Carbidopa and levodopa

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Twitching, twisting, uncontrolled repetitive movements of the tongue, lips, face, arms, or legs

• Bladder pain
• bloody or cloudy urine
• chest pain
• confusion
• difficult, burning, or painful urination
• discouragement
• feeling sad or empty
• frequent urge to urinate
• inability to move the eyes
• increased blinking or spasms of the eyelid
• irritability
• lack of appetite
• loss of interest or pleasure
• lower back or side pain
• seeing, hearing, or feeling things that are not there
• sticking out of tongue
• tiredness
• trouble concentrating
• trouble in breathing, speaking, or swallowing
• trouble sleeping
• uncontrolled twisting movements of the neck, trunk, arms, or legs
• unusual facial expressions

• Anxiety
• black, tarry stools
• bluish color
• blurred vision
• changes in skin color
• chest discomfort
• chills
• convulsions
• cough or hoarseness
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• dry mouth
• false beliefs that cannot be changed by facts
• fast, irregular, pounding, or racing heartbeat or pulse
• feelings about hurting oneself or others
• fever with or without chills
• general feeling of tiredness or weakness
• high fever
• hyperventilation
• increased in sexual ability, desire, drive, or performance
• increased interest in sexual intercourse
• increased sweating
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• loss of bladder control
• lower back or side pain
• nausea
• pain
• pain or discomfort in the arms, jaw, back, or neck
• restlessness
• seeing, hearing, or feeling things that are not there
• severe muscle stiffness
• shaking
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• swelling of the foot or leg
• swollen glands
• tenderness
• tiredness
• unusual bleeding or bruising
• unusual tiredness or weakness
• unusually pale skin
• vomiting

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• back or shoulder pain
• belching
• body aches or pain
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• diarrhea
• difficulty having a bowel movement (stool)
• ear congestion
• headache
• heartburn
• indigestion
• loss of voice
• muscle cramps
• nasal congestion
• runny nose
• sneezing
• stomach discomfort, upset, or pain
• unusual dreams
• weight loss

• Abdominal or stomach distress
• bad, unusual, or unpleasant (after) taste
• belching
• change in taste
• dark sweat
• double vision
• enlarged pupils
• feeling of warmth
• hair loss or thinning of the hair
• lack or loss of strength
• redness of the face, neck, arms, and occasionally, upper chest
• seeing double
• skin rash, hives or welts, itching

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Carbidopa and Levodopa extended-release tablets are extended-release combination of Carbidopa and Levodopa for the treatment of Parkinson's disease and syndrome.
Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as (-)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its molecular formula is C10H14N2O4·H2O and its structural formula is:

Tablet content is expressed in terms of anhydrous carbidopa, which has a molecular weight of 226.3.
Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 197.2. It is designated chemically as (-)-L-α-amino-β-(3,4-dihydroxybenzene) propanoic acid. Its molecular formula is C9H11NO4 and its structural formula is:

Carbidopa  and levodopa extended-release tablets are supplied as extended-release tablets containing either 50 mg of carbidopa USP and 200 mg of levodopa USP, or 25 mg of carbidopa USP and 100 mg of levodopa USP. Inactive ingredients: microcrystalline cellulose, colloidal silicon dioxide, hypromellose, hydroxypropyl cellulose, magnesium stearate, red ferric oxide and D&C Yellow 10 Aluminum lake.

The 50 mg/200 mg tablet is supplied as an oval, scored, biconvex, compressed tablet debossed “457” on one side and scored on other side that is buff colored with mottled appearance. The 25 mg/100 mg tablet is supplied as an oval, biconvex, compressed tablet debossed “461” on one side and plain on other side that is buff colored with mottled appearance. Carbidopa and Levodopa extended-release tablet is a polymeric-based drug delivery system that controls the release of Carbidopa and Levodopa as it slowly erodes. Carbidopa and Levodopa extended-release tablet 25 mg/100 mg is available to facilitate titration when 100 mg steps are required.

• Duopa
• Parcopa [DSC]
• Rytary
• Sinemet
• Sinemet CR

The AUC and Cmax of levodopa may be increased in elderly patients.

Parkinson disease: Treatment of Parkinson disease, postencephalitic parkinsonism, and symptomatic parkinsonism that may follow carbon monoxide and/or manganese intoxication; treatment of motor fluctuations in advanced Parkinson disease (intestinal suspension [Duopa] only).

Restless leg syndrome

Based on the American Academy of Sleep Medicine Practice Parameters for the treatment of restless legs syndrome and periodic limb movement, the use of carbidopa and levodopa is an effective and recommended treatment option in patients with restless leg syndrome (RLS); however, a risk of RLS symptom augmentation exists with this therapy. Clinical experience also suggests the utility of carbidopa and levodopa in the management of RLS [Silber 2004].

Parkinson disease:

Oral:

Immediate release tablet, orally disintegrating tablet: Note: Carbidopa/levodopa tablets are available in a 1:4 ratio of carbidopa to levodopa as well as 1:10 ratio. Tablets of the two ratios may be given separately or combined as needed to provide the optimum dosage.

Initial: Carbidopa 25 mg/levodopa 100 mg 3 times daily (preferred) or carbidopa 10 mg/levodopa 100 mg 3 to 4 times daily (typically does not provide an adequate amount of carbidopa for most patients)

Patients previously treated with levodopa <1,500 mg daily: Carbidopa 25 mg/levodopa 100 mg 3 or 4 times daily

Patients previously treated with levodopa >1,500 mg daily: Carbidopa 25 mg/levodopa 250 mg 3 or 4 times daily

Note: Discontinue levodopa at least 12 hours before starting therapy with carbidopa/levodopa. Substitute the combination drug at a dosage that will provide approximately 25% of the previous levodopa dosage.

Dosage adjustment: Alternate tablet strengths may be substituted according to individual carbidopa/levodopa requirements. Use of more than 1 dosage strength or dosing 4 times daily may be required (maximum: 8 tablets of any strength daily or 200 mg of carbidopa and 2,000 mg of levodopa)

Carbidopa 10 mg/levodopa 100 mg: Increase by 1 tablet daily or every other day, as necessary, to 2 tablets 4 times daily

Carbidopa 25 mg/levodopa 100 mg: Increase by 1 tablet daily or every other day

Carbidopa 25 mg/levodopa 250 mg: Increase by 1/2 or 1 tablet daily or every other day

Controlled-release tablet:

Patients not currently receiving levodopa: Initial: Carbidopa 50 mg/levodopa 200 mg 2 times daily, at intervals not <6 hours

Patients currently receiving levodopa: Note: Discontinue levodopa at least 12 hours before starting carbidopa/levodopa therapy. Initial: Substitute at a dosage that will provide approximately 25% of the previous levodopa dosage; usual initial dose in mild to moderate disease is carbidopa 50 mg/levodopa 200 mg 2 times daily

Patients converting from immediate-release formulation to controlled release: Initial: Dosage should be substituted at an amount that provides ~10% more of levodopa/day; total calculated dosage is administered in divided doses 2 to 3 times/day (or ≥3 times/day for patients maintained on levodopa ≥700 mg). Intervals between doses should be 4 to 8 hours while awake; when divided doses are not equal, smaller doses should be given toward the end of the day. Depending on clinical response, dosage may need to be increased to provide up to 30% more levodopa/day.

Dosage adjustment: May adjust every 3 days; intervals should be >4 hours during the waking day (maximum dose: 8 tablets/day)

Extended-release capsule: Note: Carbidopa/levodopa extended-release capsules are not interchangeable with other carbidopa/levodopa products.

Patients not currently receiving levodopa: Initial: Carbidopa 23.75 mg/levodopa 95 mg 3 times daily for 3 days; on day 4, increase to carbidopa 36.25 mg/levodopa 145 mg 3 times daily. May increase dose up to carbidopa 97.5 mg/levodopa 390 mg 3 times a day; frequency of dosing may be increased to a maximum of 5 times daily if needed and tolerated (maximum: carbidopa 612.5 mg/levodopa 2,450 mg per day).

Patients converting from immediate-release formulation to extended-release capsules: Initial: Initial dose based off of total current daily dose of levodopa in immediate-release carbidopa/levodopa as follows (frequency of dosing may be increased to a maximum of 5 times daily if needed and tolerated):

If total daily dose of levodopa is between 400 mg to 549 mg: 3 capsules of carbidopa 23.75 mg/levodopa 95 mg 3 times daily (levodopa total daily dose: 855 mg).

If total daily dose of levodopa is between 550 mg to 749 mg: 4 capsules of carbidopa 23.75 mg/levodopa 95 mg 3 times daily (levodopa total daily dose: 1,140 mg).

If total daily dose of levodopa is between 750 mg to 949 mg: 3 capsules of carbidopa 36.25 mg/levodopa 145 mg 3 times daily (levodopa total daily dose: 1,305 mg).

If total daily dose of levodopa is between 950 mg to 1249 mg: 3 capsules of carbidopa 48.75 mg/levodopa 195 mg 3 times daily (levodopa total daily dose: 1,755 mg).

If total daily dose of levodopa is ≥1,250 mg: 4 capsules of carbidopa 48.75 mg/levodopa 195 mg 3 times daily (levodopa total daily dose: 2,340 mg) or 3 capsules of carbidopa 61.25/levodopa 245 mg 3 times daily (levodopa total daily dose: 2,205 mg).

Dosage adjustment: Adjust dose as needed (maximum dose: carbidopa 612.5 mg/levodopa 2,450 mg per day).

Concomitant therapy: For patients currently treated with carbidopa/levodopa plus catechol-O-methyl transferase (COMT) inhibitors (eg, entacapone), the initial total daily dose of carbidopa/levodopa may need to be increased. Use of carbidopa/levodopa extended-release capsules in combination with other levodopa products has not been studied.

Intestinal infusion via PEG-J tube:

Intestinal suspension (Duopa): Initial: Note: Prior to initiation of therapy, convert patients from all forms of levodopa to oral immediate-release carbidopa/levodopa tablets (1:4 ratio). Total daily dose (expressed in terms of levodopa) consists of a morning dose, a continuous dose and extra doses. Maximum dose is 2,000 mg of the levodopa component (ie, one cassette per day) over 16 hours. Patients should receive their routine night-time dosage of oral immediate-release carbidopa/levodopa after discontinuation of daily infusion.

Morning dose and continuous dose: Refer to manufacturer’s labeling for morning dose and continuous dose calculations and titration instructions.

Extra doses: Can be used to manage acute "off" symptoms that are not controlled by the morning and continuous dose. Set extra dose function at 1 mL (20 mg of levodopa) initially; adjust in 0.2 mL increments if needed. Maximum: One extra dose every 2 hours. Note: Frequent extra doses may cause or worsen dyskinesias.

Discontinuation: Avoid sudden discontinuation or rapid dose reduction; taper dose or switch patients to oral immediate-release carbidopa-levodopa.

Intestinal gel (Duodopa [Canadian product]): Note: Conversion to/from oral levodopa tablet formulations and the intestinal gel formulation can be done on a 1:1 ratio. Total daily dose (expressed in terms of levodopa) consists of a morning bolus dose, a continuous maintenance dose, and additional bolus doses when necessary. Nighttime dosing may be necessary in certain rare situations (eg, nocturnal akinesia). Dosage adjustments should be carried out over a period of a few weeks. Patients should receive their routine night-time dosage of oral levodopa/carbidopa after discontinuation of daily infusion

Morning bolus dose:

Day 1: Based on a percentage of the previous morning levodopa intake and volume to fill intestinal tubing:

Previous morning dose of levodopa ≤200 mg: Administer Duodopa at 80% of dose

Previous morning dose of levodopa 201 to 399 mg: Administer Duodopa at 70% of dose

Previous morning dose of levodopa ≥400 mg: Administer Duodopa at 60% of dose

Day 2 and beyond till dose is stable: Adjust dose based on response to the previous morning levodopa intake and volume to fill intestinal tubing): Usual: Levodopa 100 to 200 mg (5 to 10 mL); Maximum: Levodopa 300 mg (15 mL)

Continuous maintenance dose: Adjustable in increments of 2 mg/hour (0.1 mL/hour) and based on previous daily intake of levodopa: Usual: Levodopa 40 to 120 mg/hour (2 to 6 mL/hour) infused up to 16 hours; Range: Levodopa 20 to 200 mg/hour (1 to 10 mL/hour). Higher doses may be necessary in exceptional cases.

Additional bolus doses: Usual: Levodopa: 10 to 40 mg (0.5 to 2 mL), if needed for rapid deterioration of motor functions (eg, hypokinesia); may give additional doses hourly until stable dose is established then give every 2 hours as needed. In patients requiring >5 additional boluses/day, consider increasing the maintenance dose

Restless legs syndrome (RLS) (off-label use; Silber, 2004): Oral:

Immediate-release tablet: Carbidopa 25 mg/levodopa 100 mg (0.5 to 1 tablet) given in the evening, at bedtime, or upon waking during the night with RLS symptoms

Controlled-release tablet: Carbidopa 25 mg/levodopa 100 mg (1 tablet) before bedtime for RLS symptoms that awaken patient during the night

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Intestinal suspension (Duopa):

Dyskinesias or levodopa-related adverse reactions within 1 hour of morning dose on preceding day: Decrease morning dose by 1 mL.

Dyskinesias or adverse reactions lasting ≥1 hour on the preceding day: Decrease the continuous dose by 0.3 mL per hour.

Dyskinesias or adverse reactions lasting for 2 or more periods of ≥1 hour on the preceding day: Decrease the continuous dose by 0.6 mL per hour.

Intestinal suspension (Duopa): Fully thaw in refrigerator prior to use. To ensure controlled thawing, take the cartons containing the seven individual cassettes out of the transport box and separate the cartons from each other. Assign a 12-week, use-by date based on the time the cartons are put into the refrigerator to thaw (may take up to 96 hours to thaw). Once thawed, the individual cartons may be packed in a closer configuration within the refrigerator. Remove one cassette from refrigerator 20 minutes prior to administration (failure to use at room temperature may result in inaccurate dosage).

Adverse events have been observed in some animal reproduction studies using this combination. Carbidopa can be detected in the umbilical cord, but absorption in fetal tissue is minimal. Levodopa crosses the placenta and can be metabolized by the fetus and detected in fetal tissue (Merchant 1995). The incidence of Parkinson disease in pregnancy is relatively rare, and information related to the use of carbidopa/levodopa in pregnant women is limited (Ball 1995; Cook 1985; Golbe 1987; Serikawa 2011; Shulman 2000). Current guidelines note that the available information is insufficient to make a recommendation for the treatment of restless legs syndrome in pregnant women (Aurora 2012).