Clinical UM Guideline

 

Subject: Enteral Carbidopa and Levodopa Intestinal Gel Suspension
Guideline #: CG-DRUG-108 Publish Date:    09/20/2018
Status: New Last Review Date:    07/26/2018

Description

This document addresses an 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).

Clinical Indications

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 when the criteria are not met and for all other indications, including, but not limited to the following:

  1. Individuals on nonselective MAO inhibitors,
  2. Individuals with Atypical PD,
  3. Individuals with Secondary PD.
Coding

The following codes for treatments and procedures applicable to this guideline 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.

HCPCS

 

J7340

Carbidopa 5 mg/levodopa 20 mg enteral suspension, 100 ml [Duopa]

 

 

ICD-10 Diagnosis

 

G20

Parkinson’s disease         

Discussion/General Information

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).

Oral levodopa combined with carbidopa is an accepted medication for individuals with symptomatic PD. 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. The gel suspension is a potential treatment option for individuals with late-stage PD who have poor function (that is, more “off” periods and fluctuations between “on/off” periods and/or dyskinesias) despite oral therapy.  

In 2008, 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 for the long-term treatment of motor fluctuations associated with advanced PD. In January 2015, the FDA granted an orphan designation and manufacturing approval for Duopa use in the United States. This product is delivered 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.

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.”

Levodopa-carbidopa intestinal gel (LCIG) has been evaluated in a double-blind, double-dummy randomized controlled trial (RCT). Results of this trial were reported by Olanow and colleagues in 2014. Multiple international centers enrolled a total of 71 individuals with advanced PD and motor complications that were uncontrolled with optimal oral 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 was change in the mean number of off-hours recorded by participants in the home diary at baseline compared to the assessment at week 12. There was a significant reduction in off-time in those treated with LCIG of -4.04 hours, compared to the oral therapy 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.

Following the 12-week double-blind phase of the RCT, 62 of 66 (94%) individuals in the LCIG group proceeded to a 52-week open-label extension. (Slevin 2015). A total of 3 participants reported at least one adverse event (AE) during the study period, with serious AEs reported by 23%. The incidence of AEs decreased gradually over the 1-year follow-up period. 

In 2018, Fernandez and colleagues reported safety outcomes in 262 individuals with PD; these included the individuals in the long-term open-label RCT extension and those from a separate 52-week open-label study. The mean duration of LCIG exposure was 4.1 years (range, 1.2 to 6.9 years). There were 38 deaths (15%), 2 of which were considered to be possibly related to gel treatment. An additional 24 individuals discontinued treatment due to AEs, the most common of which were procedure or device-related AEs. Polyneuropathy-related symptoms were reported in 22 participants (8%), of which one was a serious case. In the individuals with PN symptoms, mean laboratory values for vitamin B6, vitamin B12 and folic acid were in the normal range but mean homocysteine levels were abnormally high.

A small randomized cross-over study was published by Nyholm and colleagues (2005). A total of 24 individuals with advanced PD, motor fluctuations and dyskinesia received, in random order, 3 weeks of individualized conventional therapy and 3 weeks of carbidopa and levodopa intestinal gel suspension. Clinical outcomes, including quality of life and symptoms assessed by the Unified Parkinson’s Disease Rating Scale (UPDRS), were better during the intestinal gel intervention.

A single-arm study reporting 7-year data in individuals treated with LCIG was published by Zibetti and colleagues (2014).  A total of 59 individuals with PD were treated. Of these, 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 in outcomes were reported 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.

In 2017, Antonini and colleagues published final results of the GLORIA study (global long-term registry on efficacy and safety of LCIG in patients with advanced Parkinson’s disease in routine care). The registry study was conducted at 75 centers in 18 countries and included individuals with advanced PD who had persistent severe motor symptoms. A total of 375 individuals were enrolled and 258 (69%) completed the 24-month study. All participants received LCIG via a PEG-J tube. Clinical outcomes significantly improved after treatment. For example, compared with baseline, individuals had significant reductions in “off” time and significant reductions in “On” time with dyskinesia. At the last study visit, compared with baseline, quality of life measured by the Parkinson’s Disease Questionnaire (PDQ)-8 was significantly lower (-5.3 points, p<0.001). During the course of the study, 194 (55%) participants experienced at least one AE. The most common AEs were weight loss (6.7%), device-related infections (5.9%), device dislocations (4.8%), other device-related issues (4.8%) and polyneuropathy (4.5%). A total of 25 (7%) individuals experienced at least one AE that led to discontinuation of LCIG treatment. There were 29 deaths (8%), 5 of which were deemed possibly related to treatment and 1 of which was considered probably related. The death that was probably related occurred after 646 days of treatment and resulted from small bowel perforation and peritonitis.

Data from RCTs and long-term single-arm studies have found that enteral carbidopa and levodopa intestinal gel suspension can improve clinical outcomes in selected individuals with advanced PD. The treatment is associated with safety issues, including device-related complications and polyneuropathy.

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.

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, Poewe, W, Chauduri KR et al. Levodopa-carbidopa intestinal gel in advanced Parkinson’s: Final results of the GLORIA registry. Parkinsonism Relat Disord. 2017; 45:13-20.
  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. Fernandez HH, Boyd JT, Fung VSC et al. Long-term safety and efficacy of levodopa-carbidopa intestinal gel in advanced Parkinson’s disease. Mov Disord. 2018 Mar 23; Epub ahead of print.
  5. 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.
  6. 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.
  7. 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.
  8. 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
  9. 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.
  10. 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 May 30, 2018.
  2. 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 May 30, 2018.
  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 May 30, 2018.
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.

History

Status

Date

Action

New

07/26/2018

Medical Policy & Technology Assessment Committee (MPTAC) review. Initial document development. Moved content of DRUG.00064 Enteral Carbidopa and Levodopa Intestinal Gel Suspension to new clinical utilization management guideline document with the same title. In Clinical Indications section, consolidated ‘not medically necessary’ indications into a single ‘not medically necessary’ statement. Updated Discussion/General Information and References sections.