RECENT MAJOR CHANGES SECTION.


Warnings and Precautions, Gastrointestinal and Gastrointestinal Procedure-Related Risks (5.1) 12/2019

DOSAGE FORMS & STRENGTHS SECTION.


3 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. Enteral Suspension: 4.63 mg carbidopa and 20 mg levodopa per mL (3)

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


NDC 0074-3012-07 Duopa carbidopa and levodopa enteral suspension 4.63 mg / 20 mg per mL 7 Cassettes (100 mL each) THIS PACKAGE NOT INTENDED FOR HOUSEHOLDS WITH YOUNG CHILDREN Each mL contains 5 mg of carbidopa monohydrate (equivalent to 4.63 mg of carbidopa anhydrous) and 20 mg of levodopa. Pharmacist: Store frozen. Thaw in refrigerator prior to dispensing. See package insert for full prescribing information. Store in the refrigerator between 36-46F (2-8C). Protect from light. Store cassettes in the carton until use. Rx only abbvie

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS The following serious adverse reactions are discussed below and elsewhere in labeling: Gastrointestinal and Gastrointestinal Procedure-Related Risks [see Warnings and Precautions (5.1)] Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions (5.2)] Orthostatic Hypotension [see Warnings and Precautions (5.3)] Hallucinations/Psychosis/Confusion [see Warnings and Precautions (5.4)] Impulse Control/Compulsive Behaviors [see Warnings and Precautions (5.5)] Depression and Suicidality [see Warnings and Precautions (5.6)] Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.7)] Dyskinesia [see Warnings and Precautions (5.8)] Neuropathy [see Warnings and Precautions (5.9)] Cardiovascular Ischemic Events [see Warnings and Precautions (5.10)] Laboratory Test Abnormalities [see Warnings and Precautions (5.11)] Glaucoma [see Warnings and Precautions (5.12)] Most common adverse reactions for DUOPA (DUOPA incidence at least 7% greater than oral carbidopa-levodopa incidence) were: complication of device insertion, nausea, depression, peripheral edema, hypertension, upper respiratory tract infection, oropharyngeal pain, atelectasis, and incision site erythema. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 Parkinsons 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 Parkinsons 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 immediate-release 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 Parkinsons 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 9 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. 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.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE DUOPA is indicated for the treatment of motor fluctuations in patients with advanced Parkinsons disease. DUOPA is a combination of carbidopa (an aromatic amino acid decarboxylation inhibitor) and levodopa (an aromatic amino acid) indicated for the treatment of motor fluctuations in patients with advanced Parkinsons disease (1)

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION The maximum recommended daily dose of DUOPA is 2000 mg of levodopa (i.e., one cassette per day) administered over 16 hours (2.1) Prior to initiating DUOPA, convert patients from all forms of levodopa to oral immediate-release carbidopa-levodopa tablets (1:4 ratio) (2.2) Titrate total daily dose based on clinical response for the patient (2.2) Administer DUOPA into the jejunum through a percutaneous endoscopic gastrostomy with jejunal tube (PEG-J) with the CADD-Legacy 1400 portable infusion pump (2.3) 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)]: Conversion of patients to oral immediate-release carbidopa-levodopa tablets in preparation for DUOPA treatment. Calculation and administration of the DUOPA starting dose (Morning Dose and Continuous Dose) for Day 1. 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 patients 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. 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 immediate-release 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 carbidopa-levodopa 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 DUOPA-related adverse reactions occur, consider decreasing the Continuous Dose or stopping the infusion until the adverse reactions subside. DUOPA Titration The daily dose of DUOPA can be titrated as needed, based on the patients individual clinical response and tolerability after Day 1 of DUOPA treatment and until a stable daily dose is maintained. Adjustments to concomitant Parkinsons 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 patients 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 patients 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 J AbbVie Inc. AbbVie Inc. Table 2. Recommended Tubing Sets for Short-Term Naso-Jejunal DUOPA Administration Product Name Manufacturer AbbVie NJ AbbVie Inc. NJFT-10 Wilson-Cook Medical, Inc. Kangaroo Naso-Jejunal Feeding Tube Covidien Kangaroo Covidien 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.

INFORMATION FOR PATIENTS SECTION.


17 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 [see Dosage and Administration (2.3)]. Advise patients that foods that are high in protein may reduce the effectiveness of DUOPA [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)]. 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 [see Dosage and Administration (2.4)]. Gastrointestinal and Gastrointestinal Procedure-Related Risks Inform patients of the gastrointestinal procedure-related risks including 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. 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 (5.1)]. 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 [see Warnings and Precautions (5.2)]. 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 [see Warnings and Precautions (5.3)]. 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 [see Warnings and Precautions (5.4)]. 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 [see Warnings and Precautions (5.5)]. 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 [see Warnings and Precautions (5.6)]. 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 [see Warnings and Precautions (5.7)]. Dyskinesia Inform patients that DUOPA may cause or exacerbate pre-existing dyskinesias [see Warnings and Precautions (5.8)]. 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 [see Warnings and Precautions (5.9)]. Pregnancy Advise patients to notify their healthcare provider if they become pregnant during treatment or plan to become pregnant during therapy [see Use in Specific Populations (8.1)]. Lactation Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations (8.2)]. Manufactured by AbbVie Inc., North Chicago, IL 60064, USA or by Fresenius Kabi Norge AS, 1788 Halden, Norway For AbbVie Inc. North Chicago, IL 60064, USA 2019-2020 AbbVie Inc. 03-C123 December 2019

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 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 16.2 Storage and Handling Store in freezer at -20oC (-4oF). Thaw in refrigerator at 2oCto 8oC (36oF to 46oF) prior to dispensing. Cassettes should be protected from light and kept in the carton prior to use. Thawing instructions 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.

SPL UNCLASSIFIED SECTION.


Appendix A Pump Programming Quick Reference for Healthcare Providers This quick reference provides for step-by-step directions for several of the common pump programming tasks performed with the CADD-Legacy 1400 pump. Additional pump information including warnings, cautions and more information on pump operations is located in the referenced sections of the pump Operators Manual. Please refer to the full prescribing information for DUOPA (carbidopa and levodopa) enteral suspension for indications and usage, contraindications, warnings, precautions, and adverse reactions. Begin programming the pump by: Attaching a medication cassette reservoir Turning on the pump For instruction on attaching a medication cassette reservoir, see Section2, Pump Setup and Programming. You will need the following items to complete these steps: Pump Medication cassette reservoir Changing to Lock Level 0 (LL0) Lock level 0 (LL0) allows the health care provider to adjust settings so they are appropriate for the patient. For more information on lock levels descriptions, see Section 1, General Description. For more information on changing the lock level, see Section2, Pump Setup and Programming. **Text Omitted** Pump Programming Settings Program the pump settings to customize the medication delivery inputs for the patient. For more information see Section 2, Pump Setup and Programming. NOTE: Ensure that the pump is in lock level 0 (LL0) and appears on the screen. PressCheck for on the screen. NOTE: Not in Use is the default setting for the reservoir volume. The reservoir volume feature is not required for use, but is available at provider discretion. Pressagain. Check for on the screen. Pressor to select the desired continuous rate. Press Pump Status: The continuous rate is now set. PressCheck for on the screen. Pressor to select the extra dose amount. Press Pump Status: The extra dose amount is now set. Pressheck for on the screen Pressif you wish to clear the amount given. Press NOTE: To change a setting again, press NEXT until the appropriate screen appears. Press or to adjust the setting, then press to confirm. Changing Lockout Times Program the dose lockout times to customize medication delivery inputs for each patient. Lockout times will determine how often a patient can deliver a morning dose and an extra dose. These values should be determined during titration. For more information on DUOPA titration, refer to the full prescribing information for DUOPA (carbidopa and levodopa) enteral suspension. The biomed functions allow the health care provider access to the extra dose lockout and morning dose lockout settings. For more information about biomed functions, see Section 4, Biomed Functions. NOTE: Ensure that the pump is in lock level 0 (LL0) and is on the screen. When entering a new lockout value, any lockout time previously in effect will be cleared. **Text Omitted** Programming the Morning Dose Program the morning dose to customize medication delivery for the patient. For more information, see Section 2, Pump Setup and Programming. CAUTION: Review programming screens when complete to make sure desired programming has been entered. Check to make sure unintended changes were not made to the morning dose, continuous rate, or extra dose volume. If unintended changes were made, go to the appropriate screen and program the desired value. The pump must be running with a cassette attached and in LL0 or LL1. Start the pump, if necessary and confirm the lock level settings. NOTE: In LL0, programming in the full range is possible. In LL1, you can program up to the LL0 value. Press should appear on the screen. Pressor to select the desired morning dose volume. Pressto store the morning dose volume. Setting the Lock Level For patient use, the pump must be set to lock level 2 (LL2) or lock level 1 (LL1). For more information on lock levels descriptions, see Section 1, General Description. For more information on changing the lock level, see Section2, Pump Setup and Programming. **Text Omitted** Manufacturer: Smiths Medical ASD, Inc. 1265 Grey Fox Road St. Paul, MN 55112 USA Tel: 1 800 258 5361 (USA), +1 614 210 7300 www.smiths-medical.com CADD, CADD-Legacy, and Smiths Medical design mark are trademarks of Smiths Medical. The symbol indicates the trademark is registered in the U.S. Patent and Trademark Office and certain other countries. All other names and marks mentioned are the trade names, trademarks or service marks of their respective owners. 2015 Smiths Medical. All rights reserved. 2015-01 40-6756-01C

DESCRIPTION SECTION.


11 DESCRIPTION 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 C10H14N2O4H2O, 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: The inactive ingredients in DUOPA are carmellose sodium and purified water.

OVERDOSAGE SECTION.


10 OVERDOSAGE 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 carbidopa-levodopa. 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.

SPL MEDGUIDE SECTION.


MEDICATION GUIDE 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: Stomach and intestine (gastrointestinal) problems and problems from the procedure you will need to have to receive DUOPA (gastrointestinal procedure-related problems). Some of these problems may require surgery and may lead to death. a blockage of your stomach or intestines (bezoar) stopping movement through intestines (ileus) drainage, redness, swelling, pain, feeling of warmth around the small hole in your stomach wall (stoma) bleeding from stomach ulcers or your intestines inflammation of your pancreas (pancreatitis) infection in your lungs (pneumonia) air or gas in your abdominal cavity skin infection around the intestinal tube, pocket of infection (abscess), infection in your blood (sepsis) or abdominal cavity may occur, after surgery stomach pain, nausea or vomiting Tell your healthcare provider right away if you have any of the following symptoms of stomach and intestine problems and gastrointestinal procedure-related problems: stomach (abdominal) pain constipation that does not go away nausea or vomiting fever blood in your stool or a dark tarry stool (melanotic stool) 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 Parkinsons symptoms or recurring movement problems (motor fluctuations). Call your healthcare provider if your Parkinsons 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: take a medicine called a nonselective Monoamine Oxidase (MAO) Inhibitor (such as phenelzine or tranylcypromine) or have taken a nonselective MAO Inhibitor within the last 14 days. 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: have or have had stomach ulcers or stomach surgery have low blood pressure (hypotension) or if you feel dizzy or faint, especially when getting up from sitting or lying down have had problems with fainting (syncope) feel sleepy or have fallen asleep suddenly during the day have or have had depression (feelings of hopelessness or sadness) or any mental problems drink alcohol. Alcohol can increase the chance that DUOPA will make you feel sleepy or fall asleep when you should be awake have trouble controlling your muscles (dyskinesia) have nerve problems (peripheral neuropathy) have or have had heart problems, an abnormal heart rate or have had a heart attack in the past have or have had high blood pressure (hypertension) have eye problems that cause increased pressure in your eye (glaucoma) have a history of attacks of suddenly falling asleep and without warning have any other medical conditions are pregnant or planning to become pregnant. It is not known if DUOPA will harm your unborn baby are breastfeeding or plan to breastfeed. DUOPA can pass into your milk and may harm your baby. 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 over-the-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: medicines used to treat high blood pressure (hypertension) medicines used to treat depression called nonselective Monoamine Oxidase (MAO) Inhibitor (such as phenelzine or tranylcypromine) or have taken one within the last 14 days dopamine D2 receptor antagonists (antipsychotics or metoclopramide), and isoniazid iron or multivitamins with iron 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? Use DUOPA exactly as your healthcare provider tells you to use it. Your healthcare provider should show you how to use DUOPA before you use it for the first time. Ask your healthcare provider or pharmacist if you have any questions. Your prescribed dose of DUOPA will be programmed into your pump by a healthcare provider and should only be changed by your healthcare provider or while you are with your healthcare provider. Do not stop using DUOPA or change your dose unless you are told to do so by your healthcare provider. Tell your healthcare provider if you develop withdrawal symptoms such as fever, confusion, or severe muscle stiffness. Keep a supply of oral carbidopa-levodopa immediate release (IR) tablets with you in case you are unable to give your DUOPA infusion. DUOPA is given continuously over 16 hours through a tube that is put into your stomach called a PEG-J. A small pump (CADD-Legacy 1400) is used to move DUOPA from the medication cassette through your PEG-J tube. Your DUOPA dose has three parts: a morning dose a continuous dose extra doses DUOPA can also be given for a short time (short-term) through a tube put into your nose called a naso-jejunal (NJ) tube. The CADD-Legacy 1400 portable infusion pump should be used to give DUOPA through your PEG-J tube. See the Instructions for Use that comes with your CADD-Legacy 1400 portable infusion pump for complete instructions on how to use the pump. DUOPA comes in a small plastic container (cassette) that you connect to the pump to get your medicine. Each cassette can only be used 1 time. An opened cassette should not be reused. The cassette should not be used for longer than 16 hours. The cassette should be thrown away at the end of the infusion, even if there is some medicine still in the cassette. Disconnect the pump from your PEG-J tube after the 16 hour dosing time is finished. Use a syringe filled with room temperature water to flush your PEG-J tube. See the Instructions for Use for more information about how to flush your PEG-J tube with a syringe. After your daily DUOPA infusion, you should take your usual night-time dose of oral carbidopa-levodopa tablets as prescribed. If you stop your DUOPA infusion for more than 2 hours during your 16 hour dosing time for any reason, call your healthcare provider and take oral carbidopa-levodopa as prescribed until you are able to restart your DUOPA infusion. If you stop your DUOPA infusion for less than 2 hours, you do not need to take oral carbidopa-levodopa, but your healthcare provider may tell you to take an extra dose of DUOPA. What should I avoid while using DUOPA? Do not drive, operate machinery, or do other activities until you know how DUOPA affects you. Sleepiness and falling asleep suddenly caused by DUOPA can happen as late as 1 year after you start your treatment. What are the possible side effects of DUOPA? DUOPA may cause serious side effects, including: See What is the most important information I should know about DUOPA? Falling asleep during normal daily activities. DUOPA may cause you to fall asleep while you are doing daily activities such as driving, talking with other people, or eating. You could fall asleep without any warning. Some people using DUOPA have had car accidents because they fell asleep while driving. Do not drive or operate machinery until you are sure how DUOPA affects you. Tell your healthcare provider if you take other medicines that can make you sleepy such as sleep medicines, antidepressants, or antipsychotics. Low blood pressure when you sit or stand up quickly. After you have been sitting or lying down, stand up slowly until you know how DUOPA affects you. This may help reduce the following symptoms while you are using DUOPA: dizziness nausea sweating fainting Seeing things that are not there, hearing sounds or feeling sensations that are not real (hallucinations). Hallucinations can happen in people who use DUOPA. Tell your healthcare provider if you have hallucinations. Unusual urges. Some people taking certain medicines to treat Parkinsons disease, including DUOPA, have reported problems, such as gambling, compulsive eating, compulsive shopping, and increased sex drive. If you or your family members notice that you are having unusual urges or behaviors, talk to your healthcare provider. Depression and suicide. DUOPA can cause depression or make your depression worse. Pay close attention to sudden changes in your mood, behavior, thoughts, or feelings. Call your healthcare provider right away if you feel depressed or have thoughts of suicide. Uncontrolled sudden movements (dyskinesia). If you have new dyskinesia, or your dyskinesia gets worse, tell your healthcare provider. This may be a sign that your dose of DUOPA or other medicines to control your Parkinsons disease may need to be adjusted. Progressive weakness or numbness or loss of sensation in the fingers or feet (neuropathy). Heart attack or other heart problems. Tell your healthcare provider if you have experienced increased blood pressure, a fast or irregular heartbeat or chest pain. Abnormal blood tests. DUOPA may cause changes in certain blood tests, especially certain hormone and kidney function blood tests. Worsening of the increased pressure in your eyes (glaucoma). The pressure in your eyes should be checked after starting DUOPA. The most common side effects of DUOPA include: swelling of legs and feet nausea high blood pressure (hypertension) depression mouth and throat pain 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? Store DUOPA in the refrigerator between 36F to 46F (2C to 8C). Do not freeze. Use at room temperature. Take one DUOPA cassette out of the carton and out of the refrigerator 20 minutes prior to use. Use the product at room temperature or you may not get the right amount of medication. Protect the cassette from light and keep it in the carton before using. Use DUOPA before the expiration date printed on the cassette. 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 This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by AbbVie Inc., North Chicago, IL 60064, USA or by Fresenius Kabi Norge AS, 1788 Halden, Norway For AbbVie Inc. North Chicago, IL 60064, USA 2019-2020 AbbVie Inc. 03-C123 Revised: December 2019

INSTRUCTIONS FOR USE SECTION.


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 straight (green) connector. Enteral nutrition should only be given by the shorter angled connector (white, blue, or violet) (see Figure A and Table. Connector Colors). Table. Connector Colors. Y-Connector Size Design Gastric (g) Port Color Intestinal (i) Port Color 15 FR Original White Green New Blue 20 FR Original White New Violet Note: The original design of the Y-Connector is represented in the Figures throughout this Instructions for Use. 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 CADD-Legacy 1400 pump. The pump delivers DUOPA in 3 ways: Continuous Rate: Steady delivery of DUOPA delivered throughout the day while pump is on Morning Dose: A large dose of DUOPA given each morning Extra Dose: A small dose of DUOPA given as needed during the day You will need the following items to complete these steps: Pump DUOPA cassette Coin, like a quarter Carrying bag Syringe Syringe connector Room temperature water CADD-Legacy-1400 Pump Display The display shows programming information and messages. The main screen, which the pump displays most of the time, shows the following: 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 Only use the pump in a manner described in this Instructions for Use, after you have received training by your healthcare provider. To avoid explosion hazard, do not use the pump near flammable explosive gases. Only use extension sets that are approved for use with DUOPA (See the Full Prescribing Information for DUOPA), pay attention to all warnings and cautions associated with their use. Always have new batteries available for replacement. If power is lost, DUOPA will not be delivered. If the pump is dropped or hit, the battery door or tabs may break. Do not use the pump if the battery door or tabs are damaged because the batteries will not be correctly secured. This may cause loss of power and DUOPA will not be delivered. If the pump is dropped or hit, look at the pump for damage. Do not use a pump that is damaged or is not functioning correctly. If a gap is present between the battery door and the pump housing, this means the door is not correctly latched. If the battery door becomes detached or loose, the batteries will not be correctly secured. This could cause loss of power and DUOPA will not be delivered. Use only DUOPA cassettes for pump accuracy and to make sure the pump works correctly. Attach the DUOPA cassette correctly. A detached or incorrectly attached DUOPA cassette could cause a problem with getting your DUOPA. CAUTIONS Use only Smiths Medical accessories and replacement parts for the pump as using other brands may adversely affect the operation of the pump. Do not operate the pump at temperatures below 36F (2C) or above 104F (40C). Do not store the pump at temperatures below -4F (-20C) or above 140F (60C). Do not store the pump with a DUOPA cassette attached. Use the protective cassette provided when storing the pump. Do not keep the pump in humidity levels below 20% or above 90% relative humidity. Do not place the pump in cleaning fluid or water, or allow solution to soak into the pump, keypad, or battery compartment. Do not clean the pump with acetone, other plastic solvents, or abrasive cleaners. Do not use rechargeable NiCd or nickel metal hydride (NiMH) batteries. Do not use carbon zinc (heavy duty) batteries. They do not provide enough power for the pump to operate correctly. Do not store the pump for long periods of time with the batteries installed. Battery leakage could damage the pump. Morning Procedure Take the DUOPA carton containing the DUOPA cassettes out of the refrigerator. Check the expiration date on the carton. Do not use any of the cassettes if the expiration date has passed. Take a DUOPA cassette out of the carton. Return the carton with the remaining cassettes to the refrigerator. Do not use the cassette if the expiration date has passed or the cassette is damaged or empty. Leave the DUOPA cassette at room temperature for 20 minutes before using. Each DUOPA cassette may be used for up to 16 hours after removal from the refrigerator. WARNING: Use only DUOPA cassettes to make sure the pump works correctly. 1) Remove the cassette clip (see Figure B): Remove the cassette tube from its slot in the clip. Pull the clip from cassette to slide it off of the cassette top. 2) Attach the DUOPA cassette to the pump (see Figure C): Hold the pump so the latch faces up. Hold the DUOPA cassette so the tube points down. Insert the DUOPA cassette hooks into the hinge pins at the base of the pump. 3) Latch the DUOPA cassette into the pump: Hold the pump and DUOPA cassette upright against a flat surface. Press down on the pump, until the DUOPA cassette fits tightly against the pump (see Figure D). Use a coin to twist the latch counterclockwise until the latch lines up straight with the arrow (see Figure E). WARNING: Attach the DUOPA cassette correctly. A detached or incorrectly attached cassette could cause a problem with getting your DUOPA. 4) Remove the red cap on the end of the cassette tube (see Figure F). 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. 5) Connect the stomach tube to the cassette tube: While holding the stomach tube steady, twist off the white cap on the end of the longer straight (green) connector (see Figure G). WARNING: Do not twist the stomach tube. Connect the cassette tube to the end of the longer straight (green) connector (see Figure H). Do not connect to the shorter angled connector (white, blue, or violet). 6) Turn the pump on: Press and hold until the display turns on. Wait approximately 30 seconds for the pump to review settings. Check for on the screen. PUMP STATUS: The pump is now on but not yet delivering DUOPA. 7) Inspect the tubing for kinks or closed clamps. If needed straighten kinks or open clamps (see Figure I). 8) Start the pump: Press and hold until 3 dashes appear and then disappear from the screen. Wait approximately 15 seconds for the pump to start running. Check for on the display. 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 start 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. 9) The first key press shows the Morning Dose on the display. Press Check for on the display. The number on your display is the Morning Dose of DUOPA your healthcare provider prescribed for you. 10) The second key press starts Morning Dose delivery. Press a second time to deliver the Morning Dose. The display shows a countdown of your Morning Dose. 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. 11) Insert pump into the carrying bag (see Figure J). Other carrying cases are also available. Refer to the specific Instructions for Use, which accompanies your carrying case. 12) Wear the bag over your shoulder or neck: Place the bag strap over your shoulder or neck (see Figure K). Make sure the pump is in correct position (see Figure L). Extra Dose 1) Give an Extra Dose of DUOPA: 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. Check for on the display. Press Listen for 2 beeps. The display will show 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: 1 Syringe 1 Syringe connector Room temperature water 1 Coin, like a quarter 1) Remove the pump from the carrying bag (see Figure M). 2) Stop the Continuous Rate: Press and hold until 3 dashes appear and then disappear from the display. Check for on the display. 3) Turn the pump off: Press and hold until 3 sets of dots appear and then disappear from the display and the display turns off. Check that the display is off. 4) Clamp the cassette tube (see Figure N). 5) Disconnect the tubing: Twist the cassette tube to disconnect it from the longer straight (green) connector (see Figure O). WARNING: Do not twist the stomach tube. Replace the red cap on the cassette tube. 6) Flush the longer straight (green) connector: Connect the syringe connector to the longer straight (green) connector. Fill a syringe with room temperature tap or drinking water. Do not use hot water as it could burn the wall of your stomach or intestine. Connect the syringe to the syringe connector (see Figure P). Do not over-tighten the syringe connector or it could break. Do not use the syringe connector if it is cracked or broken. Push the syringe plunger to flush the tube. Do not force the syringe if flushing the tube is difficult. Call your healthcare provider if you are unable or have difficulty flushing your tube. Remove the syringe and the syringe connector. Replace the white cap on the longer straight (green) connector (see Figure Q). 7) Flush the shorter angled connector (white, blue, or violet): Twist the white cap off the shorter angled connector (white, blue, or violet). Connect the syringe connector to the shorter angled connector (white, blue, or violet). Fill a syringe with room temperature tap or drinking water. Do not use hot water as it could burn the wall of your stomach or intestine. Connect the syringe to the syringe connector (see Figure R). Do not over-tighten the syringe connector or it could break. Do not use the syringe connector if cracked or broken. Push the syringe plunger to flush the tube. Remove the syringe and the syringe connector. Replace the white cap on the shorter angled connector (white, blue, or violet) (see Figure S). 8) Remove the DUOPA cassette from the pump: Hold the pump and DUOPA cassette upright against a flat surface (see Figure T). Use a coin to twist the latch clockwise until the latch pops out (see Figure U). Remove the DUOPA cassette from the pump. Changing the DUOPA Cassette Take the DUOPA carton containing the DUOPA cassette out of the refrigerator. Check the expiration date on the carton. Do not use any of the cassettes if the expiration date has passed. Take a DUOPA cassette out of the carton. Return the carton with the remaining cassettes to the refrigerator. Do not use the cassette if the expiration date has passed or the cassette is damaged or empty. Leave the DUOPA cassette at room temperature for 20 minutes before using. Each DUOPA cassette may be used for up to 16 hours after removal from the refrigerator. WARNING: Use only DUOPA cassettes to make sure the pump works correctly. 1) Remove the pump from the carrying bag (see Figure V). 2) Stop the Continuous Rate: Press and hold until 3 dashes appear and then disappear from the display. Check for on the display. 3) Turn the pump off: Press and hold until 3 sets of dots appear and then disappear from the display and the display turns off. Check that the display is off. 4) Clamp the cassette tube (see Figure W). 5) Disconnect the tubing: Twist the cassette tube to disconnect it from the longer straight (green) connector (see Figure X). WARNING: Do not twist the stomach tube. Replace the red cap on the cassette tube. 6) Remove the DUOPA cassette from the pump: Hold the pump and DUOPA cassette upright against a flat surface (see Figure Y). Use a coin to twist the latch clockwise until the latch pops out (see Figure Z). Remove the DUOPA cassette from the pump. 7) Remove the cassette clip on the new DUOPA cassette (see Figure AA): Remove the cassette tube from its secured slot in the clip. Pull the clip from the cassette to slide it off of the cassette top. 8) Attach the new DUOPA cassette to the pump (see Figure BB): Hold the pump so that the latch faces up. Hold the DUOPA cassette so that the tube points down. Insert the DUOPA cassette hooks into the hinge pins at the base of the pump. 9) Latch the new DUOPA cassette into the pump: Hold the pump and DUOPA cassette upright against a flat surface. Press down on the pump until the DUOPA cassette fits tightly against the pump (see Figure CC). Use a coin to twist the latch counterclockwise until the latch lines up straight with the arrow (see Figure DD). WARNING: Attach the DUOPA cassette correctly. A detached or incorrectly attached cassette could cause a problem with getting your DUOPA. 10) Remove the red cap on the end of the cassette tube (see Figure EE). 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. 11) Connect the stomach tube to the cassette tube: While holding the stomach tube steady, twist off the white cap on the end of the longer straight (green) connector (see Figure FF). WARNING: Do not twist the stomach tube. Connect the cassette tube to the end of the longer straight (green) connector (see Figure GG). Do not connect to the shorter angled connector (white, blue, or violet). 12) Turn the pump on: Press and hold until the display turns on. Wait approximately 30 seconds for the pump to review settings. Check for on the display. PUMP STATUS: The pump is now on but not delivering DUOPA. 13) Inspect the tubing for kinks or closed clamps. If needed straighten kinks or open clamps (see Figure HH). 14) Start the pump: Press and hold until 3 dashes appear and then disappear from the display. Wait approximately 15 seconds for pump to start running. Check for on the display. PUMP STATUS: The pump is now running. 15) Insert the pump into the carrying bag (See Figure II). 16) Wear the bag on your shoulder or neck: Place the bag strap over your shoulder or neck (see Figure JJ). Make sure the pump is in correct position (see Figure KK). 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: Always have new batteries available for replacement. If power is lost, DUOPA will not be delivered. If the pump is dropped or hit, the battery door or tabs may break. Do not use the pump if the battery door or tabs are damaged because the batteries will not be correctly secured. This may lead to loss of power and DUOPA will not be delivered. If a gap is present anywhere between the battery door and the pump housing, the door is not correctly latched. If the battery door becomes detached or loose, the batteries will not be correctly secured. This could cause loss of power and DUOPA will not be delivered. CAUTION: Do not use rechargeable NiCd or nickel metal hydride (NiMH) batteries. Do not use carbon zinc (heavy duty) batteries. They do not provide enough power for the pump to operate correctly. Do not store the pump for prolonged periods of time with the batteries installed. Battery leakage could damage the pump. 1) Ensure the pump is stopped. 2) Push and hold the arrow button while sliding the battery door until it comes completely off the pump (see Figure LL). 3) Remove the used batteries (see Figure MM). 4) Install new batteries into the battery compartment. 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. 5) Listen for a beep. 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. 6) Slide the battery door back onto the pump into its original closed position (see Figure NN). 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. 1) Turn the pump on: Press and hold until the display turns on. Wait approximately 30 seconds for pump to review settings. Check for on the display. PUMP STATUS: The pump is now on but not yet delivering DUOPA. 2) Inspect the tubing for kinks or closed clamps. If needed, straighten kinks or open clamps (see Figure OO). 3) Start the pump: Press and hold until 3 dashes appear and then disappear from the display. Wait approximately 15 seconds for pump to start running. Check for on the display. PUMP STATUS: The pump is now running. 4) Change the Morning Dose: Press 1 time. Check for on the display. Press or to select the desired Morning Dose. Press to store the Morning Dose. Make sure you see the correct Morning Dose on the display. If not, repeat Steps 4c to 4e. 5) Deliver the Morning Dose: Press 1 time. NOTE: If you see Value not saved on the display, press NEXT and then repeat Steps 4c to 4e. The display shows a countdown of your Morning Dose. 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 1) Stop the Continuous Rate: Press and hold until 3 dashes appear and then disappear from the display. Check for on the display. 2) Change the Continuous Rate: Press 2 times. Check for on the display. Press or to select the desired Continuous Rate. Press to store the Continuous Rate. Make sure you see the desired Continuous Rate on the display. If not, repeat Steps 2c to 2e. 3) Start the pump: Press and hold until 3 dashes appear and then disappear from the display. NOTE: If you see Value not saved on the display, press NEXT and then repeat Steps 2c to 2e. Wait approximately 15 seconds for the pump to start running. The display will show 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 to silence the alarm. 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: Check the DUOPA cassette latch on the side of the pump and make sure the line on the latch lines up with the arrow on the side of the pump. Gently twist, push, and pull on the DUOPA cassette to make sure it is still firmly attached. Check the battery door to make sure it is still firmly attached. 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? If you accidentally drop the pump in water, pick it up quickly, dry it off with a towel, and call your healthcare provider. 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? Youll 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 Store DUOPA in the refrigerator with the temperature between 36F to 46F (2C to 8C). When the DUOPA cassette has been removed from the refrigerator, DUOPA should be used within 16 hours. The DUOPA cassettes are for single use only and should not be used for longer than 16 hours, even if some of the medicine remains. An opened cassette should not be re-used. Protect the cassette from light and keep it in the carton before using. Throwing away your DUOPA cassette or batteries Throw away the DUOPA cassette as your healthcare provider tells you to. Throw away used batteries in a manner safe for the environment, and according to any regulations that apply. This Instructions for Use has been approved by the U.S. Food and Drug Administration. AbbVie Inc. North Chicago, IL 60064, U.S.A. For DUOPA Support: 1-844-386-4968 Pump manufactured by: Smiths Medical ASD, Inc. 1265 Grey Fox Road St. Paul, MN 55112 USA Tel: 1-800-258-5361 www.smiths-medical.com 03-B884 Revised: March 2019

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS Gastrointestinal procedure-related complications may result in serious outcomes, such as need for surgery or death (5.1) May cause falling asleep during activities of daily living (5.2) Monitor patients for orthostatic hypotension, especially after starting DUOPA or increasing the dose (5.3) Hallucinations/Psychosis/Confusion: May respond to dose reduction in levodopa (5.4) Impulse Control Disorders: Consider dose reductions or stopping DUOPA (5.5) Monitor patients for depression and suicidality (5.6) Avoid sudden discontinuation or rapid dose reduction to reduce the risk of withdrawal-emergent hyperpyrexia and confusion (5.7) May cause or exacerbate dyskinesia: Consider dose reduction (5.8) Monitor patients for signs and symptoms of peripheral neuropathy (5.9) 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 Parkinsons 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 Parkinsons 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 Parkinsons 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.

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS Selective MAO-B inhibitors: May cause orthostatic hypotension (7.1) Antihypertensive drugs: May cause symptomatic postural hypotension. Dosage adjustment of the antihypertensive drug may be needed (7.2) Dopamine D2 receptor antagonists, isoniazid, iron salts, and high-protein diet may reduce the effectiveness of DUOPA (7.3, 7.4, 7.5) 7.1 Monoamine Oxidase (MAO) Inhibitors The use of nonselective MAO inhibitors with DUOPA is contraindicated [see Contraindications (4)]. 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. 7.2 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. 7.3 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 Parkinsons symptoms. 7.4 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 Parkinsons symptoms. 7.5 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.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY 13.1 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 SECTION.


8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm (8.1) 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 mothers 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.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES The efficacy of DUOPA was established in a randomized, double-blind, double-dummy, active-controlled, 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 immediate-release 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 Parkinsons 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 carbidopa-levodopa 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 carbidopa-levodopa. 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 Parkinsons Disease Treatment Group Baseline (hours) LS Mean Change from Baseline at Week 12 (hours) "Off" time Oral immediate-release carbidopa-levodopa 6.9 -2.1 DUOPA 6.3 -4.0* "On" time without troublesome dyskinesia Oral immediate-release carbidopa-levodopa 8.0 2.2 DUOPA 8.7 4.1* LS Mean Change from Baseline based on Analysis of Covariance (ANCOVA). *=Statistically Significant. 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. Figure 2. Change in Off Time Over 12 Weeks.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Carbidopa 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 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. 12.2 Pharmacodynamics 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. 12.3 Pharmacokinetics 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 (over-encapsulated 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 (-methyl-3-methoxy-4-hydroxyphenylpropionic acid and -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-O-methyldopa. When administered with carbidopa, the elimination half-life of levodopa is approximately 1.5 hours (see Figure 1). Drug Interaction Studies COMT Inhibitors Systemic exposure of levodopa is expected to increase in the presence of entacapone.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS 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 (7.1 and 7.2)]. DUOPA is contraindicated in patients taking nonselective monoamine oxidase (MAO) inhibitors (4)