Medical Policy



Subject: Enteral Carbidopa and Levodopa Intestinal Gel Suspension
Document #: DRUG.00064 Current Effective Date:    09/27/2017
Status: Reviewed Last Review Date:    08/03/2017

Description/Scope

This document addresses a novel enteral formulation of the carbidopa and levodopa intestinal (intraduodenal) gel suspension (DuopaTM , AbbVie Inc., North Chicago, IL) infusion for the treatment of late-stage Parkinson's disease (PD).

Position Statement

Medically Necessary:

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 which included the following:
    1. Oral levodopa-carbidopa; and
    2. Dopamine agonist; and
    3. One agent from the following classes:
      1. Catechol-0-methyl transferase (COMT) inhibitor; or
      2. Monoamine oxidase B (MAO)-B inhibitor.

Not Medically Necessary:

Enteral intestinal infusion of carbidopa and levodopa gel suspension is considered not medically necessary for individuals on nonselective MAO inhibitors.

Investigational and Not Medically Necessary:

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

  1. Atypical PD
  2. 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. In January 2015, the FDA has granted an orphan designation and manufacturing approval for Duopa use in the United States. 

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 control of PD symptoms. A steady concentration of levodopa is believed to provide a consistent therapeutic effect with improved motor function. 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 4 weeks of titration, dose adjustments were done on a daily basis during the first 2 weeks while the individual was hospitalized and then weekly during outpatient visits over weeks 3 and 4. Maintenance therapy occurred over the subsequent 8-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%) of 71 individuals had device-related complications which 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 3 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 function 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.

In an updated analysis of 59 individuals treated at a single center, Zibetti and colleagues (2014) reported outcome data from the 7-year use of enteral carbidopa and levodopa intestinal gel suspension. A total of 19% (11 individuals) discontinued therapy before the cut-off date for the study and 7 (12%) individuals died of complications unrelated to the drug. Improvements reported at 3 years were maintained at 7 years with over 90% improvements reported for motor fluctuations and dyskinesias along with improved quality of life despite progressive PD. The most frequent complications reported were related to kinking or dislocation of the tube.

A systematic review noted peripheral neuropathy (PN) is an infrequent but occasionally serious adverse effect from the use of enteral carbidopa and levodopa intestinal gel suspension (Muller, 2013). The authors noted that data from case controlled studies include other risk factors for PN such as the "cumulative dose of levodopa during treatment, as well as vitamin B12, B6, and/or folate deficiencies, and with dysfunction of homocysteine metabolism." The authors noted monitoring of lab values and neurologic symptoms are recommended on a routine basis. In addition, the authors cautioned that this data needs to be validated in prospective clinical trials.

According to the product information label (2016), due to the potential for hypertension, recent (within 2 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% greater than oral carbidopa-levodopa reported on the product label (2016) include the following: "Complication of device insertion, nausea, depression, peripheral edema, hypertension, upper respiratory tract infection, oropharyngeal pain, and incision site erythema."

Background/Overview

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, 2015).

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% of individuals with PD "develop motor fluctuations after starting treatment with levodopa" (Abbruzzese, 2012).

Adverse Events and Warnings
Additional warnings, precautions and recommendations from the FDA Product Information Label (20156 include the following:

Definitions

Dopamine: A neurotransmitter in the brain which plays a role in smooth, purposeful movement.

Dyskinesia: Impairment of voluntary movement, resulting in fragmentary or incomplete movements; involuntary movements.

Enteral: By way or within the gastrointestinal tract or intestine.

Off-period: A period of time when Parkinsonian symptoms re-appear because the medication has worn off or is not effective.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met: 

HCPCS  
J7340 Carbidopa 5 mg/levodopa 20 mg enteral suspension, 100 ml
   
ICD-10 Diagnosis  
G20 Parkinson's disease

When services are Not Medically Necessary:
For the situation described in the Position Statement section as not medically necessary.

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  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. Antonini A, Yegin A, Preda C, et al.; GLORIA study investigators and coordinators. Global long-term study on motor and non-motor symptoms and safety of levodopa-carbidopa intestinal gel in routine care of advanced Parkinson's disease patients; 12-month interim outcomes. Parkinsonism Relat Disord. 2015;21(3):231-235.
  3. Cáceres-Redondo MT, Carrillo F, Lama MJ, et al. Long-term levodopa/carbidopa intestinal gel in advanced Parkinson's disease. J Neurol. 2014; 261(3):561-569.
  4. 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.
  5. Müller T, van Laar T, Cornblath DR, et al. Peripheral neuropathy in Parkinson's disease: levodopa exposure and implications for duodenal delivery. Parkinsonism Relat Disord. 2013; 19(5):501-507.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. Olanow CW, Kieburtz K, Odin P, et al.; 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.
  11. Pickut BA, van der Linden C, Dethy S, et al. Intestinal levodopa infusion: the Belgian experience. Neurol Sci. 2014; 35(6):861-866.
  12. Slevin JT, Fernandez HH, Zadikoff C, et al. Long-term safety and maintenance of efficacy of levodopa-carbidopa intestinal gel: an open-label extension of the double-blind pivotal study in advanced Parkinson's disease patients. J Parkinsons Dis. 2015;5(1):165-174
  13. Zibetti M, Merola A, Artusi CA, et al. Levodopa/carbidopa intestinal gel infusion in advanced Parkinson's disease: a 7-year experience. Eur J Neurol. 2014; 21(2):312-318.
  14. 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.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Carbidopa and levodopa (Duopa) [Product Information], North Chicago, IL. AbbieVie Inc. September 2016. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/203952s004lbl.pdf . Accessed on June 5, 2017.
  2. Carbidopa/Levodopa.  In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated April 7, 2017. Available at: http://www.micromedexsolutions.com. Accessed on June 5, 2017.
  3. Pahwa R, Factor SA, Lyons KE, et al.; Quality Standards Subcommittee of the American Academy of Neurology. Practice Parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review). Neurology. 2006; 66(7):983-995.
Websites for Additional Information
  1. National Institute of Neurological Disorders and Stroke. Parkinson's Disease. Available at: https://www.ninds.nih.gov/Disorders/All-Disorders/Parkinsons-Disease-Information-Page . Accessed on June 5, 2017.
  2. U.S. National Library of Medicine. Medline Plus. Parkinson's Disease. Updated on May 18, 2017. Available at: https://www.nlm.nih.gov/medlineplus/parkinsonsdisease.html . Accessed on June 5, 2017.
Index

Parkinson's disease

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
Reviewed 08/03/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Updated References and Websites sections
  01/01/2017 Updated Coding section with 01/01/2017 HCPCS descriptor revision for code J7340.
Reviewed 08/04/2016 MPTAC review. Updated Definitions, References and Websites sections. Updated formatting in Position Statement section.
  01/01/2016 Updated Coding section with 01/01/2016 HCPCS changes; removed ICD-9 codes.
Reviewed 08/06/2015 MPTAC review. Updated Rationale, Background, Coding and References sections.
Revised 02/05/2015 MPTAC review. Added medically necessary and not medically criteria. Revised investigational and not medically necessary criterion. Updated Rationale, Background, References, Definitions and Coding sections.
New 08/14/2014 MPTAC review. Initial document development.