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DUOPA
(carbidopa and levodopa) Enteral Suspension
DUOPA is a combination of carbidopa, an inhibitor of aromatic amino acid decarboxylation, and levodopa, an aromatic amino acid.
Carbidopa is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.2. It is designated chemically as (2S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoic acid monohydrate. Its empirical formula is C10H14N2O4•H2O, and its structural formula is:
 |
The content of carbidopa in DUOPA is expressed in terms of anhydrous carbidopa which has a molecular weight of 226.3. The 4.63 mg/mL of anhydrous carbidopa is equivalent to 5.0 mg/mL of carbidopa.
Levodopa is a white, crystalline compound, slightly soluble in water, with a molecular weight of 197.2. It is designated chemically as (2S)-2-Amino-3-(3,4-dihydroxyphenyl) propanoic acid. Its empirical formula is C9H11NO4 , and its structural formula is:
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The inactive ingredients in DUOPA are carmellose sodium and purified water.
DUOPA is indicated for the treatment of motor fluctuations in patients with advanced Parkinson’s disease.
DUOPA is administered over a 16-hour infusion period. The daily dose is determined by individualized patient titration and composed of:
The maximum recommended daily dose of DUOPA is 2000 mg of the levodopa component (i.e., one cassette per day) administered over 16 hours. At the end of the 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.
Treatment with DUOPA is initiated in 3 steps [see Initiation And Titration Instructions]:
DUOPA 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 DUOPA. 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 one extra dose every 2 hours. Administration of frequent extra doses may cause or worsen dyskinesias.
Once no further adjustments are required to the DUOPA Morning Dose, Continuous Dose, or Extra Dose, this dosing regimen should be administered daily. Over time, additional changes may be necessary based on the patient’s clinical response and tolerability.
Prior to initiating DUOPA, 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 DUOPA infusion.
Healthcare providers should ensure patients take their oral Parkinson's disease medications the morning of the PEG-J procedure.
The steps for determining the initial DUOPA daily dosing (Morning Dose and Continuous Dose) for Day 1 are outlined below.
| Step 1: Calculate and administer the DUOPA Morning Dose for Day 1 | |
| a. | Determine the total amount of levodopa (in milligrams) in the first dose of oral immediaterelease carbidopa-levodopa that was taken by the patient on the previous day. |
| b. | Convert the oral levodopa dose from milligrams to milliliters by multiplying the oral dose by 0.8 and dividing by 20 mg/mL. This calculation will provide the Morning Dose of DUOPA in milliliters. |
| c. | Add 3 milliliters to the Morning Dose to fill (prime) the intestinal tube to obtain the Total Morning Dose. |
| d. | The Total Morning Dose is usually administered over 10 to 30 minutes. |
| e. | Program the pump to deliver the Total Morning Dose. |
| Step 2: Calculate and administer the DUOPA Continuous Dose for Day 1 | |
| a. | 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. Do not include the doses of oral immediate-release carbidopalevodopa taken at night when calculating the levodopa amount. |
| b. | Subtract the first oral levodopa dose in milligrams taken by the patient on the previous day (determined in Step 1 (a)) from the total oral levodopa dose in milligrams taken over 16 waking hours (determined in Step 2 (a)). Divide the result by 20 mg/mL. This is the dose of DUOPA administered as a Continuous Dose (in mL) over 16 hours. |
| c. | The hourly infusion rate (mL per hour) is obtained by dividing the Continuous Dose by 16 (hours). This value will be programmed into the pump as the continuous rate. |
| d. | 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 DUOPArelated adverse reactions occur, consider decreasing the Continuous Dose or stopping the infusion until the adverse reactions subside. |
The daily dose of DUOPA can be titrated as needed, based on the patient’s individual clinical response and tolerability after Day 1 of DUOPA treatment and until a stable daily dose is maintained. Adjustments to concomitant Parkinson’s disease medications may be needed. In the controlled trial, the average number of titration days required to establish a stable Morning and Continuous Dose was 5 days. Additional dose adjustments may be necessary over time based on the patient level of activity and disease progression.
The recommendations for adjusting the DUOPA Morning and Continuous Doses are provided below.
Morning Dose Adjustment
If there was an inadequate clinical response within 1 hour of the Morning Dose on the preceding day, adjust the Morning Dose (excluding the 3 mL to fill the tube) as follows:
If the patient experienced dyskinesias or DUOPA-related adverse reactions within 1 hour of the Morning Dose on the preceding day, decrease the Morning Dose by 1 mL.
Continuous Dose Adjustment
Consider increasing the Continuous Dose based on the number and volume of Extra Doses of DUOPA (i.e., total amount of levodopa component) that were 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 DUOPA-related adverse reactions on the preceding day:
Long-term administration of DUOPA requires placement of a PEG-J outer transabdominal tube and inner jejunal tube by percutaneous endoscopic gastrostomy. DUOPA is dispensed from medication cassette reservoirs that are specifically designed to be connected to the CADD® -Legacy 1400 pump.
Establishment of the transabdominal port should be performed by a gastroenterologist or other healthcare provider experienced in this procedure. See Table 1 for the recommended tubing sets for PEG-J administration.
For short-term, temporary administration of DUOPA prior to PEG-J tube placement, treatment may be initiated by a naso-jejunal tube with observation of the patient’s clinical response. See Table 2 for the recommended tubing sets for naso-jejunal administration.
Table 1. Recommended Tubing Sets for Long-Term PEG-J DUOPA Administration
| Product Name | Manufacturer |
| AbbVie PEG 15 and 20 Fr | AbbVie Inc. |
| AbbVie J | AbbVie Inc. |
Table 2. Recommended Tubing Sets for Short-Term Nas o-Jejunal DUOPA Administration
| Product Name | Manufacturer |
| AbbVie NJ | AbbVie Inc. |
| NJFT-10 | Wilson-Cook Medical, Inc. |
| Kangaroo™ Naso-Jejunal Feeding Tube | Covidien |
| Kangaroo™ | Covidien |
Avoid sudden discontinuation or rapid dose reduction in patients taking DUOPA.
If patients need to discontinue DUOPA, the dose should be tapered or patients should be switched to oral immediate-release carbidopa-levodopa tablets [see WARNINGS AND PRECAUTIONS].
When using a PEG-J tube, DUOPA 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.
Enteral suspension: 4.63 mg carbidopa and 20 mg levodopa per mL in a single-use cassette. Each cassette contains approximately 100 mL of suspension.
Single-use cassettes containing 4.63 mg carbidopa (as 5 mg of the monohydrate) and 20 mg levodopa per mL of enteral suspension. Each cassette contains approximately 100 mL of suspension.
Carton of 7 DUOPA cassettes: NDC 0074-3012-07
Store in freezer at -20° C (-4 °F). Thaw in refrigerator at 2° C to 8 °C (36° F to 46 °F) prior to dispensing. Cassettes should be protected from light and kept in the carton prior to use.
Manufactured by: Smiths Medical ASD, Inc. 1265 Grey Fox Road St. Paul, MN 55112 USA. Revised: Sep 2016
The following serious adverse reactions are discussed below and elsewhere in labeling:
Because clinical studies are run under widely varying conditions, the incidence of adverse reactions observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In clinical studies, 416 patients with advanced Parkinson’s disease received DUOPA. 338 patients were treated with DUOPA for more than 1 year, 233 patients were treated with DUOPA for more than 2 years, and 162 patients were treated with DUOPA for more than 3 years.
In a 12-week, active-controlled clinical trial (Study 1), a total of 71 patients with advanced Parkinson’s disease were enrolled and had a PEG-J procedure. Of these, 37 patients received DUOPA and 34 received oral immediate-release carbidopa-levodopa.
The most common adverse reactions for DUOPA (incidence at least 7% greater than oral immediaterelease carbidopa-levodopa) were: complication of device insertion, nausea, depression, peripheral edema, hypertension, upper respiratory tract infection, oropharyngeal pain, atelectasis, and incision site erythema.
Table 3 lists the incidence of adverse reactions occurring in the DUOPA-treated group (requiring at least 2 patients in this group) in Study 1 when the incidence was numerically greater than that for oral immediate-release carbidopa-levodopa.
Table 3. Adverse Reactions in Study 1 for DUOPA in Patients with Advanced Parkinson’s
disease
| Preferred Term | DUOPA (n = 37) % |
Oral immediate-release carbidopa-levodopaa (n = 34) % |
| Complication of device insertion | 57 | 44 |
| Nausea | 30 | 21 |
| Constipation | 22 | 21 |
| Incision site erythema | 19 | 12 |
| Dyskinesia | 14 | 12 |
| Depression | 11 | 3 |
| Post procedural discharge | 11 | 3 |
| Peripheral edema | 8 | 0 |
| Hypertension | 8 | 0 |
| Upper respiratory tract infection | 8 | 0 |
| Oropharyngeal pain | 8 | 0 |
| Atelectasis | 8 | 0 |
| Confusional state | 8 | 3 |
| Anxiety | 8 | 3 |
| Dizziness | 8 | 6 |
| Hiatal hernia | 8 | 6 |
| Postoperative ileus | 5 | 0 |
| Sleep disorder | 5 | 0 |
| Pyrexia | 5 | 0 |
| Excessive granulation tissue | 5 | 0 |
| Rash | 5 | 0 |
| Bacteriuria | 5 | 0 |
| White blood cells urine positive | 5 | 0 |
| Hallucination | 5 | 3 |
| Psychotic disorder | 5 | 3 |
| Diarrhea | 5 | 3 |
| Dyspepsia | 5 | 3 |
| aAll patients in the clinical trial regardless of treatment arm received a PEG-J. | ||
The most common adverse reactions associated with complications due to naso-jejunal (NJ) insertion were: oropharyngeal pain, abdominal distention, abdominal pain, abdominal discomfort, pain, throat irritation, gastrointestinal injury, esophageal hemorrhage, anxiety, dysphagia, and vomiting.
The most common adverse reactions associated with complications due to PEG-J insertion were: abdominal pain, abdominal discomfort, abdominal distension, flatulence, or pneumoperitoneum.
Additional adverse reactions that were co-reported with complication of naso-jejunal and PEG-J insertion included upper abdominal pain, duodenal ulcer, duodenal ulcer hemorrhage, erosive duodenitis, erosive gastritis, gastrointestinal hemorrhage, intussusception, peritonitis, post-operative abscess, and small intestine ulcer.
The use of nonselective MAO inhibitors with DUOPA is contraindicated [see CONTRAINDICATIONS].
Discontinue use of any nonselective MAO inhibitors at least two weeks prior to initiating DUOPA.
The use of selective MAO-B inhibitors (e.g., rasagiline and selegiline) with DUOPA may be associated with orthostatic hypotension. Monitor patients who are taking these drugs.
The concurrent use of DUOPA with antihypertensive medications can cause symptomatic postural hypotension. A dose reduction of the antihypertensive medication may be needed after starting or increasing the dose of DUOPA.
Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone, metoclopramide, papaverine) and isoniazid may reduce the effectiveness of levodopa. Monitor patients for worsening Parkinson’s symptoms.
Iron salts or multi-vitamins containing iron salts can form chelates with levodopa, carbidopa, and can cause a reduction in the bioavailability of DUOPA. If iron salts or multi-vitamins containing iron salts are co-administered with DUOPA, monitor patients for worsening Parkinson’s symptoms.
Because levodopa competes with certain amino acids for transport across the gut wall, the absorption of levodopa may be decreased in patients on a high-protein diet. Advise patients that a high-protein diet may reduce the effectiveness of DUOPA.
Included as part of the "PRECAUTIONS" Section
Because DUOPA is administered using a PEG-J or naso-jejunal tube, gastrointestinal 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. These complications may result in serious outcomes, such as the need for surgery or death.
Instruct patients to notify their healthcare provider immediately if they experience abdominal pain, prolonged constipation, nausea, vomiting, fever, or melanotic stool [see PATIENT INFORMATION].
Patients treated with levodopa, a component of DUOPA, have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on levodopa, some perceived that they had no warning signs (sleep attack), such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported more than one year after initiation of treatment.
Falling asleep while engaged in activities of daily living usually occurs in patients experiencing preexisting somnolence, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness in DUOPA-treated patients, especially since some of the events occur well after the start of treatment. Prescribers should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients who have already experienced somnolence or an episode of sudden sleep onset should not participate in these activities while taking DUOPA.
Before initiating treatment with DUOPA, advise patients about the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with DUOPA such as the use of concomitant sedating medications or the presence of sleep disorders. Consider discontinuing DUOPA in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating). If DUOPA is continued, they should be advised to avoid driving and other potentially dangerous activities that might result in harm if the patient becomes somnolent.
DUOPA-treated patients were more likely to experience a decline in orthostatic blood pressure than patients treated with oral immediate-release carbidopa-levodopa in the controlled clinical study.
Orthostatic systolic hypotension (≥30 mm Hg decrease) occurred in 73% of DUOPA-treated patients compared to 68% of patients treated with oral immediate-release carbidopa-levodopa in the controlled clinical study. Orthostatic diastolic hypotension (≥20 mm Hg decrease) occurred in 70% of DUOPAtreated patients compared to 62% of patients treated with oral immediate-release carbidopa-levodopa. Inform patients about the risk for hypotension and syncope. Monitor patients for orthostatic hypotension, especially after starting DUOPA or increasing the dose.
There is an increased risk for hallucinations and psychosis in patients taking DUOPA. In the controlled clinical trial, hallucinations occurred in 5% of DUOPA-treated patients compared to 3% of patients treated with oral immediate-release carbidopa-levodopa. Confusion occurred in 8% of DUOPA-treated patients compared to 3% of patients treated with oral immediate-release carbidopa-levodopa, and psychotic disorder occurred in 5% of DUOPA-treated patients compared to 3% of patients treated with oral immediate-release carbidopa-levodopa.
Hallucinations associated with levodopa may present shortly after the initiation of therapy and may be responsive to dose reduction in levodopa. Confusion, insomnia, and excessive dreaming may accompany hallucinations. Abnormal thinking and behavior may present with one or more symptoms, including paranoid ideation, delusions, hallucinations, confusion, psychosis, disorientation, aggressive behavior, agitation, and delirium.
Because of the risk of exacerbating psychosis, patients with a major psychotic disorder should not be treated with DUOPA. In addition, medications that antagonize the effects of dopamine used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of DUOPA [see DRUG INTERACTIONS].
Patients may experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge or compulsive eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including DUOPA, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued.
Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with DUOPA. Consider reducing the dose or discontinuing DUOPA if a patient develops such urges.
In the controlled clinical trial, 11% of DUOPA-treated patients developed depression compared to 3% of oral immediate-release carbidopa-levodopa-treated patients.
Monitor patients for the development of depression and concomitant suicidal tendencies.
A symptom complex that resembles neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in dopaminergic therapy. Avoid sudden discontinuation or rapid dose reduction in patients taking DUOPA. If DUOPA is discontinued, the dose should be tapered to reduce the risk of hyperpyrexia and confusion [see DOSAGE AND ADMINISTRATION].
DUOPA may cause or exacerbate dyskinesias. In the controlled clinical trial, dyskinesia occurred in 14% of DUOPA-treated patients compared to 12% of patients treated with oral immediate-release carbidopa-levodopa. The occurrence of dyskinesias may require a dosage reduction of DUOPA or other medications used to treat Parkinson’s disease.
In clinical studies, 19 of 412 (5%) patients treated with DUOPA developed a generalized polyneuropathy. The onset of neuropathy could be determined in 13 of 19 patients. Most cases (12/19) were classified as subacute or chronic in onset. The neuropathy was most often characterized as sensory or sensorimotor. Electrodiagnostic testing performed in 16 patients was most often (15/16) consistent with an axonal polyneuropathy, and one patient was classified as having a demyelinating neuropathy. There was insufficient information to determine the potential role of vitamin deficiencies in the etiology of neuropathy associated with DUOPA.
Patients should have clinical assessments for the signs and symptoms of peripheral neuropathy before starting DUOPA. Monitor patients periodically for signs of neuropathy after starting DUOPA, especially in patients with pre-existing neuropathy and in patients taking medications or those who have medical conditions that are also associated with neuropathy.
In clinical studies, myocardial infarction and arrhythmia were reported in patients taking carbidopalevodopa. Ask patients about symptoms of ischemic heart disease and arrhythmia, especially those with a history of myocardial infarction or cardiac arrhythmias.
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 observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear. In the clinical studies, 2 of 416 (0.5%) DUOPA-treated patients developed melanoma.
Appropriately qualified health care providers (e.g., dermatologists) should perform periodic skin examinations to monitor for melanoma in patients receiving DUOPA.
DUOPA may increase the risk for elevated (above the upper limit of normal for the reference range) blood urea nitrogen (BUN) and creatine phosphokinase (CPK). In the controlled clinical trial, the shift from a low or normal value at baseline to an increased BUN value was greater for DUOPA-treated patients (13%) than for patients treated with oral immediate-release carbidopa-levodopa (4%). The shift from a low or normal value at baseline to an increased CPK value was greater for DUOPA-treated patients (17%) than for patients treated with oral immediate-release carbidopa-levodopa (7%). The incidence of patients with a markedly increased BUN (≥10 mmol/L; ≥28 mg/dL) was greater for patients treated with DUOPA (11%) than that for patients treated with oral immediate-release carbidopalevodopa (0%). The incidence of patients with an increased CPK (>3 times the upper limit of normal) was greater for patients treated with DUOPA (9%) than that for patients treated with oral immediatewas greater for patients treated with DUOPA (9%) than that for patients treated with oral immediaterelease carbidopa-levodopa (0%).
Patients taking levodopa or carbidopa-levodopa may have increased levels of catecholamines and their metabolites in plasma and urine giving false positive results suggesting the diagnosis of pheochromocytoma in patients on levodopa and carbidopa-levodopa.
Carbidopa-levodopa may cause increased intraocular pressure in patients with glaucoma. Monitor intraocular pressure in patients with glaucoma after starting DUOPA.
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Ask patients if they have had any previous surgery in the upper part of their abdomen that may lead to difficulty in performing the gastrostomy or jejunostomy [see DOSAGE AND ADMINISTRATION].
Advise patients that foods that are high in protein may reduce the effectiveness of DUOPA [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].
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. Refer the patient to the Patient Instructions for Use for additional information (i.e., changing the DUOPA Cassette: disconnecting Steps 1-5 and reconnecting Steps 10-16).
Advise the patient to contact their healthcare provider and to take oral carbidopa-levodopa until the patient is able to resume DUOPA infusion, if the patient will have prolonged interruption of therapy lasting more than 2 hours [see DOSAGE AND ADMINISTRATION].
Inform patients of the gastrointestinal procedure-related risks including bezoar, ileus, implant site erosion/ulcer, intestinal hemorrhage, intestinal ischemia, intestinal obstruction, intestinal perforation, intussusception, pancreatitis, peritonitis, pneumoperitoneum, post-operative wound infection and sepsis. Advise patients of the symptoms of the above listed complications and instruct them to contact their healthcare provider if they experience any of these symptoms [see WARNINGS AND PRECAUTIONS].
Alert patients to the potential sedating effects caused by DUOPA, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Because somnolence is a common adverse reaction with potentially serious consequences, patients should not drive a car, operate machinery, or engage in other potentially dangerous activities until they have gained sufficient experience with DUOPA to gauge whether or not it affects their mental and/or motor performance adversely. Advise patients that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., conversations, eating, driving a motor vehicle, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician.
Advise patients of possible additive effects when patients are taking other sedating medications, alcohol, or other central nervous system depressants (e.g., benzodiazepines, antipsychotics, antidepressants, etc.) in combination with DUOPA or when taking a concomitant medication that increases plasma levels of levodopa [see WARNINGS AND PRECAUTIONS].
Advise patients that they may experience syncope and may develop hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating while taking DUOPA. Accordingly, caution patients against standing rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with DUOPA [see WARNINGS AND PRECAUTIONS].
Inform patients that they may experience hallucinations (unreal visions, sounds, or sensations) and other symptoms of psychosis can occur while taking DUOPA. Tell patients to report hallucinations, abnormal thinking, psychotic behavior or confusion to their healthcare provider promptly should they develop [see WARNINGS AND PRECAUTIONS].
Advise patients that they may experience impulse control and/or compulsive behaviors while taking DUOPA. Advise patients to inform their physician or healthcare provider if they develop new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with DUOPA [see WARNINGS AND PRECAUTIONS].
Inform patients that they may develop depression or experience worsening of depression while taking DUOPA. Instruct patients to contact their healthcare provider if they experience depression, worsening of depression, or suicidal thoughts [see WARNINGS AND PRECAUTIONS].
Advise patients to contact their healthcare provider before stopping DUOPA. Tell patients to inform their healthcare provider if they develop withdrawal symptoms such as fever, confusion, or severe muscle stiffness [see WARNINGS AND PRECAUTIONS].
Inform patients that DUOPA may cause or exacerbate pre-existing dyskinesias [see WARNINGS AND PRECAUTIONS].
Inform patients that neuropathy may develop or they may experience worsening neuropathy on DUOPA, and to contact their healthcare provider if they develop any symptoms or features suggesting neuropathy [see WARNINGS AND PRECAUTIONS].
Advise patients with Parkinson’s disease that they have a higher risk of developing melanoma. Advise patients to have their skin examined on a regular basis by a qualified healthcare provider (e.g., dermatologist) when using DUOPA [see WARNINGS AND PRECAUTIONS].
Because of the possibility that carbidopa or levodopa may be excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother [see Use In Specific Populations].
In rat, oral administration of carbidopa-levodopa for two years resulted in no evidence of carcinogenicity. DUOPA contains hydrazine, a degradation product of carbidopa. In published studies, hydrazine has been demonstrated to be carcinogenic in multiple animal species. Increases in liver (adenoma, carcinoma) and lung (adenoma, adenocarcinoma) tumors have been reported with oral administration of hydrazine in mouse, rat, and hamster.
Carbidopa was positive in the in vitro Ames test, in the presence and absence of metabolic activation, and the in vitro mouse lymphoma tk assay in the absence of metabolic activation but was negative in the in vivo mouse micronucleus assay.
In published studies, hydrazine was reported to be positive in in vitro genotoxicity (Ames, chromosomal aberration in mammalian cells, and mouse lymphoma tk) assays and in the in vivo mouse micronucleus assay.
In reproduction studies, no effects on fertility were observed in rats receiving carbidopa -levodopa.
There are no adequate or well-controlled studies in pregnant women. It has been reported from individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized. In animal studies, carbidopa-levodopa has been shown to be developmentally toxic (including teratogenic effects) at clinically relevant doses. DUOPA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
When administered to pregnant rabbits throughout organogenesis, carbidopa-levodopa caused both visceral and skeletal malformations in fetuses at all doses and ratios of carbidopa-levodopa tested. No teratogenic effects were observed when carbidopa-levodopa was administered to pregnant mice throughout organogenesis.
There was a decrease in the number of live pups delivered by rats receiving carbidopa-levodopa during organogenesis.
Carbidopa is excreted in rat milk. In a study of one nursing mother with Parkinson’s disease, excretion of levodopa in human milk was reported. Caution should be exercised when DUOPA is administered to a nursing woman.
Safety and effectiveness in pediatric patients have not been established.
In the controlled clinical trial, 49% of patients were 65 years and older, and 8% were 75 years and older. In patients 65 years and older, there was an increased risk for elevation of BUN and CPK (above the upper limit of the normal reference range for these laboratory analytes) during treatment with DUOPA compared to the risk for patients less than 65 years.
Management of acute overdosage with DUOPA is the same as management of acute overdosage with levodopa. Pyridoxine is not effective in reversing the actions of oral immediate-release carbidopalevodopa. In the event of an overdosage with DUOPA, the infusion should be stopped and the pump disconnected immediately. Administer intravenous fluids and maintain an adequate airway. Patients should receive electrocardiographic monitoring for arrhythmias and hypotension.
DUOPA is contraindicated in patients who are currently taking a nonselective monoamine oxidase (MAO) inhibitor (e.g., phenelzine and tranylcypromine) or have recently (within 2 weeks) taken a nonselective MAO inhibitor. Hypertension can occur if these drugs are used concurrently [see DRUG INTERACTIONS].
When levodopa is administered orally, it is rapidly decarboxylated to dopamine in extracerebral tissues so that only a small portion of a given dose is transported unchanged to the central nervous system. Carbidopa inhibits the decarboxylation of peripheral levodopa, making more levodopa available for delivery to the brain.
Levodopa is the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain. This is thought to be the mechanism whereby levodopa treats the symptoms of Parkinson's disease.
Because its decarboxylase inhibiting activity is limited to extracerebral tissues, administration of carbidopa with levodopa makes more levodopa available to the brain. The addition of carbidopa to levodopa reduces the peripheral effects (e.g., nausea and vomiting) due to decarboxylation of levodopa; however, carbidopa does not decrease the adverse reactions due to the central effects of levodopa.
The pharmacokinetics of carbidopa and levodopa with 16-hour intrajejunal infusion of DUOPA was evaluated in 18 patients with advanced Parkinson's disease who had been on DUOPA therapy for 30 days or longer. Patients remained on their individualized DUOPA doses.
The plasma concentrations versus time profile for levodopa with DUOPA 16-hour intrajejunal infusion is presented in Figure 1.
 |
Figure 1. Plasma Concentrations (mean ± standard deviation) versus Time Profile of Levodopa with DUOPA (levodopa, 1580 ± 403 mg; carbidopa, 366 ± 92 mg ) 16-Hour Infusion
Following initiation of the 16-hour intrajejunal infusion of DUOPA, peak plasma levels of levodopa is reached at 2.5 hours. The absorption of levodopa may be decreased in patients on a high-protein diet because levodopa competes with certain amino acids for transport across the gut wall. The gastric emptying rate does not influence the absorption of DUOPA since it is administered by continuous intestinal infusion. In a cross-study population pharmacokinetic analysis, DUOPA had comparable bioavailability to the oral immediate-release carbidopa-levodopa (25/100 mg) tablets (overencapsulated tablets). The estimated bioavailability for levodopa from DUOPA relative to oral immediate-release carbidopa-levodopa tablets was 97% (95% confidence interval; 95% to 98%).
In the controlled clinical trial, the intra-subject variability in carbidopa and levodopa plasma concentrations were lower for patients treated with DUOPA (N=33, 25% and 21%, respectively) than in patients treated with oral immediate-release carbidopa-levodopa (25/100 mg) tablets (N=28, 39% and 67%, respectively).
Carbidopa is approximately 36% bound to plasma proteins. Levodopa is approximately 10-30% bound to plasma proteins.
Carbidopa
Carbidopa is metabolized to two main metabolites (α-methyl-3-methoxy-4-hydroxyphenylpropionic acid and α-methyl-3,4-dihydroxyphenylpropionic acid). These 2 metabolites are primarily eliminated in the urine unchanged or as glucuronide conjugates. Unchanged carbidopa accounts for 30% of the total urinary excretion. The elimination half-life of carbidopa is approximately 2 hours.
Levodopa
Levodopa is mainly eliminated via metabolism by the aromatic amino acid decarboxylase (AAAD) and the catechol-O-methyl-transferase (COMT) enzymes. Other routes of metabolism are transamination and oxidation. The decarboxylation of levodopa to dopamine by AAAD is the major enzymatic pathway when no enzyme inhibitor is co-administered. O-methylation of levodopa by COMT forms 3-Omethyldopa. When administered with carbidopa, the elimination half-life of levodopa is approximately 1.5 hours (see Figure 1).
Systemic exposure of levodopa is expected to increase in the presence of entacapone.
The efficacy of DUOPA was established in a randomized, double-blind, double-dummy, activecontrolled, parallel group, 12-week study (Study 1) in patients with advanced Parkinson's disease who were levodopa-responsive and had persistent motor fluctuations while on treatment with oral immediaterelease carbidopa-levodopa and other Parkinson's disease medications.
Patients were eligible for participation in the studies if they were experiencing 3 hours or more of “Off” time on their current Parkinson's disease drug treatment and they demonstrated a clear responsiveness to treatment with levodopa. Seventy-one (71) patients enrolled in the study and 66 patients completed the treatment (3 patients discontinued treatment because of adverse reactions, 1 patient for lack of effect, and 1 patient for non-compliance).
Patients enrolled in this study had a mean age of 64 years and disease duration of 11 years. Most patients (89%) were taking at least one concomitant medication for Parkinson’s disease (e.g., dopaminergic agonist, COMT-inhibitor, MAO-B inhibitor) in addition to oral immediate-release carbidopa-levodopa. Thirty nine percent of patients were taking two or more of such concomitant medications.
Patients were randomized to either DUOPA and placebo capsules or placebo suspension and oral immediate-release carbidopa-levodopa 25/100 mg capsules. Patients in both treatment arms had a PEG-J device placement. DUOPA or placebo-suspension was infused over 16 hours daily through a PEG-J tube via the CADD® -Legacy 1400 model ambulatory infusion pump. The mean daily levodopa dose was 1117 mg/day in the DUOPA group and 1351 mg/day in the oral immediate-release carbidopalevodopa group.
The clinical outcome measure in Study 1 was the mean change from baseline to Week 12 in the total daily mean “Off” time, based on a Parkinson's disease diary. The "Off" time was normalized to a 16- hour awake period, based on a typical person's waking day and the daily infusion duration of 16 hours. The mean score decrease (i.e., improvement) in “Off” time from baseline to Week 12 for DUOPA was significantly greater (p=0.0015) than for oral immediate-release carbidopa-levodopa. Additionally, the mean score increase (i.e., improvement) in “On” time without troublesome dyskinesia from baseline to Week 12 was significantly greater (p=0.0059) for DUOPA than for oral immediate-release carbidopalevodopa. The treatment difference (DUOPA . oral immediate release carbidopa-levodopa) for decrease in “Off” time was approximately 1.9 hours and the treatment difference for the increase in “On” time without troublesome dyskinesia was approximately 1.9 hours. Results of Study 1 are shown in Table 4.
Table 4. Change from Baseline to Week 12 in "Off" Time and in "On" Time Without
Troublesome Dyskinesia in Patients with Advanced Parkinson’s Disease
| Treatment Group | Baseline (hours ) | LS Mean Change from Baseline at Week 12 (hours ) |
| "Off" time | ||
| Oral immediate-release carbidopalevodopa | 6.9 | -2.1 |
| DUOPA | 6.3 | -4.0* |
| "On" time without troublesome dyskinesia | ||
| Oral immediate-release carbidopalevodopa | 8.0 | 2.2 |
| DUOPA | 8.7 | 4.1* |
| LS Mean Change from Baseline based on Analysis of Covariance (ANCOVA). *=Statistically Significant. |
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Figure 2 shows results over time according to treatment for the efficacy variable (change from baseline in “Off” time) that served as the clinical outcome measure at the end of the trial at 12 weeks.
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Figure 2. Change in “Off” Time Over 12 Weeks.
DUOPA
(Do-oh-pa)
(carbidopa and levodopa)
Enteral Suspension
Read this Medication Guide before you start using DUOPA and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.
What is the most important information I should know about DUOPA?
DUOPA can cause serious side effects, including:
Some of these problems may require surgery and may lead to death.
You will need to have a procedure to make a small hole (called a “stoma”) in your stomach wall to place a gastro-jejunostomy tube (called a PEG-J tube) in an area of your small intestine called the jejunum. DUOPA is delivered directly to your small intestine through this tube. Your healthcare provider will talk to you about the stoma procedure. Before the stoma procedure, tell your healthcare provider if you have ever had a surgery or problems with your stomach.
Talk to your healthcare provider about what you need to do to care for your stoma. After the procedure, you and your healthcare provider will need to regularly check the stoma for any signs of infection.
If your PEG-J tube becomes kinked, knotted, or blocked this may cause you to have worsening of your Parkinson’s symptoms or recurring movement problems (motor fluctuations). Call your healthcare provider if your Parkinson’s symptoms get worse or you have slow movement while you are treated with DUOPA.
What is DUOPA?
DUOPA is a prescription medicine used for treatment of advanced Parkinson's disease. DUOPA contains 2 medicines, carbidopa and levodopa.
DUOPA should not be given to children (younger than 18 years).
Who should not use DUOPA?
Do not use DUOPA if you:
Ask your healthcare provider or pharmacist if you are not sure if you take an MAO Inhibitor.
What should I tell my healthcare provider before using DUOPA?
Before you use DUOPA, tell your healthcare provider if you:
Talk to your healthcare provider about the best way to feed your baby if you take DUOPA
Tell your healthcare provider about all the medicines you take, including prescription and overthe- counter medicines, vitamins, herbal supplements.
Using DUOPA with certain other medicines may affect each other and cause serious side effects.
Especially tell your healthcare provider if you take:
Eating high protein foods may affect how DUOPA works. Tell your healthcare provider if you change your diet.
Ask your healthcare provider or pharmacist for a list of these medicines or foods if you are not sure.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I use DUOPA?
What should I avoid while using DUOPA?
What are the possible side effects of DUOPA?
DUOPA may cause serious side effects, including:
Call your healthcare provider or get medical care right away if you have any of the above symptoms. Your healthcare provider will tell you if you should stop treatment with DUOPA and if needed, tell you how to discontinue DUOPA.
Tell your healthcare provider if you have any side effect that bothers you or does not go away. These are not all of the possible side effects of DUOPA. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800- FDA-1088.
How should I store DUOPA?
Keep DUOPA and all medicines out of the reach of children.
General information about the safe and effective use of DUOPA.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use DUOPA for a condition for which it was not prescribed. Do not give DUOPA to other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about DUOPA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about DUOPA that was written for healthcare professionals.
For more information go to www.DUOPA.com or call 1-844-386-4968.
What are the ingredients in DUOPA?
Active ingredients: carbidopa and levodopa
Inactive ingredients: carmellose sodium and purified water
INSTRUCTIONS FOR USE
DUOPA
(carbidopa and levodopa) enteral suspension
These instructions are for use along with any other instructions your healthcare provider gives you.
Please read the Medication Guide before you start using DUOPA and each time you get a refill.
For questions or problems, call DUOPA support toll free at 1- 844-386-4968.
The CADD-Legacy® 1400 pump is used for delivery of DUOPA through a tube into your stomach attached to the longer colored connector. Enteral nutrition should only be given by the shorter white connector (see Figure A).
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This Instructions for Use provides information for the CADD-Legacy® model 1400 pump only. There are other CADD-Legacy® pump models available. Read the label on the back of the pump to make sure it is a model 1400 pump.
Your healthcare provider prescribed DUOPA for you. Your healthcare provider programs your prescription into the CADD-Legacy® 1400 pump. The CADD-Legacy® 1400 pump is approved for use with DUOPA. DUOPA is provided as medication inside cassettes that connect to the CADDLegacy® 1400 pump.
The pump delivers DUOPA in 3 ways:
You will need the following items to complete these steps:
CADD-Legacy®-1400 Pump
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Display
The display shows programming information and messages. The main screen, which the pump displays most of the time, shows the following:
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DUOPA Cassette
The single-use DUOPA cassette is for use with the CADD-Legacy® 1400 pump.
Battery Compartment
Two AA batteries fit into the battery compartment.
Cassette Latch
The cassette latch secures the DUOPA cassette to the pump.
WARNINGS and CAUTIONS
Failure to follow the Warnings and Cautions below could cause return of your symptoms, damage to the pump, serious injury, or may lead to death in rare cases.
WARNINGS
CAUTIONS
Morning Procedure
WARNING: Use only DUOPA cassettes to make sure the pump works correctly.
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WARNING: Attach the DUOPA cassette correctly. A detached or incorrectly attached cassette could cause a problem with getting your DUOPA.
Save the red cap for use when you throw away the cassette.
WARNING: Do not connect the red cap to the stomach tube. It will block DUOPA flow.
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WARNING: Do not twist the stomach tube.
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PUMP STATUS: The pump is now on but not yet delivering DUOPA.
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PUMP STATUS: The pump is now running. DUOPA delivery will begin as programmed by your healthcare provider. If the pump will not start, a message should appear on the display. Refer to the Alarms and Messages section.
It will take between 10 minutes and 30 minutes to deliver your morning dose. To s tart delivery of your Morning Dose you will need to press the Morning Dose key 2 times.
NOTE: If you are unable to deliver your Morning Dose, it may be too soon since the last Morning Dose to deliver another dose. You may need to wait longer. The time between Morning Doses is decided by your healthcare provider.
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PUMP STATUS: After the Morning Dose finishes, the pump will automatically begin delivering the Continuous Rate. RUN will appear on the display. This completes DUOPA delivery for your Morning Procedure.
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Extra Dose
NOTE: If you are unable to deliver the Extra Dose, it may be too soon since the last Extra Dose to deliver another and you may need to wait longer. The time between Extra Doses and the amount of DUOPA in the Extra Dose is decided by your healthcare provider.
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PUMP STATUS: The pump is now delivering the Extra Dose. When it finishes, RUN will appear on the display and the Continuous Rate will continue to run.
For instructions on changing a DUOPA cassette, see Changing the Cassette.
Evening Procedure
You will need:
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Changing the DUOPA Cassette
WARNING: Use only DUOPA cassettes to make sure the pump works correctly.
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WARNING: Attach the DUOPA cassette correctly. A detached or incorrectly attached cassette could cause a problem with getting your DUOPA.
Save the red cap to use when discarding the cassette.
WARNING: Do not connect the red cap to the stomach tube as it will block DUOPA flow.
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PUMP STATUS: The pump is now on but not delivering DUOPA.
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PUMP STATUS: The pump is now running.
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Changing the Batteries :
If you see LowBat or Battery Depleted on the display, change the batteries. Use 2 new AA alkaline batteries such as DURACELL® or EVEREADY® ENERGIZER®. The pump keeps all the important information when the batteries are removed.
WARNING:
CAUTION:
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NOTE: Insert the batteries correctly based on the picture in the battery compartment. If you insert the batteries backwards, the display will remain blank. Reinsert the batteries, making sure to match the + and – markings with the battery compartment picture.
PUMP STATUS: The pump is now powered. The power-up sequence will start, the pump will go through an electronic self-test, and then the pump will beep 6 times at the end of the power-up sequence. All of the display indicators, the software revision, and each setting will appear briefly. If you do not hear a beep, and the display is off, the pump is not powered. Check that the batteries are correctly inserted.
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Change the Morning Dose
Your healthcare provider may have set your pump to allow for dose changes to your Morning Dose and Continuous Rate (Lock Level 1). Do not change your medicine dose without approval and training from your healthcare provider.
Talk with your healthcare provider to decide when to change your Morning Dose and Continuous Rate. Do not change your Extra Dose unless your healthcare provider tells you to. If your Extra Dose requires changes, your healthcare provider will provide instructions.
Change the Morning Dose
WARNING: Do not use the Prime button. Priming is for use by your healthcare provider only.
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PUMP STATUS: The pump is now on but not yet delivering DUOPA.
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PUMP STATUS: The pump is now running.
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NOTE: If you see “Value not saved” on the display, press NEXT and then repeat Steps 4c to 4e.
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PUMP STATUS: After the Morning Dose finishes, the pump will begin delivering the Continuous Rate. RUN will appear on the display.
NOTE: If you are unable to deliver a Morning Dose, it may be too soon since the last Morning Dose to deliver another and you may need to wait longer. The time between Morning Doses is decided by your healthcare provider.
Change the Continuous Rate
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NOTE: If you see “Value not saved” on the display, press NEXT and then repeat Steps 2c to 2e.
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PUMP STATUS: The pump is now running.
Alarms and Messages
The table below shows some of the common alarms that you may hear from the pump. With all
alarms, read the display before pressing
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| What you see: | What you hear: | Meaning | Response |
| Error | Two-Tone Alarm | An error with the pump has occurred. | Contact your healthcare provider. |
| High Pressure | Two-Tone Alarm | There is pressure backed up in the tubing. | Check tubing for clamps, kinks, or blockages. Make sure the red cap has been removed from the DUOPA cassette tube. Flush connectors if necessary. If it is not possible to flush the tubes, contact your healthcare provider as your tube may be blocked. |
| LowBat | 3 Two-Tone Beeps Every 5 minutes | The pump batteries are low. | Change the batteries right away. |
| Upstream Occlusion | Two-Tone Alarm | If your healthcare provider has the Upstream Occlusion Sensor set to ON and a blockage in the DUOPA cassette is detected, this alarm will sound. | Detach the DUOPA cassette. Check if the DUOPA cassette is empty. If not empty, reattach the DUOPA cassette. Restart the pump to continue delivery. Contact your healthcare provider if the alarm continues. |
| No message on display | Two-Tone Alarm | Batteries were removed within approximately 15 seconds after stopping the pump. | Install new batteries to silence the alarm. Otherwise, the alarm will stop within a short period of time. |
| Display shows current pump status | 2 Beeps (Long-Short) | The DUOPA cassette is not lined up with the pump or DUOPA is not flowing from the DUOPA cassette to the pumping mechanism. Very cold or extremely thick DUOPA may cause this alarm as well. | Press NEXT to silence the alarm. The pump continues to run. Make sure the DUOPA cassette is correctly lined up with the pump and DUOPA is flowing. Take the DUOPA cassette out of the refrigerator for 20 minutes before attaching to the pump. |
| Battery Depleted | Two-Tone Alarm | Batteries are dead. | Install new batteries. To continue delivery, restart the pump when completed. |
| Key pressed, Please release | Two-Tone Alarm | Key is being held down. | Stop pressing key. If the alarm persists, close the cassette tube clamp and remove the pump from use. Contact your healthcare provider. |
| No Disposable, Clamp Tubing | Two-Tone Alarm | Disposable refers to the DUOPA Cassette. No Disposable means the DUOPA cassette was removed. The pump is not sensing proper cassette attachment. | Clamp the cassette tube and disconnect it from your stomach tube. A DUOPA cassette must be correctly attached in order for the pump to run. Press NEXT to silence the alarm. |
| No Disposable, Pump won't run | Two-Tone Alarm | Disposable refers to the DUOPA Cassette. You have tried to start the pump without a disposable DUOPA cassette attached. | Press NEXT to silence the alarm. A DUOPA cassette must be correctly attached for the pump to run. |
| Service Due See manual | Two-Tone Alarm | The pump is scheduled for service. | Press NEXT to silence the alarm. The pump is still working, but contact your healthcare provider for further instructions. |
Frequently Asked Questions
What if I drop the pump or hit it against a hard surface?
Do the following right away:
If the DUOPA cassette or the battery door is loose or damaged, do not use the pump.
Stop the pump right away, close the tubing clamp, and contact your healthcare provider.
What should I do if I drop the pump in water?
WARNING: If the pump is dropped or hit, look at the pump for damage. Do not use a pump that is damaged or is not working correctly.
What should I do if I need to bathe while wearing the pump?
You’ll need to detach the pump before you shower, bathe, or swim. Reattach the pump to the stomach tubing afterwards and restart it.
What should I do if I need to have a medical test while wearing the pump?
The pump may need to be removed prior to certain medical tests. Be sure to talk to your doctor about your DUOPA pump before you take these tests.
STORAGE and DISPOSAL
Storage
Throwing away your DUOPA cassette or batteries
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
