Duopa

Dosage Forms And Strengths

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

Storage And Handling

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.

Thawing Onstructions For Pharmacies

• Assign a 12 week “Use By” date based on the time the cartons are put into the refrigerator to thaw.
• Fully thaw DUOPA in the refrigerator prior to dispensing.
• In order to ensure controlled thawing of DUOPA, 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.

Manufactured by: Smiths Medical ASD, Inc. 1265 Grey Fox Road St. Paul, MN 55112 USA. Revised: Sep 2016

DUOPA is indicated for the treatment of motor fluctuations in patients with advanced Parkinson’s disease.

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 :

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.

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.

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.

Table 1. Recommended Tubing Sets for Long-Term PEG-J DUOPA Administration

Table 2. Recommended Tubing Sets for Short-Term Nas o-Jejunal DUOPA Administration

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.

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.

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.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

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 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.

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.

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 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.

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.

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.

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.

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 .

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.

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.

Cardiovascular Ischemic Events

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.

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 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.

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 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.

Glaucoma

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

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Administration Information

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.

Advise patients that foods that are high in protein may reduce the effectiveness of DUOPA.

Interruption Of DUOPA Infusion

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.

Gastrointestinal And Gastrointestinal Procedure-Related Risks

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.

Falling Asleep During Activities Of Daily Living And Somnolence

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.

Orthostatic Hypotension

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.

Hallucinations/Psychosis/Confusion

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 .

Impulse Control/Compulsive Behaviors

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.

Depression And Suicidality

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.

Withdrawal-Emergent Hyperpyrexia And Confusion

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.

Dyskinesia

Inform patients that DUOPA may cause or exacerbate pre-existing dyskinesias.

Neuropathy

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 .

Melanoma

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.

Nursing Mothers

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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

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.

Mutagenesis

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.

Impairment Of Fertility

In reproduction studies, no effects on fertility were observed in rats receiving carbidopa -levodopa.

Use In Specific Populations

Pregnancy

Pregnancy Category C

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.

Nursing Mothers

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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

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.

SIDE EFFECTS

The following serious adverse reactions are discussed below and elsewhere in labeling:

• Gastrointestinal and Gastrointestinal Procedure-Related Risks
• Falling Asleep During Activities of Daily Living and Somnolence
• Orthostatic Hypotension
• Hallucinations/Psychosis/Confusion
• Impulse Control/Compulsive Behaviors
• Depression and Suicidality
• Withdrawal-Emergent Hyperpyrexia and Confusion
• Dyskinesia
• Neuropathy
• Cardiovascular Ischemic Events
• Melanoma
• Laboratory Test Abnormalities
• Glaucoma

Clinical Trials Experience

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

Procedure And Device- Related Adverse Reactions

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.

DRUG INTERACTIONS

Monoamine Oxidase (MAO) Inhibitors

The use of nonselective MAO inhibitors with DUOPA is contraindicated.

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.

Antihypertensive 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 And Isoniazid

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

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.

High-Protein Diet

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.

Pregnancy Category C

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.

The following serious adverse reactions are discussed below and elsewhere in labeling:

• Gastrointestinal and Gastrointestinal Procedure-Related Risks
• Falling Asleep During Activities of Daily Living and Somnolence
• Orthostatic Hypotension
• Hallucinations/Psychosis/Confusion
• Impulse Control/Compulsive Behaviors
• Depression and Suicidality
• Withdrawal-Emergent Hyperpyrexia and Confusion
• Dyskinesia
• Neuropathy
• Cardiovascular Ischemic Events
• Melanoma
• Laboratory Test Abnormalities
• Glaucoma

Clinical Trials Experience

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

Procedure And Device- Related Adverse Reactions

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.

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.

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

Absorption And Bioavailability

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).

Distribution

Carbidopa is approximately 36% bound to plasma proteins. Levodopa is approximately 10-30% bound to plasma proteins.

Metabolism And Elimination

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).

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain