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    Anti-Parkinson Drugs, Dopamine Precursors

    DEA CLASS

    Rx

    DESCRIPTION

    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

    COMMON BRAND NAMES

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

    HOW SUPPLIED

    Atamet/Carbidopa, Levodopa/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

    DOSAGE & INDICATIONS

    For the treatment of idiopathic Parkinson's disease, post-encephalitic parkinsonism, and symptomatic parkinsonism that may follow injury to the nervous system by carbon monoxide intoxication and/or manganese intoxication.
    For the treatment of motor fluctuations in patients with advanced Parkinson's disease.
    Enteral suspension dosage (naso-jejunal tube for short-term administration or PEG-J for long-term administration)
    Adults

    Prior to initiating the enteral suspension on Day 1, convert patients from all other forms of levodopa to oral immediate-release carbidopa; levodopa tablets (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. Healthcare providers should 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 patient's level of activity and disease progression. The maximum recommended daily dose of carbidopa; levodopa 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, patients will disconnect the pump from the PEG-J and take their night-time dose of oral immediate-release carbidopa-levodopa tablets. 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 milliliters. Add 3 mLs 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 per 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 occur, consider decreasing the continuous dose or stopping the infusion until the adverse reactions 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 less than or equal to 6 mL, 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 adverse reactions 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 the patient’s clinical response. Consider decreasing the continuous dose if the patient experienced troublesome dyskinesia, or other troublesome treatment-related adverse reactions on the preceding day as follows: For troublesome adverse reactions lasting 1 hour or more, decrease the continuous dose by 0.3 mL/hour. For troublesome adverse reactions 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. The extra dose frequency should be limited 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 tablets. 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.

    Oral dosage (immediate-release tablets; e.g., Sinemet)
    Adults

    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. 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.

    Oral dosage (extended-release tablets; e.g., Sinemet CR)
    Adults

    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).

    Oral dosage (extended-release capsules; e.g., Rytary)
    Adults

    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.

    For the treatment of restless legs syndrome (RLS)†.
    Oral dosage
    Adults

    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.

    For the treatment of amblyopia†.
    Oral dosage (immediate-release products)
    Children 4 years and older and Adolescents

    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

    MAXIMUM DOSAGE

    Adults

    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/2000 mg/day using 25 mg/250 mg tablet.
    Extended-release tablets (e.g., Sinemet CR): Most patients are adequately controlled on doses that provide up to 1600 mg/day PO of levodopa.
    Extended-release capsules (e.g., Rytary): 612.5 mg/2450 mg/day PO.
    Enteral suspension (e.g., Duopa): 2000 mg/day of the levodopa component administered enterally over 16 hours.

    Geriatric

    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/2000 mg/day using 25 mg/250 mg tablet.
    Extended-release tablets (e.g., Sinemet CR): Most patients are adequately controlled on doses that provide up to 1600 mg/day PO of levodopa.
    Extended-release capsules (e.g., Rytary): 612.5 mg/2450 mg/day PO.
    Enteral suspension (e.g., Duopa): 2000 mg/day of the levodopa component administered enterally over 16 hours.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Not indicated.

    Neonates

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

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

    Renal Impairment

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

    ADMINISTRATION

    Oral Administration

    Many products may be taken with or without food. However, 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.
    Do not administer at the same time as a multivitamin containing iron or iron supplements as these may reduce 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.

    Oral Solid Formulations

    Immediate-release tablets (e.g., Sinemet):
    Administer with 6 to 8 ounces of water at least 30 minutes before eating or 1 hour after meals to maximize absorption.
    May be taken with a small non-protein snack, such as fruit or a cracker, to avoid nausea.
    Administer at regular intervals as prescribed to provide therapeutic coverage and lessen "wearing off" time.
     
    Extended-release tablets (e.g., Sinemet CR):
    Do not crush or chew; swallow intact.
    Dosing intervals range from 4 to 8 hours while awake and are individualized to the patient.
     
    Extended-release capsules (Rytary):
    Swallow whole. Do not chew, divide or crush the capsules.
    May give with or without food. A high-fat, high-calorie meal may delay the absorption of levodopa by about 2 hours.
    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-Oral

    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.

    Other Administration Route(s)

    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.

    STORAGE

    Atamet:
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Duopa:
    - Prior to dispensing, store in refrigerator (36 to 46 degrees F)
    - Protect from light
    - Store at -4 degrees F
    - Store in carton until time of use
    Parcopa:
    - Protect from light
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Rytary:
    - Protect from light
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    SINEMET:
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    SINEMET CR:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    The administration of carbidopa; levodopa is contraindicated in any patient who has demonstrated a hypersensitivity to carbidopa, levodopa, or any inactive ingredients in the formulations.

    Dyskinesia

    Carbidopa; levodopa therapy can cause dyskinesias that may require a dosage reduction of the product used or a dosage reduction of other medications used for the treatment of Parkinson's disease. Because carbidopa permits more levodopa to reach the brain and more dopamine to be formed, dyskinesias (involuntary movements), may occur at lower dosages and sooner with carbidopa; levodopa than with levodopa alone.

    Abrupt discontinuation, hyperthermia, mental status changes, surgery

    Avoid abrupt discontinuation of carbidopa; levodopa therapy. Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been associated with dose reductions and withdrawal of carbidopa, levodopa or other medications with dopaminergic properties, and may be life-threatening. Hyperpyrexia and confusion are uncommon but they may be life-threatening with a variety of features, including hyperthermia/fever/hyperpyrexia, muscle rigidity, involuntary movements, altered consciousness/mental status changes, delirium, autonomic dysfunction, tachycardia, tachypnea, sweating, hypo- or hypertension, and abnormal laboratory findings (e.g., creatine phosphokinase (CPK) elevation, leukocytosis, myoglobinuria, and increased serum myoglobin). The early diagnosis of this condition is important for the appropriate management of these patients, which includes intensive medical monitoring and management. 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 anticholinergic toxicity, heat stroke, drug fever, or a primary central nervous system (CNS) pathology. If a patient needs to discontinue or reduce their daily dose of this product, the dose should be decreased slowly, with supervision from a health care provider, especially if the patient is also receiving neuroleptics. If a patient requires general anesthesia for surgery, carbidopa; levodopa may be continued as long as the patient is permitted to take fluids and medication by mouth. Cases of neuroleptic malignant syndrome have been reported post-surgery so close monitoring is warranted; re-institute carbidopa; levodopa therapy as soon as possible after the procedure. In addition, some patients receiving levodopa have experienced postoperative bleeding episodes, so hematological studies are recommended for all patients who undergo surgery while receiving this drug.

    MAOI therapy

    The administration of non-selective monoamine oxidase inhibitor therapy (MAOI therapy) is contraindicated with carbidopa; levodopa. Concomitant use of non-selective MAOIs with carbidopa-levodopa combinations can result in hypertensive crisis. Nonselective MAO inhibitors must be discontinued at least 2 weeks prior to initiating therapy with levodopa; carbidopa. Selective MAO-B inhibitors and other standard drugs for Parkinson's disease may be used concomitantly with carbidopa; levodopa; however, dosage adjustments of therapies may be required.

    Cardiac arrhythmias, cardiac disease, hypotension, myocardial infarction, orthostatic hypotension, syncope

    Caution should be exercised when prescribing carbidopa; levodopa to Parkinson's patients who are prone to hypotension or orthostatic hypotension. Syncope and/or orthostatic hypotension have been reported with drugs that increase dopaminergic tone, including levodopa; carbidopa. Reports of syncope are generally more frequent in patients who have experienced prior episodes of documented hypotension. Monitor for orthostatic hypotension, especially after initiation of treatment or after increasing the carbidopa; levodopa dose. Cardiac monitoring in a facility with provisions for intensive cardiac care is recommended during initial titration of carbidopa-levodopa in Parkinson's patients with significant cardiac disease, including patients a history of myocardial infarction who have residual cardiac arrhythmias (i.e., atrial, nodal, or ventricular arrhythmias).

    Behavioral changes, depression, psychosis, suicidal ideation

    All patients receiving carbidopa; levodopa should be monitored closely for changes in thought processes, moods, or behaviors. Carbidopa; levodopa may cause mental status and behavioral changes, which may be severe, including psychotic-like behavior, during treatment. All patients should be observed carefully for the development of depression with concomitant suicidal tendencies or suicidal ideation. Patients with past or current psychosis should be treated with caution. Dopaminergic therapy in patients with Parkinson's disease has been associated with hallucinations and may lead to drug withdrawal or patient hospitalization in rare instances. These reactions are thought to be due to increased brain dopamine following administration of levodopa.

    Coadministration with other CNS depressants, driving or operating machinery, ethanol ingestion

    Carbidopa; levodopa has the potential to cause drowsiness or somnolence. There have been postmarketing reports of patients who have experienced sudden episodes of falling asleep when taking dopaminergic agents. In some cases, excessive drowsiness has resulted in automobile accidents or other harmful events in the course of daily living. Patients should be advised of this effect and be instructed to use extreme caution when driving or operating machinery or performing other tasks that require alertness while receiving carbidopa; levodopa. Reassessment for drowsiness or oversedation is necessary throughout therapy. Sleep disorders, coadministration with other CNS depressants, or interacting medications may increase the risk of falling asleep while on this medication. Patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Advise patients to speak with their health care prescriber before ethanol ingestion or taking sedating medications or before taking other CNS depressant medications because of the possible additive effects in combination with carbidopa; levodopa. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), this drug product should ordinarily be discontinued. If a decision is made to continue treatment, patients should be advised to avoid driving or other potentially dangerous activities. There is insufficient data to establish if dose reduction will eliminate sudden episodes of falling asleep.

    Impulse control symptoms

    Some patients receiving medications that increase dopaminergic tone have reported intense and uncontrollable impulse control symptoms, such as urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, or other intense urges. Advise patients that they may experience impulsive and/or compulsive behaviors while taking 1 or more of the medications used for the treatment of Parkinson's disease. Ask patients about the development of new or increased gambling urges, sexual urges, urges for uncontrolled spending, or other intense urges while being treated with carbidopa; levodopa. Advise patients to inform their physician or health care provider if they experience new or increased symptoms of this type while taking this medication. Consider dose reduction or discontinuation if a patient develops these symptoms during treatment.

    Closed-angle glaucoma

    Carbidopa; levodopa is generally contraindicated for use in patients with closed-angle glaucoma. Levodopa therapy can cause mydriasis which can increase intraocular pressure. Patients with other types of glaucoma may be treated cautiously with carbidopa; levodopa if intraocular pressure is controlled and monitored.

    GI bleeding, GI obstruction, GI perforation, intussusception, peptic ulcer disease

    Carbidopa; levodopa combinations may increase the risk of upper GI bleeding in patients with a history of active peptic ulcer disease, so it should be used with extreme caution in such patients. Because the enteral suspension (i.e., Duopa) is administered into the jejunum using a PEG-J or naso-jejunal tube (NJ tube), intestinal complications can occur. These complications include bezoar, ileus, implant site erosion/ulcer, intestinal hemorrhage, intestinal ischemia, intestinal obstruction, intestinal perforation, intussusception, pancreatitis, peritonitis, pneumoperitoneum, and post-operative wound infection. It may be prudent to use the enteral suspension formulation with caution in patients with a history of GI perforation or GI obstruction or risk factors for these events. These complications may result in serious outcomes, such as death or the need for surgery. Patients should be instructed to notify their healthcare provider immediately if they experience abdominal pain, prolonged constipation, nausea, vomiting, fever, or melanotic stool while receiving carbidopa; levodopa enteral suspension.

    Diabetes mellitus

    Use carbidopa; levodopa with caution during the interpretation of certain urine tests in patients with diabetes mellitus. When a test tape is used for determination of ketonuria in patients taking carbidopa; levodopa, a false-positive urinary ketone test may result. This reaction will not be altered by boiling the urine specimen. Additionally, false-negative tests may result with the use of glucose-oxidase methods of testing for glucosuria.

    Melanoma

    Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk is due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear. Patients and providers are advised to monitor for melanoma frequently and on a regular basis when using carbidopa; levodopa for any indication. Ideally, periodic skin examination should be performed by appropriately qualified individuals (e.g., dermatologists).

    Pheochromocytoma

    Cases of falsely diagnosed pheochromocytoma in patients on carbidopa; levodopa therapy have been reported very rarely. Caution should be exercised when interpreting the plasma and urine levels of catecholamines and their metabolites in patients on carbidopa; levodopa therapy.

    Asthma, pulmonary disease, pulmonary fibrosis, retroperitoneal fibrosis

    Carbidopa; levodopa should be administered cautiously to patients with severe pulmonary disease or bronchial asthma. Use caution when combining carbidopa; levodopa with other dopaminergic treatments. Cases of retroperitoneal fibrosis, pulmonary fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening have been reported in some patients treated with ergot-derived dopaminergic agents. These complications may resolve when the drug is discontinued, but complete resolution does not always occur. Although these adverse reactions may be related to the ergoline structure of these compounds, a possible causal role of non-ergot drugs (e.g., levodopa), which increase dopaminergic activity, has also been considered. The rate of such complications is very low.

    Peripheral neuropathy

    Patients should be evaluated for signs and symptoms of peripheral neuropathy before starting carbidopa; levodopa enteral suspension. In addition, patients should be monitored periodically for signs of neuropathy during treatment with the enteral suspension, particularly those with pre-existing neuropathy or who have a medical condition that may be associated with a risk for neuropathy (e.g., diabetes mellitus, Guillain-Barre syndrome, vitamin B12 deficiency, thiamine deficiency, alcoholism, systemic lupus erythematosus (SLE), acquired immunodeficiency syndrome (AIDS), rheumatoid arthritis). Also use caution in patients who are receiving medications associated with a potential risk for neuropathy (e.g., "statins", metronidazole, some medications for HIV infection, fluoroquinolones, certain chemotherapy agents, or excessive dose of pyridoxine). During clinical trials, 5% of patients treated with the enteral suspension developed a generalized polyneuropathy, most often characterized as sensory or sensorimotor. Electrodiagnostic results were primarily consistent with an axonal polyneuropathy in those patients who underwent the testing (15/16). There was insufficient information to determine the potential role of vitamin deficiencies in the etiology of neuropathy associated with carbidopa; levodopa enteral suspension.

    Hepatic disease, renal disease

    There is a very general precaution that carbidopa; levodopa combinations should be administered with caution to patients with renal disease or hepatic disease. No dosage adjustments are recommended based on renal or hepatic impairment; titration occurs to clinical response.

    Geriatric

    Although no overall meaningful differences in safety or effectiveness were observed between geriatric and younger adults in clinical trials of carbidopa; levodopa, a greater sensitivity of some geriatric patients to the products cannot be ruled out. Therefore, careful monitoring is advisable. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, antiparkinson medications may cause significant confusion, restlessness, delirium, dyskinesia, nausea, dizziness, hallucinations, and agitation. In addition, there is an increased risk of postural hypotension and falls, particularly during concurrent use of antihypertensive medications.

    Pregnancy

    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.

    Breast-feeding

    Caution should be exercised when carbidopa; levodopa is administered to a woman who is breast-feeding. It is not known whether carbidopa is excreted in human milk. Levodopa has been detected in human milk. 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. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants

    Carbidopa; levodopa combinations have not been adequately studied for safety and efficacy in children and adolescents less than 18 years of age. This drug combination is not indicated in infants. Juvenile onset Parkinson's disease is very rare.

    Phenylketonuria

    Patients with phenylketonuria patients should be informed that carbidopa; levodopa orally disintegrating tablets (ODT) contain aspartame, a source of phenylalanine. For example, the Parcopa product contains phenylalanine 3.4 mg per 25/100 ODT, 3.4 mg per 10/100 ODT, and 8.4 mg per 25/250 ODT.

    ADVERSE REACTIONS

    Severe

    akinesia / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    intussusception / Delayed / Incidence not known
    peptic ulcer / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    GI obstruction / Delayed / Incidence not known
    bezoar / Delayed / Incidence not known
    GI perforation / 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
    new primary malignancy / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    suicidal ideation / Delayed / Incidence not known

    Moderate

    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
    hot flashes / Early / Incidence not known
    bullous rash / 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

    Mild

    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
    diarrhea / Early / 0.6-5.0
    vomiting / Early / 1.8-5.0
    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
    dysgeusia / Early / Incidence not known
    hypersalivation / Early / Incidence not known
    hiccups / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    weight gain / Delayed / Incidence not known
    weight loss / Delayed / Incidence not known
    pyrosis (heartburn) / 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
    alopecia / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    flushing / 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

    DRUG INTERACTIONS

    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.
    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.
    Amphetamine; Dextroamphetamine Salts: (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.
    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.
    Apomorphine: (Minor) Concurrent administration of apomorphine and levodopa may significantly reduce the threshold levodopa concentration necessary for an improved motor response, leading to an increased duration of effect without a change in the maximal response to levodopa therapy. Monitor the patient for any needed dosage adjustments.
    Asenapine: (Major) Asenapine is a central dopamine antagonist and may inhibit the clinical response to antiparkinsonian agents with dopamine agonist properties by blocking dopamine receptors in the brain. Due to the CNS depressant effects of asenapine, additive drowsiness may occur with Parkinson's treatments like entacapone, pramipexole, ropinirole, or tolcapone. In general, atypical antipsychotics like asenapine are less likely to interfere with these therapies than traditional antipsychotic agents. However, asenapine should be avoided in patients requiring medication for Parkinson's disease unless the benefit of asenapine therapy outweighs the risk of decreased therapeutic response to levodopa or other treatments.
    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; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (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.
    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.
    Atropine; Diphenoxylate: (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; Edrophonium: (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; Hyoscyamine; Phenobarbital; 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.
    atypical antipsychotic: (Major) Antipsychotic agents may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain. In general, however, the 'atypical antipsychotics' are less likely to interfere with these therapies than traditional antipsychotic agents (e.g., phenothiazines). Antipsychotics should be avoided during therapy for Parkinson's disease unless the benefit of the drug outweighs the risk of decreased therapeutic response to levodopa or other treatments. In general, experts consider quetiapine the atypical antipsychotic of choice in Parkinson's patients due to a lower incidence of extrapyramidal symptoms, although the choice of antipsychotic medication must always be made on a case-by-case decision.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (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.
    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.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (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. Metronidazole has been associated with peripheral neuropathy, with the prevalence and severity of the neuropathy being directly related to the cumulative dose and duration of therapy. Peripheral neuropathy has also been reported in patients treated with other nitroimidazole drugs including tinidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (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. Metronidazole has been associated with peripheral neuropathy, with the prevalence and severity of the neuropathy being directly related to the cumulative dose and duration of therapy. Peripheral neuropathy has also been reported in patients treated with other nitroimidazole drugs including tinidazole.
    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.
    Bupropion: (Major) Use bupropion cautiously in patients taking levodopa or combination drugs containing levodopa (e.g., carbidopa; levodopa and carbidopa; levodopa; entacapone). Both drugs are dopamine agonists; cumulative effects may result in central nervous system (CNS) toxicity. Adverse reactions reported with coadministration have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. If levodopa is used concurrently, low initial dosing and slow dosage titration of bupropion may be warranted.
    Bupropion; Naltrexone: (Major) Use bupropion cautiously in patients taking levodopa or combination drugs containing levodopa (e.g., carbidopa; levodopa and carbidopa; levodopa; entacapone). Both drugs are dopamine agonists; cumulative effects may result in central nervous system (CNS) toxicity. Adverse reactions reported with coadministration have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. If levodopa is used concurrently, low initial dosing and slow dosage titration of bupropion may be warranted.
    Cabergoline: (Minor) Cabergoline and levodopa both increase dopaminergic function centrally. Cabergoline is used as an adjunct to levodopa/carbidopa therapy in patients with Parkinson's disease experiencing motor fluctuations. Although this combination appears safe and effective overall, additive neurologic effects are possible. Hallucinations have been reported with the concurrent use of cabergoline and levodopa.
    Calcium-channel blockers: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Central-acting adrenergic agents: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with levodopa should generally be avoided because of the possibility of additive sedative effects. 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.
    Cetirizine; Pseudoephedrine: (Moderate) Concurrent use of cetirizine/levocetirizine with levodopa should generally be avoided because of the possibility of additive sedative effects. 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.
    Chlorpromazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Chlorthalidone; Clonidine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Clonidine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    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) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Codeine; Promethazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    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.
    Dexmethylphenidate: (Moderate) Increased dopaminergic effects may occur during coadministration of dexmethylphenidate, an inhibitor of dopamine reuptake, and medications that increase dopaminergic activity such as levodopa. Dopaminergic side effects, such as nausea, loss of appetite, weight loss, insomnia, tremor, nervousness, or changes in mood or behavior, are possible.
    Dextromethorphan; Promethazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    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.
    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.
    Enflurane: (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 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.
    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.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa. Administration of iron salts, including polysaccharide-iron complex, should be separated from levodopa by at least 2 hours.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa. Administration of iron salts, including polysaccharide-iron complex, should be separated from levodopa by at least 2 hours.
    Fluphenazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Food: (Major) Foods with a high protein content may interfere with the absorption of levodopa. It has been recommended to take levodopa at least 30 minutes before eating or one hour after meals. (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) Phenytoin or fosphenytoin can possibly interfere with the effects of levodopa; the mechanism of the interaction has not been established. The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by phenytoin. Monitor carefully for loss of therapeutic response.
    Furazolidone: (Major) Concomitant use of levodopa and drugs with monoamine oxidase inhibitor activity, such as furazolidone, can result in hypertensive crisis. Simultaneous use of these agents should be avoided if possible.
    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.
    Guanabenz: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Guanfacine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Haloperidol: (Major) Antipsychotic agents may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain. Haloperidol should be avoided during therapy for Parkinson's disease unless the benefit of the drug outweighs the risk of decreased therapeutic response to levodopa or other treatments.
    Halothane: (Major) The use of levodopa with halothane may enhance cardiac adverse effects of halothane. 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.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    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.
    Iloperidone: (Major) Iloperidone is a central dopamine antagonist and may inhibit the clinical response to antiparkinsonian agents with dopamine agonist properties by blocking dopamine receptors in the brain. In general, atypical antipsychotics like iloperidone are less likely to interfere with these therapies than traditional antipsychotic agents. However, iloperidone should be avoided in patients requiring medication for Parkinson's disease unless the benefit of iloperidone therapy outweighs the risk of decreased therapeutic response to levodopa or other treatments.
    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: (Major) Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa. Administration of iron salts, including polysaccharide-iron complex, should be separated from levodopa by at least 2 hours.
    Iron: (Major) Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa. Administration of iron salts, including polysaccharide-iron complex, should be separated from levodopa by at least 2 hours.
    Isocarboxazid: (Severe) 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.
    Kava Kava, Piper methysticum: (Major) Kava kava, Piper methysticum has been reported to increase the symptoms of Parkinson's disease. The antagonism of dopamine by kava kava could account for the observed effects. Until more is known, concurrent use of kava kava in patients on therapy for Parkinson's disease, like levodopa, should be done only under the care of a health care professional, and use together is not recommended. Monitor the patient for decreased effectiveness of prescribed medications.
    Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with levodopa should generally be avoided because of the possibility of additive sedative effects. 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.
    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.
    Lisdexamfetamine: (Major) Levodopa, due to its conversion to dopamine, may increase the risk of developing amphetamine-induced cardiac arrhythmias; dosage reductions of lisdexamfetamine may be advisable when the two agents are used concurrently.
    Loop diuretics: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Loxapine: (Major) Loxapine, a dopamine receptor antagonist, is a pharmacologic antagonist to drugs such as levodopa, which is a dopamine agonist. Loxapine can antagonize the actions of this drug.
    Lurasidone: (Major) In general, antipsychotics can worsen the motor symptoms of Parkinson's disease thereby decreasing the overall effectiveness of antiparkinsonian agents. Lurasidone should be avoided in patients receiving medications for Parkinson's disease unless the benefit of lurasidone therapy outweighs the risk of decreased therapeutic response to levodopa or other treatments.
    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.
    Meperidine; Promethazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Mesoridazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    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) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Methylphenidate: (Moderate) Increased dopaminergic effects may occur during coadministration of methylphenidate, an inhibitor of dopamine reuptake, and medications that increase dopaminergic activity such as levodopa. Dopaminergic side effects, such as nausea, loss of appetite, weight loss, insomnia, tremor, nervousness, or changes in mood or behavior, are possible.
    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.
    Metronidazole: (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. Metronidazole has been associated with peripheral neuropathy, with the prevalence and severity of the neuropathy being directly related to the cumulative dose and duration of therapy. Peripheral neuropathy has also been reported in patients treated with other nitroimidazole drugs including tinidazole.
    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) In general, antipsychotics can worsen the motor symptoms of Parkinson's disease thereby decreasing the overall effectiveness of antiparkinsonian agents. Molindone should be avoided in patients receiving medications for Parkinson's disease unless the benefit of molindone therapy outweighs the risk of decreased therapeutic response to levodopa or other treatments. (Major) In general, antipsychotics can worsen the motor symptoms of Parkinson's disease thereby decreasing the overall effectiveness of antiparkinsonian agents. Therefore, molindone should be avoided in patients receiving medications for Parkinson's disease unless the benefit of molindone therapy outweighs the risk of decreased therapeutic response to levodopa or other treatments.
    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) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Perphenazine; Amitriptyline: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Phenelzine: (Severe) 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.
    Phenothiazines: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Phenoxybenzamine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Phentolamine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Phenylephrine; Promethazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Phenytoin: (Moderate) Phenytoin or fosphenytoin can possibly interfere with the effects of levodopa; the mechanism of the interaction has not been established. The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by phenytoin. Monitor carefully for loss of therapeutic response.
    Pimozide: (Major) Antipsychotic agents may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and should be avoided during therapy for Parkinson's disease unless the benefit of the drug outweighs the risk of decreased therapeutic response to levodopa or other treatments.
    Polysaccharide-Iron Complex: (Major) Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa. Administration of iron salts, including polysaccharide-iron complex, should be separated from levodopa by at least 2 hours.
    Potassium-sparing diuretics: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    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.
    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) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Promethazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    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: (Severe) Pyridoxine, vitamin B6, in doses as low as 10 mg/day, can accelerate the rate of aromatic amino acid decarboxylation, thus increasing the peripheral conversion of levodopa to dopamine. This action diminishes levodopa's therapeutic effects by decreasing the amount of levodopa that is available to cross into the CNS. Patients receiving levodopa single-agent therapy should avoid vitamin B6 supplements.
    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.
    Reserpine: (Severe) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. Rauwolfia alkaloids, such as reserpine, deplete dopamine stores in the brain, thereby antagonizing the effects of levodopa.
    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.
    S-adenosyl-L-methionine, SAM-e: (Major) Levodopa therapy has been reported to cause a decrease in S-adenosyl-L-methionine, SAM-e, concentrations within the CNS. The implications of this pharmacologic activity are not known at this time. Intracerebral injections of SAM-e have been reported to induce Parkinson's like symptoms in animals. However, at least one clinical report of the use of SAM-e for the treatment of depression in Parkinson's patients has been published. The authors reported that while significant improvement in the Hamilton rating scale for depression occurred, none of the 21 patients required alterations in their levodopa dosage. The motor component of the disease was not affected. Until more is known about the CNS effects of SAM-e supplementation, SAM-e should be used cautiously in patients on levodopa therapy.
    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) Concurrent therapy with MAO-B inhibitors and levodopa may be associated with severe orthostatic hypotension not attributable to levodopa alone. Dosages of levodopa should be reduced 2 to 3 days after beginning selegiline therapy.
    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: (Major) Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa. Administration of iron salts, including polysaccharide-iron complex, should be separated from levodopa by at least 2 hours.
    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.
    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: (Severe) Coadministration of carbidopa; levodopa with tetrabenazine is not recommended. Tetrabenazine can deplete dopamine stores in the brain, thereby antagonizing the effects of levodopa.
    Thiazide diuretics: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Thiethylperazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Thioridazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Thiothixene: (Major) Concomitant use of thiothixene and levodopa is not recommeneded. By blocking dopamine receptors in the brain, thiothixene may inhibit the clinical antiparkinsonian response to levodopa. In addition, concomitant use may cause additive drowsiness. In general, avoid thiothixene in patients requiring therapy for Parkinson's disease unless the benefit of the neuroleptic outweighs the risk of decreased therapeutic response to antiparkinsonian therapy.
    Tranylcypromine: (Severe) 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) Tricyclic antidepressants exhibit 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.
    Trifluoperazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    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. It is not known whether carbidopa is excreted in human milk. Levodopa has been detected in human milk. 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. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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.

    Oral Route

    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.

    Other Route(s)

    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.