Description
This document addresses a novel enteral formulation of the carbidopa and levodopa intestinal (intraduodenal) gel suspension (Duopa^TM, AbbVie Inc., North Chicago, IL) infusion for the treatment of advanced Parkinson's disease (PD).

Background
PD is a type of motor system disorder resulting from the loss of dopamine-producing brain cells and typically affects individuals 50 years of age and older, but may affect younger individuals. The four primary symptoms of this disorder include tremor (trembling); rigidity (stiffness of the limbs and trunk); bradykinesia (slowness of movement); and postural instability (impaired balance and coordination). These symptoms become more pronounced and affect daily activities at different rates of progression for each individual. The goal of treatment is to minimize the symptoms from this disorder in adults (National Institute of Neurological Disorders and Stroke, 2014).

Approximately 60,000 Americans are diagnosed each year, and men are one and a half times more likely to have Parkinson's than women. According to the Parkinson's Disease Foundation, there are approximately 1 million Americans affected by the disease. Approximately 10 percent of individuals with PD "develop motor fluctuations after starting treatment with levodopa" (Abbruzzese, 2012).

Policy 
Enteral intestinal infusion of carbidopa and levodopa gel suspension is considered MEDICALLY NECESSARY for the treatment of motor fluctuations when the following criteria are met: 

1. Individual has advanced Parkinson's disease with complicated motor fluctuations that have not been adequately controlled with optimal medical therapy that included the following:
   1. Oral levodopa-carbidopa; and
   2. One agent from the following classes:
      • Dopamine agonist
      • Catechol-0-methyl transferase (COMT) inhibitor; or
      • Monoamine oxidase B (MAO)-B inhibitor. and
2. The individual has been evaluated by a neurologist, who prescribes and manages treatment with the drug
3. Medication is not used concurrently with nonselective monoamine oxidase inhibitors (MAOIs) or use within the last 14 days  

Enteral intestinal infusion of carbidopa and levodopa gel suspension is considered NOT MEDICALLY NECESSARY for individuals on nonselective MAO inhibitors.  

Enteral intestinal infusion of carbidopa and levodopa gel suspension is considered INVESTIGATIONAL when the criteria are not met and for all other indications, including, but not limited to, individuals with the following: 

• Atypical PD
• Secondary PD

Rationale 
Carbidopa and levodopa intestinal gel is a novel intraduodenal formulation of the dopamine precursor levodopa and the dopa-decarboxylase inhibitor carbidopa for the treatment of late-stage PD in individuals who have poor function (that is, more "off" periods and fluctuations between "on/off" periods and/or dyskinesias) despite oral therapy with levodopa and carbidopa. This product is delivered over 16 hours using a portable pump directly into the duodenum through a tube inserted via percutaneous endoscopic gastrostomy (PEG) with an outer trans-abdominal tube and an inner intestinal (jejunostomy) tube. The U.S. Food and Drug Administration (FDA) had granted fast track status to the phase III development program for carbidopa and levodopa intraduodenal gel in February 2008 for the long-term treatment of motor fluctuations associated with advanced PD. The FDA has granted an orphan designation and manufacturing approval for use in the United States in January 2015. 

The enzymes responsible for the degradation of levodopa are inhibited by carbidopa. The goal of combining the two drugs is to achieve greater plasma concentrations of levodopa than that achieved with levodopa alone. Large variations in plasma drug concentration can occur with conventional oral levodopa therapy, resulting in inadequate maintenance of the symptoms of PD. A steady concentration of levodopa is believed to provide a consistent therapeutic effect and stabilize motor function more effectively. Therefore, a gel suspension of carbidopa and levodopa was developed for 16 hours of continuous portable infusion pump delivery into the jejunum. Infusing directly to the jejunum avoids drug degradation in the stomach, aids rapid absorption and helps to achieve constant plasma concentrations of levodopa.

Results from a randomized, double-blind, double-dummy trial were reported by Olanow and colleagues (2014). Multiple international centers enrolled a total of 71 individuals with advanced PD and motor complications that were uncontrolled with optimal therapy (levodopa and carbidopa; dopamine agonist; and one or more agents from the COMT inhibitor or MAO-B inhibitor class). The trial excluded individuals with atypical or secondary parkinsonism. All participants had percutaneous gastrojejunostomy (PEG-J) tubes placed. Individuals were randomized to placebo intestinal gel infusion and oral over-encapsulated immediate release levodopa-carbidopa or levodopa-carbidopa intestinal gel infusion plus oral placebo. During the first four weeks of titration, dose adjustments were done on a daily basis during the first two weeks while the individual was hospitalized and then weekly during outpatient visits over weeks three and four. Maintenance therapy occurred over the subsequent eight-week period. Rescue therapy with immediate release oral levodopa-carbidopa was available for participants with persistent off-periods despite therapy in either group. A total of 66 participants had completed the trial and were available for data analysis. The primary endpoint of the change in the mean number of off-hours recorded by participants in the home diary at baseline compared to the assessment at week 12 was met. There was a reduction in off-time in those treated with the carbidopa and levodopa intestinal gel -4.04 hours, compared to the placebo group with -2.14 hours for a treatment difference of -1.91 hours (95% confidence interval, -3.05 hours to -0.76 hours; p = 0.0015). Overall, 63 (89 percent) of 71 individuals had device-related complications that included insertion complications, tube dislocations, malfunctions of the pump and pneumoperitoneum. Most complications occurred early and were mild-to-moderate in severity, and resolution was achieved for all individuals. The authors noted this is the first randomized controlled trial to demonstrate a benefit of reduced off periods with 16 hours of continuous infusion of carbidopa and levodopa intestinal gel infused into the jejunum. However, the authors noted long-term studies were needed to determine the efficacy of this novel gel formulation to improve dyskinesias and to further assess any long-term adverse events.

In a study with long-term follow-up, initiation of carbidopa and levodopa intestinal gel required hospitalization for an average period of 11 days (range 7 – 17 days) (Zibetti, 2013). The first three days involved placement of a nasogastric tube, initiation of continuous carbidopa and levodopa intestinal gel (calculated on the oral dosage requirements) and dose adjustments to achieve maximal motor performance without relevant dyskinesia. Then the J-tube was placed and the carbidopa and levodopa intestinal gel was converted to the J-tube infusion. The authors noted reduced motor fluctuations and dyskinesias along with improved quality of life despite progressive PD. Adverse events are the same as oral carbidopa and levodopa (dyskinesias, hallucinations), and additional complications related to the J-tube: surgical placement complications, infections, perforation, tube kinking, dislocating (retrograde migration back into stomach) and difficulty with pump programming. 

According to the product information label (2015), due to hypertension, recent (within two weeks) or concurrent use of Duopa with nonselective MAO inhibitors (for example, phenelzine and tranylcypromine) is contraindicated.

Most common adverse reactions with an incidence rate at least 7 percent greater than oral carbidopa-levodopa reported on the product label (2015) include the following: "Complication of device insertion, nausea, depression, peripheral edema, hypertension, upper respiratory tract infection, oropharyngeal pain and incision site erythema."

References 

1. Abbruzzese G, Barone P, Bonuccelli U, et al. Continuous intestinal infusion of levodopa/carbidopa in advanced Parkinson's disease: efficacy, safety and patient selection. Funct Neurol. 2012; 27(3):147-154.
2. Jugel C, Ehlen F, Taskin B, et al. Neuropathy in Parkinson's disease patients with intestinal levodopa infusion versus oral drugs. PLoS One. 2013; 8(6):e66639.
3. Nyholm D, Johansson A, Lennernäs H, Askmark H. Levodopa infusion combined with entacapone or tolcapone in Parkinson disease: a pilot trial. Eur J Neurol. 2012; 19(6):820-826.
4. Nyholm D, Klangemo K, Johansson A. Levodopa/carbidopa intestinal gel infusion long-term therapy in advanced Parkinson's disease. Eur J Neurol. 2012; 19(8):1079-1085.
5. Nyholm D, Nilsson Remahl AI, Dizdar N, et al. Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease. Neurology. 2005; 64(2):216-223.
6. Nyholm D, Odin P, Johansson A, et al. Pharmacokinetics of levodopa, carbidopa, and 3-O-methyldopa following 16-hour jejunal infusion of levodopa-carbidopa intestinal gel in advanced Parkinson's disease patients. AAPS J. 2013; 15(2):316-323.
7. Olanow CW, Kieburtz K, Odin P, et al; for the LCIG Horizon Study Group. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study. Lancet. 2014; 13(2):141-149.
8. Zibetti M, Merola A, Ricchi V, et al. Long-term duodenal levodopa infusion in Parkinson's disease: a 3-year motor and cognitive follow-up study. J Neurol. 2013; 260(1):105-114.
9. Carbidopa and levodopa (Duopa) [Product Information], North Chicago, IL. AbbieVie Inc. January 2015. Available at: http://www.rxabbvie.com/pdf/duopa_pi.pdf.  Accessed on January 12, 2015.
10. National Institute of Neurological Disorders and Stroke. Parkinson's Disease. Updated July 8, 2014. Available at: http://www.ninds.nih.gov/disorders/parkinsons_disease/parkinsons_disease.htm.  Accessed on January 12, 2015. 

Coding Section 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

Drug Information

• The maximum recommended daily dose of DUOPA is 2,000 mg of levodopa (i.e., one cassette per day) administered over 16 hours.
• Prior to initiating DUOPA, convert patients from all forms of levodopa to oral immediate-release carbidopa-levodopa tablets (1:40 ratio).
• Titrate total daily dose based on clinical reponse for the patient.
• Administer DUOPA into the jejunum through a percutaneous endoscopic gastrostomy with jejunal tube (PER-J) with the CADD^®-Legacy 1400 portable infusion pump.

Adverse Events and Warnings
Additional warnings, precautions and recommendations from the FDA product information label (2015) include the following: 

• Gastrointestinal procedure-related complications may result in serious outcomes, such as need for surgery or death.
• May cause falling asleep during activities of daily living.
• Monitor patients for orthostatic hypotension, especially after starting Duopa or increasing the dose.
• Hallucinations/psychosis/confusion: May respond to dose reduction in levodopa.
• Impulse control disorders: Consider dose reductions or stopping Duopa.
• Monitor patients for depression and suicidality.
• Avoid sudden discontinuation or rapid dose reduction to reduce the risk of withdrawal-emergent hyperpyrexia and confusion.
• May cause or exacerbate dyskinesia: consider dose reduction.
• Monitor patients for signs and symptoms of peripheral neuropathy.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community; U.S. FDA approval status; nationally accepted standards of medical practice and accepted standards of medical practice in this community; Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers; reference to federal regulations; other plan medical policies and accredited national guidelines.

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