 mL to the morning dose to fill (prime) the intestinal tube to obtain the total morning dose. Program the pump to deliver the total morning dose, which is usually administered over 10 to 30 minutes. DAY 1 CONTINUOUS DOSING: Determine the amount of oral immediate-release levodopa that the patient received from oral immediate-release carbidopa-levodopa doses throughout the previous day (16 waking hours), in milligrams (mg). Do not include the doses of oral immediate-release carbidopa-levodopa taken at night when calculating the levodopa amount. Subtract the first oral levodopa dose in milligrams (mg) taken by the patient on the previous day from the total oral levodopa dose in milligrams (mg) taken over 16 waking hours. Divide the result by 20 mg/mL. This is the dose of carbidopa; levodopa suspension administered as a continuous dose (in mL) over 16 hours. The hourly infusion rate (mL/hour) is obtained by dividing the continuous dose by 16 (hours). The hourly infusion rate will be programmed into the pump as the continuous rate. If persistent or numerous "off" periods occur during the 16-hour infusion, consider increasing the continuous dose or using the extra dose function. If dyskinesia or levodopa-related adverse reactions (ADRs) occur, consider decreasing the continuous dose or stopping the infusion until the ADRs subside. MORNING DOSE ADJUSTMENTS: If there was an inadequate response within 1 hour of the morning dose on the prior day, adjust the morning dose (excluding the 3 mL to fill the tube) as follows: If the morning dose on the prior day was 6 mL or less, increase the morning dose by 1 mL. If the morning dose on the preceding day was greater than 6 mL, increase the morning dose by 2 mL. If the patient experienced dyskinesias or levodopa-related ADRs within 1 hour of the morning dose on the prior day, decrease the morning dose by 1 mL. CONTINUOUS DOSE ADJUSTMENTS: Consider increasing the continuous dose based on the number and volume of extra doses of carbidopa; levodopa (i.e., total amount of levodopa component) that was needed for the previous day and clinical response. Consider decreasing the continuous dose if the patient experienced troublesome dyskinesia, or other troublesome treatment-related ADRs on the preceding day as follows: For troublesome ADRs lasting 1 hour or more, decrease the continuous dose by 0.3 mL/hour. For troublesome ADRs lasting for 2 or more periods of 1 hour or more, decrease the continuous dose by 0.6 mL/hour. EXTRA DOSES: The enteral infusion pump has an extra dose function that can be used to manage acute "off" symptoms that are not controlled by the morning dose and the continuous dose administered over 16 hours. The extra dose function should be set at 1 mL (20 mg of levodopa) when starting the enteral suspension. If the amount of the extra dose needs to be adjusted, it is typically done in 0.2 mL increments. Limit the extra dose frequency to 1 extra dose every 2 hours. Administration of frequent extra doses may cause or worsen dyskinesias. TREATMENT DISCONTINUATION: Avoid sudden discontinuation or rapid dose reduction. If discontinuation is needed, the dose should be tapered or patients should be switched to oral immediate-release carbidopa; levodopa. When using a PEG-J tube, the drug can be discontinued by withdrawing the tube and letting the stoma heal. The removal of the tube should only be performed by a qualified healthcare provider.

INITIAL TREATMENT: The usual initial dose for patients who have not previously received levodopa is 1 carbidopa 25 mg/levodopa 100 mg tablet PO 3 times per day. The dosage may be increased by 1 tablet every day or every other day up to a maximum of 8 tablets per day. If carbidopa 10 mg/levodopa 100 mg is used, the dosage may be started with 1 tablet 3 or 4 times a day. However, this may not provide an adequate amount of carbidopa for many patients. Therefore, the dosage may be increased by 1 tablet every day or every other day up to a total of 8 tablets (i.e., 2 tablets PO 4 times a day). MAINTENANCE TREATMENT: Individualize and adjust dosing regimen according response and tolerability. At least 70 mg to 100 mg of carbidopa per day should be provided. When a greater proportion of carbidopa is required, 1 tablet of carbidopa 25 mg/levodopa 100 mg may be substituted for each carbidopa 10 mg/levodopa 100 mg tablet. When more levodopa is required, carbidopa 25 mg/levodopa 250 mg should be substituted for carbidopa 25 mg/levodopa 100 mg or carbidopa 10 mg/levodopa 100 mg. If necessary, the dosage of carbidopa 25 mg/levodopa 250 mg may be increased by one-half or 1 tablet every day or every other day to a maximum of 8 tablets daily. For patients requiring smaller dose adjustments, carbidopa/levodopa tablets that are functionally scored (Dhivy) may be used to adjust doses in increments of 6.25 mg/25 mg. Experience with total daily doses of carbidopa greater than 200 mg is limited. Because both therapeutic and adverse responses (e.g., involuntary movements) occur more rapidly with carbidopa-levodopa than with levodopa alone, patients should be monitored closely during the dose adjustment period, and changes made accordingly. Blepharospasm may be a useful early sign of excess dosage in some patients. CONVERTING PATIENTS FROM LEVODOPA TO CARBIDOPA-LEVODOPA: Levodopa must be discontinued at least 12 hours before starting carbidopa-levodopa. A daily dosage of carbidopa-levodopa should be chosen that will provide approximately 25% of the previous levodopa dosage. Patients who are taking less than 1500 mg of levodopa a day should be started on 1 tablet of carbidopa 25 mg/levodopa 100 mg PO 3 or 4 times a day. The suggested starting dosage for most patients taking more than 1500 mg of levodopa is 1 tablet of carbidopa 25 mg/levodopa 250 mg PO 3 or 4 times a day.

INITIAL TREATMENT: The usual initial dose is Sinemet CR 1 carbidopa 50 mg/levodopa 200 mg tablet PO twice daily. Most patients have been adequately treated with the extended-release tablets in doses that provide 400 mg to 1,600 mg of levodopa per day. The dosing intervals should be 4 to 8 hours apart during the waking day. Dosage adjustments should generally be made at 3-day intervals. Doses 2,400 mg or more per day levodopa or shorter intervals (less than 4 hours) have been used, but are usually not recommended. Dosage adjustments may be necessary when other antiparkinson medication is added. A dose of regular-release carbidopa-levodopa (one-half or 1 tablet) can be added to the dosage regimen of the extended-release formulation in selected patients with advanced disease who need additional immediate-release levodopa for brief times during the daytime. CONVERTING PATIENTS FROM LEVODOPA TO CARBIDOPA-LEVODOPA: Initiate therapy at approximately 25% of the previous dosage of levodopa alone. In patients with mild to moderate disease, the usual initial dosage is 1 carbidopa 50 mg/levodopa 200 mg extended-release tablet twice daily. CONVERTING PATIENTS FROM IMMEDIATE-RELEASE CARBIDOPA-LEVODOPA TO EXTENDED-RELEASE CARBIDOPA-LEVODOPA: Substitute extended-release tablets at a dosage that provides approximately 10% more levodopa per day than the immediate-release tablets, although this may need to be increased to a dosage that provides up to 30% more levodopa per day. The dosing intervals should be 4 to 8 hours apart during the waking day. The following general guidelines may be used to initiate therapy. For patients receiving 300 mg/day to 400 mg/day of levodopa as immediate-release carbidopa-levodopa, the suggested starting regimen of Sinemet CR is carbidopa 50 mg/levodopa 200 mg twice daily. For patients receiving 500 mg/day to 600 mg/day of levodopa as immediate-release carbidopa-levodopa, the suggested starting regimen of Sinemet CR is carbidopa 50 mg/levodopa 200 mg 3 times daily or a total of 300 mg levodopa twice daily. For patients receiving 700 mg/day to 800 mg/day of levodopa as immediate-release carbidopa-levodopa, the suggested starting regimen of Sinemet CR is a total of 800 mg levodopa in 3 divided doses (e.g., 300 mg in the morning, 300 mg in the afternoon, and 200 mg in the evening). For patients receiving 900 mg/day to 1,000 mg/day of levodopa as immediate-release carbidopa-levodopa, the suggested starting regimen of Sinemet CR is a total of 1,000 mg levodopa in 3 divided doses (e.g., 400 mg in the morning, 400 mg in the afternoon, and 200 mg in the evening).

INITIAL TREATMENT: Rytary 23.75 mg/95 mg PO three times a day for the first 3 days. On Day 4, may increase the dose to 36.25 mg/145 mg three times a day. Based on response and tolerability, the dose may be further increased up to a maximum dose of 97.5 mg/390 mg three times a day. The dosing frequency may be changed from three times a day up to a maximum of five times a day if more frequent dosing is needed and is tolerated. The maximum recommended daily dose is 612.5 mg/2,450 mg. CONVERTING PATIENTS FROM IMMEDIATE-RELEASE CARBIDOPA-LEVODOPA TO EXTENDED-RELEASE CARBIDOPA-LEVODOPA: Dosages of other carbidopa and levodopa products are not interchangeable with carbidopa; levodopa extended-release capsules; therefore, the following conversions are recommended. For patients receiving 400 mg to 549 mg levodopa as immediate-release carbidopa-levodopa, the suggested starting dose of Rytary is 3 capsules (23.75 mg/95 mg each capsule) 3 times daily (total 855 mg of levodopa daily). For patients receiving 550 mg to 749 mg levodopa as immediate-release carbidopa-levodopa, the suggested starting dose of Rytary is 4 capsules (23.75 mg/95 mg each capsule) 3 times daily (total 1,140 mg of levodopa daily). For patients receiving 750 mg to 949 mg levodopa as immediate-release carbidopa-levodopa, the suggested starting dose of Rytary is 3 capsules (36.25 mg/145 mg each capsule) 3 times daily (total 1,305 mg of levodopa daily). For patients receiving 950 mg to 1,249 mg levodopa as immediate-release carbidopa-levodopa, the suggested starting dose of Rytary is 3 capsules (48.75 mg/195 mg each capsule) 3 times daily (total 1,755 mg of levodopa daily). For patients receiving 1,250 mg or more levodopa as immediate-release carbidopa-levodopa, the suggested starting dose of Rytary is 4 capsules (48.75 mg/195 mg each capsule) 3 times daily (total 2,340 mg of levodopa daily) OR 3 capsules (61.25 mg/245 mg each capsule) 3 times daily (total 2,205 mg of levodopa daily). The dosage frequency may be changed from 3 times a day up to 5 times a day based on efficacy and tolerability. For conversion from carbidopa; levodopa; entacapone, the recommended conversions may need to be increased. NOTE: Avoid sudden discontinuation or rapid dose reduction. Tapering is recommended when treatment is being discontinued.

A bedtime dose of immediate-release carbidopa-levodopa starting at 25 mg/100 mg has been suggested. Levodopa dosages as high as 600 mg/day in divided doses have been employed. Dosages may be increased rapidly based on individual response and are usually given prior to bedtime in most studies. A rebound phenomenon has been described in some patients receiving Sinemet 25/100 at bedtime during prolonged use (several weeks) of regular and sustained-release Sinemet. These patients experienced morning symptoms of RLS. The authors claimed that the morning symptoms could be controlled with daytime administration of the sustained-release product, but could not exclude the possibility of returned symptoms of RLS later in the day. (Morning symptoms disappeared when the dosage was changed to 2 doses of Sinemet CR 50/100 in the evening and 1 dose of 25/100 in the morning.) The reason for this phenomenon has not been determined, but should be considered when using levodopa for RLS.

Various doses have been studied including levodopa-carbidopa 1.02/0.25 mg/kg PO 3 times daily, or 0.5 mg levodopa (with a 25% fixed-dose combination of carbidopa) PO 3 times daily; some studies compared the drug with patching or occlusion while others added the drug to patching/occlusion. Limited data indicate that there may be some benefit to combining levodopa/carbidopa with occlusion therapy. A single-dose study of 20 children (4 to 14 years) with amblyopia all undergoing occlusion therapy, compared levodopa-carbidopa 25/6.25 mg or 50/12.5 mg to placebo. Significant improvement of 1 line in visual acuity was observed at both levodopa/carbidopa dosages whereas no significant improvement in visual acuity was noted with use of placebo. In a 7-week study, 13 amblyopic children (7 to 12 years) who no longer responded to occlusion or penalization therapy were randomized to treatment with levodopa/carbidopa 1.02/0.25 mg/kg 3 times daily with or without occlusion (occlusion was used for 3 hours/day). A significantly greater improvement in visual acuity of the amblyopic eye was observed in the occlusion group compared to the non-occlusion group (2.1 lines vs. 0.8 lines, p = 0.002). In addition, the occlusion group maintained a greater improvement in the visual acuity of the amblyopic eye 4 weeks after study termination. No statistically significant difference was noted in the visual acuity of the dominant eye 4 weeks after study termination. In another 7-week study, amblyopic patients (4 to 22 years) were randomized to receive treatment with levodopa alone (0.5 mg/kg with a 25% fixed-dose combination of carbidopa 3 times daily), levodopa with part-time occlusion (3 hours/day), or levodopa with full-time occlusion (during all waking hours). None of the patients 15 years or older responded to therapy. An improvement in visual acuity occurred in 74% of the patients (n = 53), regardless of occlusion therapy. Forty-four of the responders were followed up 1 year after cessation of levodopa-carbidopa therapy. Improvement in visual acuity was maintained in approximately 50% of these patients. Although the addition of occlusion (part-time or full-time) did not facilitate recovery of vision, improvement in visual acuity was maintained for a longer duration in the patients who received full-time occlusion than in those receiving levodopa-carbidopa alone or with part-time occlusion.

†Indicates off-label use

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Alfentanil: (Major) Prior to general anesthesia, levodopa may be continued as long as the patient is permitted to take oral medication. If levodopa-based therapy is interrupted temporarily, the usual daily dosage may be reinstituted or titrated upward to the normal dosage as soon as the patient is able to take oral medications. The patient should be observed for symptoms resembling neuroleptic malignant syndrome, and the usual regimen should be administered as soon as the patient is able to take oral medication.
Amantadine: (Minor) Amantadine can increase the efficiency of levodopa by its action on central nerve terminals.
Amisulpride: (Major) Avoid using these drugs together. Amisulpride is a central dopamine antagonist and can antagonize the actions of dopamine agonists such as levodopa. Amisulpride is generally used perioperatively to prevent and treat postoperative nausea and vomiting. Prior to general anesthesia, levodopa may be continued as long as the patient is permitted to take oral medication. If levodopa-based therapy is interrupted temporarily, the usual daily dosage may be reinstituted or titrated upward to the normal dosage as soon as the patient is able to take oral medications.
Amoxapine: (Moderate) Amoxapine exhibits antimuscarinic activity and can decrease gastric motility, decreasing the bioavailability of levodopa. In addition, severe hypertension occurred in a limited number of patients who received levodopa in combination with a tricyclic antidepressant.
Angiotensin II receptor antagonists: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Angiotensin-converting enzyme inhibitors: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Atropine: (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
Atropine; Difenoxin: (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
atypical antipsychotic: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or levodopa during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and levodopa may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with levodopa and other antiparkinson's treatments than traditional antipsychotics.
Belladonna; Opium: (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Minor) Through its central antimuscarinic actions, hyoscyamine can potentiate the dopaminergic effects of levodopa. Clinicians should be ready to decrease doses of levodopa if hyoscyamine is added.
Benzphetamine: (Major) Levodopa, due to its conversion to dopamine, may increase the risk of developing amphetamine-induced cardiac arrhythmias; dosage reductions or discontinuation of benzphetamine is recommended if the two agents are used concurrently.
Benztropine: (Minor) Through its central antimuscarinic actions, antimuscarinics such as benztropine can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if benztropine is added.
Beta-blockers: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
Brentuximab vedotin: (Major) There was a 5% incidence of generalized polyneuropathy during clinical trial evaluation of carbidopa; levodopa enteral suspension (Duopa). The manufacturer recommends an initial evaluation for signs and symptoms of peripheral neuropathy, and periodic monitoring for peripheral neuropathy during treatment with Duopa, particularly in patients receiving other medications that are associated with neuropathy. Peripheral neuropathy has been reported with the use of brentuximab vedotin. Brentuximab vedotin-induced peripheral neuropathy is cumulative.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Coadministration of glycopyrrolate with levodopa may decrease levodopa serum concentrations. If coadministration is necessary, monitor clinical response to levodopa and increase levodopa dose accordingly.
Bupropion: (Moderate) Use bupropion and levodopa with caution and monitor for CNS toxicity, including restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness, which may result from cumulative dopamine agonist effects.
Bupropion; Naltrexone: (Moderate) Use bupropion and levodopa with caution and monitor for CNS toxicity, including restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness, which may result from cumulative dopamine agonist effects.
Calcium-channel blockers: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and levodopa. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as levodopa, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Central-acting adrenergic agents: (Moderate) Monitor blood pressure during concomitant use of levodopa and central-acting adrenergic agents due to risk for additive hypotension.
Chlorpromazine: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other.
Chlorthalidone; Clonidine: (Moderate) Monitor blood pressure during concomitant use of levodopa and central-acting adrenergic agents due to risk for additive hypotension.
Clonidine: (Moderate) Monitor blood pressure during concomitant use of levodopa and central-acting adrenergic agents due to risk for additive hypotension.
Cocaine: (Major) Concomitant use of cocaine with levodopa (including carbidopa; levodopa and carbidopa; levodopa; entacapone) can result in an increase in the risk of developing cardiac arrhythmias. Levodopa should be used cautiously in patients who are known users of cocaine. Conversely, electrocardiographic monitoring should be considered when using cocaine in patients receiving levodopa.
Codeine; Phenylephrine; Promethazine: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other.
Codeine; Promethazine: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other.
Dacarbazine, DTIC: (Moderate) Levodopa response may be decreased during chemotherapy with dacarbazine, DTIC. If dacarbazine is used in a patient stabilized on levodopa therapy, practitioners may wish to be alert for needed adjustments in the levodopa regimen to maintain patient status.
Darifenacin: (Minor) Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. Antimuscarinics, by slowing GI transit, may also decrease levodopa bioavailability; however, this mechanism appears to be of modest clinical significance. Antimuscarinic agents targeted specifically for urinary incontinence may be less likely to produce pronounced effects on levodopa response than those with more pronounced systemic action.
Dextromethorphan; Bupropion: (Moderate) Use bupropion and levodopa with caution and monitor for CNS toxicity, including restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness, which may result from cumulative dopamine agonist effects.
Dicyclomine: (Minor) Anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
Diphenoxylate; Atropine: (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
Doxazosin: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Droperidol: (Major) Droperidol, a butyrophenone derivative, is a dopamine D2 receptor antagonist and thus, may reduce the therapeutic effects of levodopa, which is an agonist at dopamine D2 receptors. Avoidance of droperidol use in a patient with Parkinson's disease may be advisable unless the benefit of droperidol outweighs the risk of CNS depressive effects and decreased therapeutic response to dopamine agonists.
Droxidopa: (Major) Droxidopa is directly metabolized to norepinephrine by dopa-decarboxylase; therefore, coadministration with dopa-decarboxylase inhibitors (e.g., carbidopa) may prevent the conversion of droxidopa to norepinephrine outside of the central nervous system (CNS). Patients in the clinical trials with droxidopa received concomitant medications used to treat Parkinson's disease. Patients taking droxidopa with levodopa/dopa-decarboxylase inhibitor combinations (e.g., carbidopa; levodopa or carbidopa; levodopa; entacapone) had decreased clearance of droxidopa, an increase in exposure (AUC) to droxidopa of approximately 100%, and an increase in exposure to 3-OM-DOPS of approximately 50%. However, in clinical trials, it was found that the decreased clearance was not associated with a significant need for a different treatment dose or increases in associated adverse events. No dose adjustments are expected to be required. However, the manufacturer states that in some patients, it is possible that dose adjustments for droxidopa will be required.
Eplerenone: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Epoprostenol: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Esketamine: (Major) Because of the possibility of additive sedative effects, caution is advisable during concurrent use of dopaminergic agents, such as levodopa, and CNS depressants, such as esketamine. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and levodopa. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as levodopa, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Ferric Maltol: (Moderate) Administration of iron salts, including polysaccharide-iron complex or multivitamins containing iron, should be separated from oral levodopa by at least 2 hours to avoid reduction in levodopa efficacy. Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa products.
Fluphenazine: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other.
Food: (Major) Advise patients to avoid cannabis use while taking CNS depressants due to the risk for additive CNS depression and potential for other cognitive adverse reactions. (Major) Many levodopa products may be taken with or without food. Follow the directions of the product prescribed. However, foods with a high protein content may delay or impair the oral absorption of levodopa and may reduce efficacy. The Parkinson's Foundation states that most patients have no problem taking levodopa-containing products with meals, but some experience less benefit if they take such products with a stomach full of protein (including meats, cheeses and other dairy products). When this occurs, it is recommended to only take carbidopa/levodopa along with non-protein foods. For patients with more advanced PD, it is best to take levodopa-containing medications 30 to 60 minutes before eating a meal to limit food interference. If nausea occurs, the products may be taken with a small non-protein snack, such as fruit or a cracker, to help. (Major) Patients with Parkinson's disease should avoid foods high in fat around the time of taking carbidopa; levodopa. These foods may delay gastric emptying, which can decrease and delay the absorption of levodopa. (Major) Patients with Parkinson's disease should avoid foods high in fiber around the time of taking carbidopa; levodopa. These foods may delay gastric emptying, which can decrease and delay the absorption of levodopa.
Fosphenytoin: (Moderate) Monitor for loss of efficacy in during concomitant use of levodopa and fosphenytoin. The beneficial effects of levodopa in Parkinson disease have been reported to be revered by phenytoin.
Gabapentin: (Major) Initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of gabapentin and levodopa. Concomitant use of gabapentin with levodopa may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression. Dopaminergic agents, such as levodopa, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Glycopyrrolate: (Moderate) Coadministration of glycopyrrolate with levodopa may decrease levodopa serum concentrations. If coadministration is necessary, monitor clinical response to levodopa and increase levodopa dose accordingly.
Glycopyrrolate; Formoterol: (Moderate) Coadministration of glycopyrrolate with levodopa may decrease levodopa serum concentrations. If coadministration is necessary, monitor clinical response to levodopa and increase levodopa dose accordingly.
Guanfacine: (Moderate) Monitor blood pressure during concomitant use of levodopa and central-acting adrenergic agents due to risk for additive hypotension.
Haloperidol: (Major) Due to opposing effects on central dopaminergic activity, haloperidol and levodopa may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to haloperidol. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Monitor blood pressure during concomitant use of levodopa and central-acting adrenergic agents due to risk for additive hypotension.
Hyoscyamine: (Minor) Through its central antimuscarinic actions, hyoscyamine can potentiate the dopaminergic effects of levodopa. Clinicians should be ready to decrease doses of levodopa if hyoscyamine is added.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Minor) Through its central antimuscarinic actions, hyoscyamine can potentiate the dopaminergic effects of levodopa. Clinicians should be ready to decrease doses of levodopa if hyoscyamine is added.
Iloprost: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Indacaterol; Glycopyrrolate: (Moderate) Coadministration of glycopyrrolate with levodopa may decrease levodopa serum concentrations. If coadministration is necessary, monitor clinical response to levodopa and increase levodopa dose accordingly.
Iron Salts: (Moderate) Administration of iron salts, including polysaccharide-iron complex or multivitamins containing iron, should be separated from oral levodopa by at least 2 hours to avoid reduction in levodopa efficacy. Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa products.
Iron: (Moderate) Administration of iron salts, including polysaccharide-iron complex or multivitamins containing iron, should be separated from oral levodopa by at least 2 hours to avoid reduction in levodopa efficacy. Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa products.
Isocarboxazid: (Contraindicated) Levodopa is contraindicated for concurrent use with non-selective MAOIs, such as isocarboxazid. Levodopa, a catecholamine precursor, can lead to a relative catecholamine (e.g., dopamine, norepinephrine, and epinephrine) excess when combined with a MAOI. Hypertensive crisis and other adverse cardiovascular effects can occur. At least 2 weeks should elapse between discontinuation of one agent and initiation of therapy with the other.
Isoflurane: (Major) If administered before halogenated anesthetics, levodopa without a concurrent decarboxylase inhibitor has been associated with cardiac arrhythmias. This interaction is presumably due to the levodopa-induced increases in plasma dopamine. Levodopa single-agent therapy should be discontinued 6 to 8 hours before administering halogenated anesthetics. Otherwise, when general anesthesia is required, levodopa may be continued as long as the patient is permitted to take oral medication. Patients should be observed for signs of neuroleptic malignant syndrome while therapy is interrupted, and the usual levodopa regimen should be administered as soon as the patient is able to take oral medication.
Isoniazid, INH: (Major) Concurrent use of levodopa with drugs that have MAOI-type activity, such as isoniazid, INH should be avoided if possible. Levodopa, a catecholamine precursor, can lead to a relative catecholamine (e.g., dopamine, norepinephrine, and epinephrine) excess when combined with a MAOI. Hypertension and other adverse cardiovascular effects can occur. (Major) There was a 5% incidence of generalized polyneuropathy during clinical trial evaluation of carbidopa; levodopa enteral suspension (Duopa). The manufacturer recommends an initial evaluation for signs and symptoms of peripheral neuropathy, and periodic monitoring for peripheral neuropathy during treatment with Duopa, particularly in patients receiving other medications that are associated with neuropathy. Isoniazid, INH can cause peripheral neuropathy due to pyridoxine antagonism or increased excretion of pyridoxine. In addition, concomitant use of carbidopa; levodopa and drugs with monoamine oxidase inhibitor (MAOI) activity, such as isoniazid, INH, can result in hypertensive crisis or unstable blood pressure changes. Simultaneous use of these agents or combination products containing isoniazid (e.g., isoniazid, INH; pyrazinamide, PZA; rifampin or isoniazid, INH; rifampin) should be avoided if possible.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Concurrent use of levodopa with drugs that have MAOI-type activity, such as isoniazid, INH should be avoided if possible. Levodopa, a catecholamine precursor, can lead to a relative catecholamine (e.g., dopamine, norepinephrine, and epinephrine) excess when combined with a MAOI. Hypertension and other adverse cardiovascular effects can occur. (Major) There was a 5% incidence of generalized polyneuropathy during clinical trial evaluation of carbidopa; levodopa enteral suspension (Duopa). The manufacturer recommends an initial evaluation for signs and symptoms of peripheral neuropathy, and periodic monitoring for peripheral neuropathy during treatment with Duopa, particularly in patients receiving other medications that are associated with neuropathy. Isoniazid, INH can cause peripheral neuropathy due to pyridoxine antagonism or increased excretion of pyridoxine. In addition, concomitant use of carbidopa; levodopa and drugs with monoamine oxidase inhibitor (MAOI) activity, such as isoniazid, INH, can result in hypertensive crisis or unstable blood pressure changes. Simultaneous use of these agents or combination products containing isoniazid (e.g., isoniazid, INH; pyrazinamide, PZA; rifampin or isoniazid, INH; rifampin) should be avoided if possible.
Isoniazid, INH; Rifampin: (Major) Concurrent use of levodopa with drugs that have MAOI-type activity, such as isoniazid, INH should be avoided if possible. Levodopa, a catecholamine precursor, can lead to a relative catecholamine (e.g., dopamine, norepinephrine, and epinephrine) excess when combined with a MAOI. Hypertension and other adverse cardiovascular effects can occur. (Major) There was a 5% incidence of generalized polyneuropathy during clinical trial evaluation of carbidopa; levodopa enteral suspension (Duopa). The manufacturer recommends an initial evaluation for signs and symptoms of peripheral neuropathy, and periodic monitoring for peripheral neuropathy during treatment with Duopa, particularly in patients receiving other medications that are associated with neuropathy. Isoniazid, INH can cause peripheral neuropathy due to pyridoxine antagonism or increased excretion of pyridoxine. In addition, concomitant use of carbidopa; levodopa and drugs with monoamine oxidase inhibitor (MAOI) activity, such as isoniazid, INH, can result in hypertensive crisis or unstable blood pressure changes. Simultaneous use of these agents or combination products containing isoniazid (e.g., isoniazid, INH; pyrazinamide, PZA; rifampin or isoniazid, INH; rifampin) should be avoided if possible.
Isoproterenol: (Major) Levodopa is the metabolic precursor to dopamine. Since a portion of administered levodopa is converted to dopamine peripherally, concomitant administration with isoproterenol should be used with caution as the risk of cardiovascular toxicity is increased.
Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and levodopa. Concurrent use may result in additive CNS depression. Dopaminergic agents, such as levodopa, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lemborexant and levodopa. Dosage adjustments of lemborexant and levodopa may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Administration of iron salts, including polysaccharide-iron complex or multivitamins containing iron, should be separated from oral levodopa by at least 2 hours to avoid reduction in levodopa efficacy. Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa products.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Administration of iron salts, including polysaccharide-iron complex or multivitamins containing iron, should be separated from oral levodopa by at least 2 hours to avoid reduction in levodopa efficacy. Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa products.
Linezolid: (Major) Concomitant use of levodopa (including carbidopa; levodopa and carbidopa; levodopa; entacapone) and drugs with monoamine oxidase inhibitor (MAOI) activity, such as linezolid, can result in hypertensive crisis. Simultaneous use of these agents should be avoided if possible.
Loop diuretics: (Moderate) Monitor blood pressure during concomitant levodopa and loop diuretic use due to risk for additive hypotension; a loop diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Loxapine: (Major) Due to opposing effects on central dopaminergic activity, loxapine and levodopa may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to loxapine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Macimorelin: (Major) Avoid use of macimorelin with drugs that may transiently elevate growth hormone concentrations, such as levodopa. Healthcare providers are advised to discontinue levodopa therapy and observe a sufficient washout period before administering macimorelin. Use of these medications together may impact the accuracy of the macimorelin growth hormone test.
Maprotiline: (Moderate) Maprotiline exhibits antimuscarinic activity and can decrease gastric motility, decreasing the bioavailability of levodopa. In addition, severe hypertension occurred in a limited number of patients who received levodopa in combination with a tricyclic antidepressant.
Mecamylamine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Methamphetamine: (Major) Levodopa, due to its conversion to dopamine, may increase the risk of developing amphetamine-induced cardiac arrhythmias; dosage reductions of amphetamines are recommended if the two agents are used concurrently.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Minor) Through its central antimuscarinic actions, hyoscyamine can potentiate the dopaminergic effects of levodopa. Clinicians should be ready to decrease doses of levodopa if hyoscyamine is added.
Methscopolamine: (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
Methyldopa: (Moderate) Monitor blood pressure during concomitant use of levodopa and central-acting adrenergic agents due to risk for additive hypotension.
Metoclopramide: (Major) Metoclopramide is a central dopamine antagonist. Metoclopramide can antagonize the actions of dopamine agonists such as levodopa. In addition, metoclopramide may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Dyskinesias and other extrapyramidal effects have been reported during treatment with various anti-parkinson's medications, particularly levodopa. A symptom complex resembling neuroleptic malignant syndrome in association with rapid dose reduction, withdrawal of, or changes in anti-parkinsonian therapy has also been observed. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and dopamine agonists; however, coadministration should be avoided if possible.
Metyrosine: (Major) The extrapyramidal effects of metyrosine can antagonize the effects of levodopa. Dosage adjustments of either of these medications may be required.
Molindone: (Major) Due to opposing effects on central dopaminergic activity, molindone and levodopa may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Animal studies have not shown increased toxicity when molindone is given concurrently with representative members of the antiparkinson drugs class.
Nabilone: (Major) Because of the possibility of additive sedative effects, caution is advisable during concurrent use of dopaminergic agents, such as levodopa, and CNS depressants. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Neostigmine; Glycopyrrolate: (Moderate) Coadministration of glycopyrrolate with levodopa may decrease levodopa serum concentrations. If coadministration is necessary, monitor clinical response to levodopa and increase levodopa dose accordingly.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Administration of iron salts, including polysaccharide-iron complex or multivitamins containing iron, should be separated from oral levodopa by at least 2 hours to avoid reduction in levodopa efficacy. Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa products.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Administration of iron salts, including polysaccharide-iron complex or multivitamins containing iron, should be separated from oral levodopa by at least 2 hours to avoid reduction in levodopa efficacy. Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa products.
Oliceridine: (Major) Concomitant use of oliceridine with levodopa may cause excessive sedation and somnolence. Limit the use of oliceridine with levodopa to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Oxybutynin: (Minor) Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. Antimuscarinics, by slowing GI transit, may also decrease levodopa bioavailability; however, this mechanism appears to be of modest clinical significance. Antimuscarinic agents targeted specifically for urinary incontinence may be less likely to produce pronounced effects on levodopa response than those with more pronounced systemic action.
Papaverine: (Major) The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by coadministration of papaverine; avoid concurrent use in these patients. Papaverine may block dopamine receptors in the striatum and result in loss of control of Parkinson's disease in patients who are taking levodopa.
Perphenazine: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other.
Perphenazine; Amitriptyline: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other.
Phenelzine: (Contraindicated) Levodopa is contraindicated for concurrent use with non-selective MAOIs, such as phenelzine, due to increased risk of hypertensive crisis. At least 2 weeks should elapse between discontinuation of one agent and initiation of therapy with the other.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added. (Minor) Through its central antimuscarinic actions, hyoscyamine can potentiate the dopaminergic effects of levodopa. Clinicians should be ready to decrease doses of levodopa if hyoscyamine is added.
Phenothiazines: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other.
Phenoxybenzamine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Phenytoin: (Moderate) Monitor for loss of efficacy in during concomitant use of levodopa and phenytoin. The beneficial effects of levodopa in Parkinson disease have been reported to be revered by phenytoin.
Pimozide: (Major) Due to opposing effects on central dopaminergic activity, pimozide and levodopa may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to pimozide. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Polysaccharide-Iron Complex: (Moderate) Administration of iron salts, including polysaccharide-iron complex or multivitamins containing iron, should be separated from oral levodopa by at least 2 hours to avoid reduction in levodopa efficacy. Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa products.
Potassium-sparing diuretics: (Moderate) Monitor blood pressure during concomitant levodopa and potassium-sparing diuretic use due to risk for additive hypotension; a potassium-sparing diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Pramipexole: (Minor) Pramipexole increases the Cmax of levodopa and decreases Tmax from 2.5 to 0.5 hrs.
Prazosin: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Pregabalin: (Major) Initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of pregabalin and levodopa. Concomitant use of pregabalin with levodopa may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression. Dopaminergic agents, such as levodopa, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Procarbazine: (Major) Concomitant use of levodopa and drugs with monoamine oxidase inhibitor (MAOI) activity (e.g., procarbazine) can result in hypertensive crisis. Simultaneous use of these agents should be avoided if possible.
Prochlorperazine: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other.
Promethazine: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other.
Promethazine; Dextromethorphan: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other.
Promethazine; Phenylephrine: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other.
Propantheline: (Moderate) Anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
Propofol: (Major) If administered before halogenated anesthetics, levodopa without concomitant use of a decarboxylase inhibitor has been associated with cardiac arrhythmias. This interaction is presumably due to the levodopa-induced increases in plasma dopamine. Levodopa single-agent therapy should be discontinued 6 to 8 hours before administering halogenated anesthetics. Otherwise, when general anesthetics are required, levodopa may be continued as long as the patient is permitted to take oral medication. Patients should be observed for signs of neuroleptic malignant syndrome while therapy is interrupted, and the usual levodopa regimen should be administered as soon as the patient is able to take oral medication.
Pyridoxine, Vitamin B6: (Moderate) Monitor for reduced levodopa efficacy during concomitant use of pyridoxine (vitamin B6). Pyridoxine, in doses as low as 10 mg/day, may reverse the effects of levodopa by increasing the rate of aromatic amino acid decarboxylation. Carbidopa inhibits this action of pyridoxine.
Rasagiline: (Moderate) There may be some increase in rasagiline blood levels in the presence of levodopa, the effect is modest and rasagiline dosing need not be modified in the presence of carbidopa; levodopa. Rasagiline and carbidopa; levodopa are frequently used together; however, there is the possibility of increased dyskinesia and postural hypotension when combined.
Rotigotine: (Moderate) In clinical studies, concurrent use of L-dopa/carbidopa with rotigotine had no effect on the pharmacokinetics of either agent. However, rotigotine may potentiate the dopaminergic side effects of levodopa via a pharmacodynamic interaction. Subsequent worsening of pre-existing dyskinesias may occur.
Safinamide: (Moderate) Safinamide and carbidopa; levodopa are indicated for use in combination; however, there is the possibility of new onset dyskinesias or exacerbation of pre-existing dyskinesias. Patients should be advised to contact their health care provider if they notice new or worsening dyskinesias while taking these medicines together.
Sapropterin: (Major) Coadministration of sapropterin and levodopa has been associated with seizures. Post-marketing safety surveillance showed 3 patients (all with underlying neurologic disorder) develop convulsions, exacerbation of convulsions, over-stimulation, or irritability while receiving concomitant levodopa and sapropterin.
Scopolamine: (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
Selegiline: (Moderate) Monitor blood pressure during concomitant use of levodopa and selegiline. Concomitant use of levodopa with selective MAO-B inhibitors may be associated with orthostatic hypotension.
Sevoflurane: (Major) If administered before halogenated anesthetics, levodopa without a concurrent decarboxylase inhibitor has been associated with cardiac arrhythmias. This interaction is presumably due to the levodopa-induced increases in plasma dopamine. Levodopa single-agent therapy should be discontinued 6 to 8 hours before administering halogenated anesthetics. Otherwise, when general anesthesia is required, levodopa may be continued as long as the patient is permitted to take oral medication. Patients should be observed for signs of neuroleptic malignant syndrome while therapy is interrupted, and the usual levodopa regimen should be administered as soon as the patient is able to take oral medication.
Sodium Ferric Gluconate Complex; ferric pyrophosphate citrate: (Moderate) Administration of iron salts, including polysaccharide-iron complex or multivitamins containing iron, should be separated from oral levodopa by at least 2 hours to avoid reduction in levodopa efficacy. Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa products.
Solifenacin: (Minor) Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. Antimuscarinics, by slowing GI transit, may also decrease levodopa bioavailability; however, this mechanism appears to be of modest clinical significance. Antimuscarinic agents targeted specifically for urinary incontinence may be less likely to produce pronounced effects on levodopa response than those with more pronounced systemic action.
Solriamfetol: (Moderate) Monitor for dopamine-mediated effects including nausea, vomiting, dizziness, tremor, and changes in moods or behaviors if solriamfetol, a central dopamine and norepinephrine reuptake inhibitor, is administered with other dopaminergic drugs, such as levodopa. Caution is recommended since this combination has not been evaluated.
Tedizolid: (Major) Concomitant use of levodopa and drugs with monoamine oxidase inhibitor (MAOI) activity (e.g., tedizolid) can result in hypertensive crisis or unstable blood pressure changes. Simultaneous use of these agents should be avoided if possible.
Tetrabenazine: (Moderate) Monitor for a decrease in levodopa efficacy during concomitant tetrabenazine use. Levodopa and tetrabenazine may antagonize each other's effects: levodopa is metabolized to dopamine while tetrabenazine depletes dopamine stores and acts as a dopamine receptor blocker. While concomitant use is generally not recommended for this reason, combination therapy may be beneficial in the management of some levodopa-related dyskinesias.
Thiazide diuretics: (Moderate) Monitor blood pressure during concomitant levodopa and thiazide diuretic use due to risk for additive hypotension; a thiazide diuretic dosage adjustment may be necessary. Symptomatic postural hypotension has occurred when carbidopa; levodopa was added in a person receiving antihypertensive drugs.
Thioridazine: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other.
Thiothixene: (Major) Due to opposing effects on central dopaminergic activity, thiothixene and levodopa may interfere with the effectiveness of each other. Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to thiothixene. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors.
Tranylcypromine: (Contraindicated) Levodopa is contraindicated for concurrent use with non-selective MAOIs, such as tranylcypromine, due to the increased risk of hypertensive crisis. At least 2 weeks should elapse between discontinuation of one agent and initiation of therapy with the other.
Treprostinil: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Tricyclic antidepressants: (Moderate) Monitor blood pressure and for symptoms of dyskinesia during concomitant levodopa and tricyclic antidepressant use. There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use.
Trifluoperazine: (Major) Avoid concurrent use if possible and consider an atypical antipsychotic as an alternative to the phenothiazine. If coadministration cannot be avoided, monitor for changes in movement, moods, or behaviors. Due to opposing effects on central dopaminergic activity, phenothiazines and levodopa may interfere with the effectiveness of each other.
Trihexyphenidyl: (Minor) The doses of trihexyphenidyl and levodopa may need to be adjusted when the drugs are given simultaneously. Trihexyphenidyl can potentiate the dopaminergic effects of levodopa.
Vasodilators: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.

Atamet/Carbidopa, Levodopa/Dhivy/SINEMET Oral Tab: 10-100mg, 25-100mg, 25-250mg
Carbidopa, Levodopa/Parcopa Oral Tab Orally Dis: 10-100mg, 25-100mg, 25-250mg
Carbidopa, Levodopa/SINEMET/SINEMET CR Oral Tab ER: 25-100mg, 50-200mg
Duopa Intrajejunal Susp: 1mL, 4.63-20mg
Rytary Oral Cap ER: 23.75-95mg, 36.25-145mg, 48.75-195mg, 61.25-245mg

NOTE: Experience with daily dosages of carbidopa greater than 200 mg/day PO is limited.
Immediate-release carbidopa; levodopa (e.g., Sinemet): 80 mg/800 mg/day PO using 10 mg/100 mg tablet; 200 mg/800 mg/day PO using 25 mg/100 mg tablet; 200 mg/2,000 mg/day using 25 mg/250 mg tablet.
Immediate-release carbidopa;levodopa functionally-scored tablets (e.g., Dhivy): 200 mg/800 mg/day PO using 25 mg/100 mg tablet.
Extended-release tablets (e.g., Sinemet CR): Most patients are adequately controlled on doses that provide up to 1,600 mg/day PO of levodopa.
Extended-release capsules (e.g., Rytary): 612.5 mg/2,450 mg/day PO.
Enteral suspension (e.g., Duopa): 2,000 mg/day of the levodopa component administered enterally over 16 hours.

NOTE: Experience with daily dosages of carbidopa greater than 200 mg/day PO is limited.
Immediate-release carbidopa; levodopa (e.g., Sinemet): 80 mg/800 mg/day PO using 10 mg/100 mg tablet; 200 mg/800 mg/day PO using 25 mg/100 mg tablet; 200 mg/2,000 mg/day using 25 mg/250 mg tablet.
Immediate-release carbidopa;levodopa functionally-scored tablets (e.g., Dhivy): 200 mg/800 mg/day PO using 25 mg/100 mg tablet.
Extended-release tablets (e.g., Sinemet CR): Most patients are adequately controlled on doses that provide up to 1,600 mg/day PO of levodopa.
Extended-release capsules (e.g., Rytary): 612.5 mg/2,450 mg/day PO.
Enteral suspension (e.g., Duopa): 2,000 mg/day of the levodopa component administered enterally over 16 hours.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Not indicated.

Not indicated.

The combination of levodopa with carbidopa is used for the treatment of Parkinson's disease. Current evidence indicates that symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson's disease because it does not cross the blood-brain barrier. The administration of these drugs increases dopamine levels within the corpus striatum.
Levodopa: Levodopa is the metabolic precursor of dopamine. Levodopa diffuses into the central nervous system where it is converted to dopamine. The resulting change in dopamine-acetylcholine balance is believed to improve nerve impulse control and to be the basis of the drug's antiparkinsonian activity.
Carbidopa: Carbidopa is a noncompetitive decarboxylase inhibitor that, when administered with levodopa, inhibits the peripheral conversion of levodopa to dopamine, thereby increasing the CNS bioavailability of levodopa by roughly 75%. Carbidopa does not cross the blood-brain barrier. The addition of carbidopa allows lower doses of levodopa to be used and minimizes adverse reactions from levodopa such as nausea and vomiting. The carbidopa-levodopa combination also allows for a more rapid and even titration of levodopa dosage. With combination therapy, certain adverse effects (e.g., dyskinesias) will occur sooner and at lower levodopa dosages during therapy than with levodopa alone, as these adverse effects are centrally mediated.

The combination of carbidopa-levodopa is administered orally as regular-release tablets, extended-release tablets, and extended-release capsules, and as an enteral suspension delivered into the jejunum via a programmable enteral infusion pump. Carbidopa-levodopa distributes throughout the body. Plasma protein binding of carbidopa and levodopa are clinically insignificant. Less than 1% of levodopa would reach the CNS if given without carbidopa. Carbidopa reduces the dosage of levodopa required to produce a given effect in the CNS by about 75%. Carbidopa does not penetrate the CNS. When administered with levodopa, carbidopa inhibits the peripheral metabolism of levodopa resulting in increases in both plasma levels and the plasma half-life of levodopa and decreases levels of dopamine and homavanillic acid in the plasma and urine. Carbidopa allows a larger percentage of the levodopa dose to enter the CNS where it is metabolized to dopamine by L-aromatic amino acid decarboxylase and 3-O-methyldopa. Peripheral dopa-decarboxylase may be saturated by carbidopa in other carbidopa/levodopa products at 70—100 mg/day, which produces equivalent exposure to 140—200 mg of carbidopa in the extended-release capsules. The two metabolites of carbidopa are primarily eliminated in the urine unchanged or as a glucuronide. Unchanged carbidopa accounts for 30% of the total urinary elimination. The plasma half-life of levodopa in the presence of carbidopa is roughly 1—2 hours. The half-life of carbidopa is about 2 hours. Carbidopa; levodopa is eliminated renally as dopamine metabolites and small amounts of unchanged drug.
 
The full therapeutic effects of conventional carbidopa-levodopa dosage forms at any given dosage can be observed 2—3 weeks after therapy is first initiated, but some patients require up to 6 months before maximal response to a given dosage is seen.
 
Affected cytochrome P450 (CYP450) enzymes and drug transporters: None.

After oral administration, amino acid transport mechanisms carry levodopa across the membrane of the GI tract, with approximately 30—50% of the drug entering the circulation. As a result, it is thought that high concentrations of amino acids in the GI tract (i.e., a high-protein diet) can interfere with absorption of levodopa. There is evidence, however, to suggest that amino acid-levodopa transport competition is more likely to occur during levodopa active transport across the blood-brain barrier.
Immediate release tablets: At steady-state, the bioavailability of levodopa is 99%. The bioavailability of carbidopa at steady state is 99% from the regular-release tablet. The time to Cmax after a single dose is 0.5 hours. Following administration of the regular release tablets, the duration of action is 5 hours. However, the duration of effect is patient- and disease-dependent; some patients with advanced disease require every 2 hour dosing of immediate-release levodopa formulations.
Extended-release tablets: At steady-state, the bioavailability of levodopa in the extended-release tablet is 70—75% compared with regular-release tablets. The bioavailability of carbidopa at steady state from the extended-release tablet is 58%. The time to Cmax after a single dose is 2 hours for the extended-release tablet. The bioavailability and Cmax of levodopa after a single dose of a carbidopa 50 mg/levodopa 200 mg extended-release tablet increased by 50% and 25%, respectively, when administered with food. During clinical studies using similar daily doses, plasma levodopa concentrations with the extended-release tablet fluctuated in a narrower range than those with the regular-release tablets. Plasma trough levels were higher with the extended-release tablet. The extended-release tablet releases levodopa and carbidopa over a 4- to 6-hour period; the apparent half-life of levodopa may be prolonged because of continuous absorption.
Extended-release capsules: At steady-state, the bioavailability of levodopa is 70% for the extended-release capsule relative to regular-release tablet. The bioavailability of carbidopa at steady state is 50% from the extended-release capsules. Maximum concentrations of the carbidopa component of the extended-release capsule occur at about 3 hours, while the levodopa component achieves an initial peak concentration in 1 hour. In one study of healthy adults, a high-fat, high-calorie meal reduced the Cmax of the extended-release capsules by about 21% and increased the AUC about 13% for levodopa compared to administration in a fasted state. There may be a delay of 2 hours in the absorption of the extended-release capsules when taken with a high-fat, high-calorie meal, and absorption may be decreased by a high protein meal. However, the manufacturer states that the product may be taken with or without food. Plasma concentrations are maintained for about 4 to 5 hours before declining.

Intrajejunal Route (Duopa)
Following a 16-hour intrajejunal infusion of Duopa via a PEG-J tube, peak plasma levels of levodopa occur at approximately 2.5 hours. The gastric emptying rate does not influence the absorption since the enteral suspension is administered by continuous intestinal infusion. In a population pharmacokinetic analysis, the enteral suspension had comparable bioavailability to oral immediate-release carbidopa; levodopa (25/100 mg) tablets. The estimated bioavailability for levodopa from the enteral suspension relative to oral immediate-release carbidopa; levodopa tablets is 97%. The absorption of levodopa may be decreased in patients on a high-protein diet due to competition between levodopa and certain amino acids for transportation across the gut wall.

There are no adequate or well-controlled studies of carbidopa; levodopa during pregnancy. Because the pregnancy outcome data are too limited to be conclusive, carbidopa; levodopa should be used in pregnancy only if the potential benefit outweighs the potential risk to the fetus. It has been reported from individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized. Instruct female patients to notify their physicians if they become pregnant or intend to become pregnant during carbidopa; levodopa therapy. Limited data suggest that carbidopa crosses the placenta in humans in low concentrations. Levodopa crosses the placenta and reaches levels in the fetus comparable to maternal blood, although pregnancy outcomes have been primarily unremarkable. Two miscarriages were reported in the first trimester during use of carbidopa-levodopa, and 1 infant exposed to levodopa in utero was reported to have osteomalacia. Maternal complications reported in 3 pregnancies during use of carbidiopa-levodopa included first trimester vaginal bleeding, third trimester nausea and vomiting, depression, and preeclampsia. In animals, administration of carbidopa-levodopa during pregnancy was associated with developmental toxicity, including increased incidences of fetal malformations. Visceral and skeletal malformations were observed in rabbits at all doses and ratios of carbidopa-levodopa tested. In rats, there was a decrease in live births. The effects of carbidopa; levodopa in labor and delivery are unknown.

Caution should be exercised when carbidopa; levodopa is administered to a woman who is breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. It is not known whether carbidopa is excreted in human milk. Levodopa has been detected in human milk; however, there are no adequate data on the effects of levodopa or carbidopa on the breastfed infant, or the effects of milk production. In a case report of a breast-feeding mother with Parkinson's disease receiving sustained-release (SR) carbidopa/levodopa 50/200 mg 4 times daily, peak levels of levodopa in milk occurred 3 hours after a dose and returned to baseline after 6 hours. After receiving the same dose of the immediate-release (IR) formulation, similar results were observed, with the exception of a higher milk:plasma ratio with the IR product (0.32 vs. 0.28). The infant ingested 0.127 mg and 0.181 mg of levodopa after maternal intake of the SR and IR products, respectively. It was estimated that the infant received an average of 0.3% of the maternal weight-adjusted dosage of the SR product and 0.5% of the maternal weight-adjusted dose of the IR product. Levodopa did not inhibit lactation. No adverse effects were observed in her infant, whose development was normal at 2 years of age. The authors suggest that nursing or pumping milk at times of lower levodopa breast milk levels may help minimize the amount of levodopa received by an infant. Because levodopa can inhibit prolactin secretion, interference with lactation is possible. Partial to complete suppression of lactation has been observed in female patients given levodopa for galactorrhea. If carbidopa; levodopa must be administered during breast-feeding, the breast-fed infant should be monitored for commonly encountered adverse effects associated with dopaminergic therapy including dyskinesias, insomnia, sedation, nausea, and constipation.