Medical Policies - Prescription Drugs


Levodopa-Carbidopa Enteral Suspension (e.g. Duopa) for The Treatment of Parkinson Disease.

Number:RX504.015

Effective Date:07-15-2018

Coverage:

CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT

Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

Levodopa-carbidopa enteral suspension (e.g. Duopa®) may be considered medically necessary for the treatment of motor fluctuations in individuals with advanced idiopathic Parkinson’s disease (PD), who meet all of the following criteria:

1. Presence of bradykinesia and at least one other cardinal PD feature (tremor, rigidity, postural instability); and

2. Levodopa responsive with clearly defined “On” periods*; and

3. Persistent motor complications with disabling “Off” periods** for a minimum of 3 hours/day despite optimal medical therapy with:

a. Dopamine agonists; and

b. Oral levodopa and carbidopa; and

c. One agent from the following class;

1. Catechol-O-methyl transferase (COMT) inhibitors; or

2. Monoamine oxidase (MAO) B inhibitors.

*NOTE: "On” periods refer to periods of adequate control of PD symptoms.

**NOTE: "Off” periods refer to periods of the day when the medication is not working well, causing worsening of PD symptoms.

Levodopa-carbidopa enteral suspension is considered experimental, investigational and/or unproven for all other indications, including but not limited to patients with:

Atypical Parkinson’s disease (“Parkinson’s Plus” syndrome); or

Secondary Parkinson’s disease.

NOTE: Duopa is contraindicated in patients taking nonselective monoamine oxidase (MAO) inhibitors, in patients that are not candidates for percutaneous endoscopic gastro-jejunal (PEG-J) tube placement, and in patients where long-term use of a PEG-J is contraindicated.

A pump for administering levodopa-carbidopa enteral suspension may be considered medically necessary durable medical equipment (DME) for persons who meet the criteria for levodopa-carbidopa enteral suspension.

Description:

Parkinson's disease (PD) is a chronic, progressive neurodegenerative condition resulting from the death of the dopamine containing nerve cells in one of the movement control centers of the brain (substantia nigra). (1) Approximately 60,000 Americans are diagnosed with PD each year, and this number does not reflect the thousands of cases that go undetected. An estimated 6 to 10 million people worldwide are living with PD. There is a rising prevalence with age and a higher prevalence and incidence of PD in males. (2)

Some forms of PD have genetic or familial risk factors. PD can be either primary or secondary. Primary PD is referred to as idiopathic (having no known cause), while secondary PD is due to known causes like toxins, drugs and conditions which may include multiple cerebral infarctions and degenerative conditions such as progressive supra-nuclear palsy (PSP) and multiple system atrophy (MSA). (3)

Atypical parkinsonism includes a variety of neurological disorders in which patients have some clinical features of PD, but the symptoms are caused not only by cell loss in the substantia nigra (the brain area most affected in classic PD), but also by additional degeneration of cells in the parts of the nervous system that normally contain dopamine receptors (striatum). Patients appear to have PD, but the cause of their symptoms is different from that of classic PD. Patients with atypical parkinsonism have symptoms similar to PD, including resting tremors, slowed movement, stiffness, gait difficulty and postural instability, but in addition have symptoms and signs that are not typically present in PD, hence the term "Parkinsonism plus syndrome.” Patients usually have a poor response or no response to levodopa which is a common feature to all forms of atypical PD. In contrast to typical PD, in which dopamine receptors are spared, patients with atypical parkinsonian disorders have lost their dopamine receptors and therefore they do not respond to levodopa as well as those with typical PD. Additional imaging studies may be helpful in differentiating Parkinsonism from atypical Parkinsonism. (3)

The diagnosis of PD is primarily based on clinical, patient history and examination. People with PD classically present with the signs and symptoms associated with Parkinsonism. Symptoms may include tremor (shaking), rigidity in muscles, bradykinesia (slow movements), and problems maintaining normal posture. Although PD is predominantly a movement disorder, other impairments frequently develop including psychiatric problems such as depression and dementia.

Autonomic disturbances and pain (which is rarely a presenting feature of PD) may later ensue, to cause significant disability and handicap with impaired quality of life (QOL) for the affected person. (1)

Carbidopa/levodopa is the gold-standard medication for the treatment of motor symptoms in PD, and is most often taken orally as Sinemet®. (4) But as Parkinson’s disease advances, carbidopa/levodopa becomes effective for shorter time periods, making it necessary for people to take the drug multiple times a day. Even then, people taking carbidopa/levodopa orally experience periods in which the drug “wears off," meaning levodopa levels in the blood may drop and the patients motor symptoms exacerbate prior to the next dose. These “off times” are particularly problematic in advanced PD because gastrointestinal (GI) issues delay the medication’s ability to reach the small intestine, where the drug is absorbed. (5)

Regulatory Status

On January 09, 2015, Duopa® (AbbVie) was approved by the United States Food and Drug Administration (FDA) as an orphan drug. Duopa is an enteral-suspension combination of levodopa and carbidopa, and is indicated for the treatment of PD. Duopa is administered as a continuous 16-hour infusion into the jejunum through a percutaneous endoscopic gastrostomy-jejunal tube (PEG-J), using a CADD®-Legacy 1400 portable infusion pump. (6)

Rationale:

This policy was originally created in July 2015 and has been updated with searches of published literature through April 30, 2018. Following is a summary of key literature to date.

In 2014, Olanow et al. (7) assessed the safety and efficacy of levodopa-carbidopa intestinal gel (LCIG) delivered continuously through an intrajejunal percutaneous tube. The 12-week study was a randomized, double-blind, double-dummy, double-titration trial. Adults (aged ≥ 30 years) with advanced Parkinson's disease (PD) and motor complications were enrolled throughout 26 centers in Germany, New Zealand, and the United States (U.S.) Eligible participants had jejunal placement of a percutaneous gastrojejunostomy tube, and were then randomly allocated (1:1) to treatment with immediate-release oral levodopa-carbidopa plus placebo intestinal gel infusion or LCIG infusion in addition to an oral placebo. Randomization was stratified by site, with a mixed block size of 2 or 4. The primary endpoint was change from baseline to final visit in motor off-time. Change in motor on-time without troublesome dyskinesia as a prespecified key secondary outcome was evaluated. Efficacy in a full-analysis set of participants with data for baseline and at least 1 post-baseline assessment, and imputed missing data with the last observation carried forward approach. Safety was addressed in randomly allocated patients who underwent the percutaneous gastrojejunostomy procedure. From baseline to 12 weeks in the full-analysis set, mean off-time decreased by 4.04 hour(s) (standard error [SE] 0.65) for 35 patients allocated to the LCIG group compared with a decrease of 2.14 hour(s) (0.66) for 31 patients allocated to immediate-release oral levodopa-carbidopa (difference -1.91 hours(s) [95% confidence interval [CI] -3.05 to -0.76]; p=0.0015). Mean on-time without troublesome dyskinesia increased by 4.11 hour(s) (SE 0.75) in the intestinal gel group and 2.24 hour(s) (0.76) in the immediate-release oral group (difference 1.86 [95% CI 0.56 to 3.17]; p=0.0059). In the safety analyses 35 (95%) of 37 patients allocated to the LCIG group had adverse events (AEs; five [14%] serious), as did 34 (100%) of 34 patients allocated to the immediate-release oral levodopa-carbidopa group (seven [21%] serious), mainly associated with the percutaneous gastrojejunostomy tube. The authors concluded that the continuous delivery of LCIG offers a promising option for control of advanced PD with motor complications.

In 2014, Cáceres-Redondo et al. (8) reported on the motor and cognitive outcome of LCIG treatment in advanced PD after a period of at least 24 months. Twenty-nine patients with advanced PD who started LCIG via 1 center between 2007 and 2013 were examined. Motor fluctuations, PD symptoms, activities of daily living and impact on quality of life (QOL) were evaluated as well as cognitive outcome using a battery of neuropsychological tests. All AEs were recorded. Of the 29 PD patients who initiated LCIG, 16 patients reached the follow-up evaluation (24 months), after a mean time-period of 32.2 ± 12.4 months. Six patients did not fulfil the 24-month follow-up visit and were evaluated after a mean time period of 8.6 ± 5.4 months. Seven patients discontinued the treatment before the scheduled visit. "Off" time and "On" dyskinesia duration were significantly reduced. LCIG improved QOL and non-motor symptoms, despite overall unchanged total levodopa doses prior to LCIG beginning. Motor and cognitive decline were detected. A relatively high number of AEs occurred during the follow-up, above all, technical problems with the infusion device and mild problems related with gastrostomy. There were four cases of peripheral neuropathy (PN), 2 of which were considered serious. Data confirmed that LCIG is beneficial in the long-term treatment of advanced PD despite a decline in cognitive functions in a subgroup of patients, probably due to disease progression. PN in patients with LCIG may be more frequent than the published data suggest.

Motor complications in PD are associated with long-term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. LCIG is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG-J), which reduces levodopa-plasma-level fluctuations and can translate to reduced motor complications. In 2014, Fernandez et al. (9) presented the end results of the largest international, prospective, 54-week, open-label LCIG study. PD patients with severe motor fluctuations (>3 h/day "off" time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post-LCIG initiation. Safety was the primary endpoint measured through AEs, device complications, and number of completers. Secondary endpoints included diary-assessed “off” time, "on" time with and without troublesome dyskinesia, unified Parkinson's disease rating scale (UPDRS), and health-related QOL outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG-J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty-seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (P < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% (P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and health-related QOL outcomes were also improved throughout. In the advanced PD population, LCIG's safety profile consisted primarily of AEs associated with the device/procedure, levodopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and health-related QOL sustained over 54 weeks.

In 2014, Zibetti et al. (10) stated that LCIG infusion is becoming an established therapeutic option for advanced PD patients with fluctuating symptoms unresponsive to conventional oral treatment. As the implementation of LCIG therapy is increasing, there is a need for safety and efficacy data from current clinical practice. All PD patients treated with LCIG at 1 center over a 7-year period were analyzed to determine the duration of treatment, retention rate, reasons for discontinuation, LCIG efficacy in motor complications, modifications of concomitant therapy and AEs. Of the 59 patients, seven subjects (12%) died of causes unrelated to LCIG infusion and 11 patients (19%) discontinued therapy prior to the cut-off date. Duodopa improved motor complications and over 90% of patients reported an improvement in their QOL, autonomy and clinical global status. The most common AEs were dislocation and kinking of the intestinal tube. The study concluded that LCIG infusion is effective for the long-term treatment of advanced PD patients and exerts a positive and clinically significant effect on motor complications with a relatively low dropout rate.

In 2015, Slevin and colleagues (11) sought to examine the long-term safety, efficacy and QOL of LCIG. Patients received 52 weeks of open-label LCIG treatment following a 12-week double-blind, double-dummy trial in which they were randomized to either LCIG or immediate-release oral levodopa-carbidopa. Patient cohort designation was by receipt of LCIG in the preceding trial randomization (continuing-LCIG versus LCIG-naïve patients). Sixty-two of 66 subjects in the double-blind proceeded to the open-label extension. Most subjects (95%) reported ≥1 AEs; only 3 subjects (4.8%) discontinued due to AEs. AE incidence declined gradually over 52 weeks. Serious AEs were reported by 23%. LCIG-naïve patients (N = 29) showed a decrease in "Off" time and an increase in "On" time without troublesome dyskinesia (change from baseline to final visit in mean [SD] hours = -2.34 [2.78] P < 0.001 and 2.19 [3.70] P = 0.005, respectively), while continuing-LCIG patients (N = 33) showed sustained "Off" time duration and further improvement in "On" time without troublesome dyskinesia (-0.42 [2.67] P = 0.377 and 1.00 [2.58] P = 0.036, respectively). Most patients in both groups (LCIG-naïve, continuing-LCIG, respectively) were rated 'Much Improved' or 'Very Much Improved' at final visit on the Clinical Global Impression-Improvement scale (69.0%, 69.7%). The authors concluded that LCIG patients continued to derive benefit from LCIG while the magnitude of improvement among LCIG-naïve patients was similar to that observed for patients on LCIG. The overall AE profile was consistent with previous phase 3 clinical trials.

Professional Guidelines and Position Statements

In 2017, the National Institute for Health and Clinical Excellence (NICE) issued guidance specific to PD in adult patients. This guidance states that levodopa-carbidopa intestinal gel is currently available through the National Health Service (NHS) England clinical commissioning policy. NICE recommended that this policy is reviewed. (12)

Summary of Evidence

Levodopa-carbidopa enteral suspension (e.g. Duopa®) is approved by the United States (U.S.) Food and Drug Administration (FDA) as an orphan drug for advanced Parkinson’s disease (PD). The FDA trial did not include atypical or secondary PD patients; therefore, this drug has only been proven to improve outcomes in advanced PD patients who have failed standard drug therapy to include dopamine agonists, oral levadopa and carbidopa, Catechol-O-methyl transferase (COMT) inhibitors and monoamine oxidase (MAO) B inhibitors.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

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.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

64999, 95999, 99199

HCPCS Codes

E0779, E0781, E1399, J3490, J7340, J7799

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-PX manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-PX manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a National coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. Parkinson’s Foundation. What is Parkinson’s (2018). Available at <http://parkinson.org> (accessed 2018 May 15).

2. Parkinson’s Foundation. Statistics on Parkinson’s (2018). Available at <http://parkinson.org> (accessed 2018 May 14).

3. Parkinson's Foundation. Types of Parkinsonisms (2018). Available at <http://parkinson.org> (accessed 2018 May 16).

4. Parkinson's Foundation. Levadopa (2018). Available at <http://parkinson.org> (accessed 2018 May 16).

5. Parkinson's Foundation. Managing Parkinson's mid-stride: A treatment guide to Parkinsons’s disease (2018). Available at <http://parkinson.org> (accessed 2018 May 16).

6. FDA-Drugs: FDA label DUOPA® (carbidopa and levodopa) enteral suspension (2016 September). Available at <https://www.fda.gov> (accessed 2018 May 14).

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 Neurol. 2014; 13(2):141-149. PMID 24361112

8. 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. PMID 24477490

9. Fernandez HH, Standaert DG, Hauser RA, et al. Levodopa-carbidopa intestinal gel in advanced Parkinson's disease: Final 12-month, open-label results. Mov Disord. 2014 December 24. PMID 25545465

10. 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. PMID 24313838

11. 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):165-74. PMID 25588353

12. National Institute for Health and Clinical Excellence (NICE). Parkinson's disease in adults. Clinical Guideline 71. London, UK: NICE; 2017. Available at <http://www.nice.org.uk> (accessed 2018 May 24).

Policy History:

Date Reason
7/15/2018 Document updated with literature review. Coverage unchanged. Added references 1, 3-5, 11.
11/1/2016 Reviewed. No changes.
7/15/2015 New medical document. Levodopa-Carbidopa enteral suspension (e.g. Duopa) may be considered medically necessary for the treatment of motor fluctuations in individuals with advanced idiopathic Parkinson’s disease (PD), who meet all of the following criteria: 1) Presence of bradykinesia and at least one other cardinal PD feature (tremor, rigidity, postural instability); and 2) Levodopa responsive with clearly defined “On” periods*; and 3) Persistent motor complications with disabling “Off” periods** for a minimum of 3 hours/day despite optimal medical therapy with: a)Dopamine agonists; and b)Oral Levodopa and Carbidopa; and c)One agent from the following class; Catechol-O-methyl transferase (COMT) inhibitors; or Monoamine oxidase (MAO) B inhibitors. Levodopa-Carbidopa enteral suspension is considered experimental, investigational and/or unproven including but not limited to patients with: 1) Atypical Parkinson’s disease “Parkinson’s Plus” syndrome); or 2) Secondary Parkinson’s disease. Note added to reflect the following contraindications: 1) Duopa is contraindicated in patients taking nonselective monoamine oxidase (MAO) inhibitors, 2) in patients that are not candidates for percutaneous endoscopic gastro-jejunal (PEG-J) tube placement, and 3) in patients were long-term use of a PEG-J is contraindicated. A pump for administering Levodopa-Carbidopa enteral suspension may be considered medically necessary durable medical equipment (DME) for persons who meet the criteria for Levodopa-Carbidopa enteral suspension

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