Duopa

2.1 DUOPA Daily Dose

DUOPA is administered over a 16-hour infusion period. The daily dose is determined by individualized patient titration and composed of:

• A Morning Dose
  
• A Continuous Dose
  
• Extra Doses

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 Dosage and Administration ( 2.2)]:

1. Conversion of patients to oral immediate-release carbidopa-levodopa tablets in preparation for DUOPA treatment.
   
2. Calculation and administration of the DUOPA starting dose (Morning Dose and Continuous Dose) for Day 1.
   
3. Titration of the dose as needed based on individual clinical response and tolerability.

Extra Doses

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.

2.2 Initiation and Titration Instructions

Prepare for DUOPA Treatment

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.

Determine the DUOPA Starting Dose for Day 1

The steps for determining the initial DUOPA daily dosing (Morning Dose and Continuous Dose) for Day 1 are outlined below.

DUOPA Titration

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 Morning Dose on the preceding 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 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:

• For troublesome adverse reactions lasting for a period of one hour or more, decrease the Continuous Dose by 0.3 mL per hour.
  
• For troublesome adverse reactions lasting for two or more periods of one hour or more, decrease the Continuous Dose by 0.6 mL per hour.

2.3 Administration Information

• DUOPA should be used at room temperature. Take one DUOPA 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.
  
• DUOPA is delivered as a 16-hour infusion through either a naso-jejunal tube for short-term administration or through a PEG-J for long-term administration.
  
• 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 PEG-J should be disconnected from the pump at the end of the daily 16-hour administration period and flushed with room temperature potable water with a syringe.

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.

2.4 Discontinuation of DUOPA

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 ( 5.7)].

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.

8.1 Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with the use of DUOPA in pregnant women. In animal studies, carbidopa-levodopa has been shown to be developmentally toxic (including teratogenic effects) at clinically relevant doses (see Data).

The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

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.

8.2 Lactation

Risk Summary

Levodopa has been detected in human milk after administration of carbidopa-levodopa. There are no data on the presence of carbidopa in human milk, the effects of levodopa or carbidopa on the breastfed infant, or the effects on milk production. However, inhibition of lactation may occur because levodopa decreases secretion of prolactin in humans. Carbidopa is excreted in rat milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DUOPA and any potential adverse effects on the breastfed infant from DUOPA or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

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.

5.1 Gastrointestinal and Gastrointestinal Procedure-Related Risks

Because DUOPA is administered using a PEG-J or naso-jejunal tube, gastrointestinal complications can occur.

These complications include abscess, bezoar, ileus, implant site erosion/ulcer, intestinal hemorrhage, intestinal ischemia, intestinal obstruction, intestinal perforation, intussusception, pancreatitis, peritonitis, pneumonia (including aspiration pneumonia), pneumoperitoneum, post-operative wound infection, and sepsis. 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 Counseling Information ( 17)].

5.2 Falling Asleep During Activities of Daily Living and Somnolence

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.

5.3 Orthostatic Hypotension

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 DUOPA-treated 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.

5.4 Hallucinations/Psychosis/Confusion

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 ( 7.3)].

5.5 Impulse Control/Compulsive Behaviors

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.

5.6 Depression and Suicidality

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.

5.7 Withdrawal-Emergent Hyperpyrexia and Confusion

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 ( 2.4)].

5.8 Dyskinesia

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.

5.9 Neuropathy

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.

5.10 Cardiovascular Ischemic Events

In clinical studies, myocardial infarction and arrhythmia were reported in patients taking carbidopa-levodopa. Ask patients about symptoms of ischemic heart disease and arrhythmia, especially those with a history of myocardial infarction or cardiac arrhythmias.

5.11 Laboratory Test Abnormalities

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 carbidopa-levodopa (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 immediate-release 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.

5.12 Glaucoma

Carbidopa-levodopa may cause increased intraocular pressure in patients with glaucoma. Monitor intraocular pressure in patients with glaucoma after starting DUOPA.