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ph-1090

Amantadine Extended Release Prior Authorization with Quantity Limit Program Summary

Policy Number: PH-1090

This program applies to Blue Partner, Commercial, GenPlus, NetResults A series, SourceRx and Health Insurance Marketplace formularies.

POLICY REVIEW CYCLE

Effective Date	Date of Origin
04-01-2024	04-01-2018

FDA APPROVED INDICATIONS AND DOSAGE

Agent(s)	FDA Indication(s)	Notes	Ref#
Gocovri^® (amantadine ER) Extended-release capsule	Treatment of dyskinesia in patients with Parkinson’s disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications Adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes		1
Osmolex ER^® (amantadine ER) Extended-release tablet	Treatment of: Parkinson’s disease Drug-induced extrapyramidal reactions in adult patients		3

Agent(s)

FDA Indication(s)

Notes

Ref#

Gocovri^®

(amantadine ER)

Extended-release capsule

Treatment of dyskinesia in patients with Parkinson’s disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications

Adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes

Osmolex ER^®

(amantadine ER)

Extended-release tablet

Treatment of:

Parkinson’s disease
Drug-induced extrapyramidal reactions in adult patients

See package insert for FDA prescribing information: https://dailymed.nlm.nih.gov/dailymed/index.cfm

CLINICAL RATIONALE

Parkinson's Disease

Parkinson’s disease (PD) is a chronic, progressive, neurodegenerative disorder resulting from the loss of dopamine-producing cells of the substantia nigra.(5) The four primary symptoms of PD are tremor, or trembling in hands, arms, legs, jaw, and face; rigidity, or stiffness of the limbs and trunk; bradykinesia, or slowness of movement; and postural instability, or impaired balance and coordination.(2,5) Other symptoms may include depression and other emotional changes; difficulty swallowing, chewing, and speaking; urinary problems or constipation; skin problems; and sleep disruptions.(2,5) There are currently no blood or laboratory tests that have been proven to help in diagnosing PD. Therefore, diagnosis is based on medical history and neurological examinations. The disease is difficult to accurately diagnose, thus doctors may request (and sometimes repeat) brain scans or laboratory tests in order to rule out other diseases.(7) However, noninvasive diagnostic imaging, such as positron emission tomography (PET) can support a doctor's diagnosis. Conventional methods for diagnosis include the following:(11)

The presence of two of the three primary symptoms
The absence of other neurological signs upon examination
No history of other possible causes of parkinsonism, such as the use of tranquilizer medications, head trauma or stroke
Responsiveness to Parkinson's medications, such as levodopa

Management of PD requires consideration of patient’s symptoms, age, stage of disease, degree of functional disability, and level of physical activity and production. A comprehensive care plan should be in place, as agreed to by the person, their family members, and specialist and secondary healthcare providers.(5) Treatment of early stage PD typically includes levodopa, dopamine agonists (e.g., bromocriptine, pramipexole, ropinirole, rotigotine), and monoamine oxidase B inhibitors (MAO-B; e.g., rasagiline, selegiline). Treatment as PD advances includes additional agents such as anticholinergic agents, catechol-O-methyltransferase (COMT) inhibitors, and amantadine.(2,4,5)

Levodopa is converted into dopamine by the body, and therefore helps to replace the dopamine that is lost as part of PD. It is currently the first choice (and thus the most commonly prescribed) treatment for the motor symptoms of PD.(4,5) Dopamine agonists mimic the role of dopamine in the brain but aren’t as effective as levodopa, thus typically reserved for those whose motor symptoms do not impact quality of life. Dopamine agonists may be employed as either monotherapy in early PD or in combination with other antiparkinsonian drugs for the treatment of more advanced disease.(4,5) MAO-B inhibitors block an enzyme that metabolizes dopamine, thereby increasing the amount of dopamine available in the brain. MAO-B inhibitors are typically added as adjunct to levodopa if motor fluctuations develop despite optimal levodopa therapy, and/or if dyskinesia has developed.(5,7)

Although initially effective, dopaminergic therapies are eventually complicated by the development of motor complications such as motor fluctuations and dyskinesia. Motor fluctuations include “on” and “off” states, where patients experience periods of when the medication wears off and the PD symptoms reappear. “Wearing off”, characterized by reemergence of symptoms near the end of the dose interval, is the first and most commonly encountered motor fluctuation in patients with PD. Dyskinesia is defined as drug-induced involuntary movements including chorea and dystonia. Motor complications are usually addressed with levodopa adjustments and the addition of adjunctive medications. Motor fluctuations and dyskinesia can be resistant to medical therapy.(8)

Amantadine increases dopamine release and inhibits dopamine uptake. Amantadine may be considered for patients with dyskinesias not adequately managed by modifying existing therapy.(5) Amantadine also has shown additional benefit in reducing “off” time.(8,9) Until there is a comparison between ER formulations of amantadine and generic amantadine, it is uncertain whether the potential benefits justify the cost.(10)

Efficacy

Amantadine for the treatment of dyskinesia in patients with PD was assessed in two randomized, double-blind, placebo-controlled efficacy trials. In both studies, the primary efficacy endpoint was the change in total score of the Unified Dyskinesia Rating Scale (UDysRS) between baseline and Week 12. In both studies, a significant decrease in mean UDysRS total score (reduction in dyskinesia) was observed at Week 12 compared to placebo.(1)The effect of amantadine IR formulation on dyskinesias has been examined in multiple small studies. In a 6-week, placebo-controlled, double-blind, crossover study, PD patients (n=18) receiving amantadine IR (average dose of 350 mg/day) had around a 60% reduction in dyskinesia compared with placebo.(6) The authors conducted a follow-up study and found that 13 of 17 patients originally treated in the short-term study had a 56% reduction in dyskinesia scores at 1 year.(7)

In a randomized, double-blind, placebo-controlled trial, 126 patients with levodopa-induced dyskinesia were randomly assigned to ER amantadine (274 mg capsule at bedtime) or placebo. At 12 weeks compared with placebo, the active drug reduced the duration, severity, and impact of dyskinesia as measured by the UDysRS. In addition, treatment with the active drug reduced mean "off" time by 0.6 hours, while mean "off" time increased 0.3 hours with placebo. The most common significant adverse effects were mild and reversible visual hallucinations.(8) A subsequent trial with 77 patients reported similar results at 12 weeks, demonstrating reduced severity of dyskinesia and reduced mean "off" time by 0.5 hours, while mean "off" time increased 0.6 hours with placebo.(9)

Safety

Gocovri and Osmolex ER are both contraindicated in patients with end-stage renal disease (i.e., creatinine clearance below 15 mL/min/1.73 m²).(1,3)

REFERENCES

Number	Reference
1	Gocovri prescribing information. Adamas Pharma, LLC. January 2021.
2	National Institute of Neurological Disorders and Stroke. Parkinson’s Disease Information Page. Updated April 2020. Available at: www.ninds.nih.gov/Disorders/All-Disorders/Parkinsons-Disease-Information-Page.
3	Osmolex ER prescribing information. Vertical Pharmaceuticals LLC. March 2021.
4	Fox SH, Katzenschlager R, Lim SY, et al. International Parkinson and Movement Disorder Society Evidence-Based Medicine Review: Update on Treatments for the Motor Symptoms of Parkinson’s Disease. Mov Disord. 2018 Aug;33(8):1248-1266.
5	National Institute for Health and Care Excellence (NICE). Guideline on Parkinson’s Disease in Adults (NG71). July 2017. Available at: https://www.nice.org.uk/guidance/ng71.
6	Verhagen Metman L, Del Dotto P, van den Munckhof P, Fang J, Mouradian MM, Chase TN. Amantadine as Treatment for Dyskinesias and Motor Fluctuations in Parkinson’s Disease. Neurology. 1998;50(5):1323–1326.
7	Verhagen Metman L, Del Dotto P, LePoole K, Konitsiotis S, Fang J, Chase TN. Amantadine for Levodopa-Induced Dyskinesias: A 1-Year Follow-Up Study. Arch Neurol. 1999;56:1383-1386.
8	Pahwa R, Tanner CM, Hauser RA, et al. ADS-5102 (Amantadine) Extended-Release Capsules for Levodopa-Induced Dyskinesia in Parkinson Disease (EASE-LID Study). JAMA Neurol. 2017 Aug;74(8):941-949.
9	Oertel W, Eggert K, Pahwa R, et al. Randomized, Placebo-Controlled Trial of ADS-5102 (Amantadine) Extended-Release Capsules for Levodopa-Induced Dysinesia in Parkinson’s Disease (EASE-LID-3). Mov Disord. 2017 Dec;32(12):1701-1709.
10	Shukla AW. Extended-Release Amantadine – A Smart Pill for Treatment of Levodopa-Induced Dyskinesia but Does the Evidence Justify the Cost? JAMA Neurol. 2017;74(8):904-905.
11	American Association of Neurological Surgeons. Parkinson’s Disease. Updated 2022. Available at: https://www.aans.org/en/Patients/Neurosurgical-Conditions-and-Treatments/Parkinsons-Disease.

POLICY AGENT SUMMARY PRIOR AUTHORIZATION

Target Brand Agent(s)	Target Generic Agent(s)	Strength	Targeted MSC	Available MSC	Final Age Limit	Preferred Status

Gocovri	amantadine hcl cap er	137 MG ; 68.5 MG	M ; N ; O ; Y	N
Osmolex er	amantadine hcl tab er	129 MG ; 193 MG	M ; N ; O ; Y	N
Osmolex er	amantadine hcl tab er	129 & 193 MG	M ; N ; O ; Y	N

POLICY AGENT SUMMARY QUANTITY LIMIT

Target Brand Agent Name(s)	Target Generic Agent Name(s)	Strength	QL Amount	Dose Form	Day Supply	Duration	Addtl QL Info	Allowed Exceptions	Targeted NDCs When Exclusions Exist

	Amantadine HCl Tab ER 24HR 258 MG (Base Equivalent)		30	Tablets	30	DAYS
Gocovri	Amantadine HCl Cap ER 24HR 137 MG (Base Equivalent)	137 MG	60	Capsules	30	DAYS
Gocovri	Amantadine HCl Cap ER 24HR 68.5 MG (Base Equivalent)	68.5 MG	30	Capsules	30	DAYS
Osmolex er	Amantadine HCl Tab ER 24HR 129 MG (Base Equivalent)	129 MG	30	Tablets	30	DAYS
Osmolex er	Amantadine HCl Tab ER 24HR 193 MG (Base Equivalent)	193 MG	30	Tablets	30	DAYS
Osmolex er	Amantadine HCl Tab ER 24HR Pak 129 MG & 193 MG (322 MG Dose)	129 & 193 MG	1	Box	30	DAYS

CLIENT SUMMARY – PRIOR AUTHORIZATION

Target Brand Agent Name(s)	Target Generic Agent Name(s)	Strength	Client Formulary
Gocovri	amantadine hcl cap er	137 MG ; 68.5 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Osmolex er	amantadine hcl tab er	129 MG ; 193 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Osmolex er	amantadine hcl tab er	129 & 193 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

CLIENT SUMMARY – QUANTITY LIMITS

Target Brand Agent Name(s)	Target Generic Agent Name(s)	Strength	Client Formulary
	Amantadine HCl Tab ER 24HR 258 MG (Base Equivalent)		Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Gocovri	Amantadine HCl Cap ER 24HR 137 MG (Base Equivalent)	137 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Gocovri	Amantadine HCl Cap ER 24HR 68.5 MG (Base Equivalent)	68.5 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Osmolex er	Amantadine HCl Tab ER 24HR 129 MG (Base Equivalent)	129 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Osmolex er	Amantadine HCl Tab ER 24HR 193 MG (Base Equivalent)	193 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Osmolex er	Amantadine HCl Tab ER 24HR Pak 129 MG & 193 MG (322 MG Dose)	129 & 193 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

PRIOR AUTHORIZATION CLINICAL CRITERIA FOR APPROVAL

Module	Clinical Criteria for Approval
	Initial Evaluation Target Agent(s) will be approved when ALL of the following are met: ONE of the following: The requested agent is Gocovri AND ALL of the following: The patient has a diagnosis of Parkinson’s disease AND ONE of the following: The requested agent will be used for the treatment of dyskinesia OR The requested agent will be used for the adjunctive treatment in patients experiencing “off” episodes AND BOTH of the following: The patient is currently treated with levodopa-based therapy AND The patient will continue levodopa-based therapy in combination with the requested agent OR The requested agent is Osmolex ER AND ONE of the following: The patient has a diagnosis of Parkinson’s disease OR The patient has a diagnosis of drug-induced extrapyramidal reactions AND the prescriber has assessed and adjusted, if applicable, any medications known to cause extrapyramidal symptoms OR The patient has another FDA approved indication for the requested agent AND If the patient has an FDA approved indication, then ONE of the following: The patient’s age is within FDA labeling for the requested indication for the requested agent OR The prescriber has provided information in support of using the requested agent for the patient’s age for the requested indication AND ONE of the following: The patient has tried and had an inadequate response to immediate release amantadine OR The patient has an intolerance or hypersensitivity to immediate release amantadine that is not expected to occur with the requested agent OR The patient has an FDA labeled contraindication to immediate release amantadine that is not expected to occur with the requested agent AND The prescriber is a specialist in the area of the patient’s diagnosis (e.g., neurologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND The patient does NOT have any FDA labeled contraindications to the requested agent Length of Approval: 12 months NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria. Step therapy requirement may not apply if a prior health plan paid for the medication - documentation of a paid claim may be required. Renewal Evaluation* Target Agent(s) will be approved when ALL of the following are met: The patient has been previously approved for the requested agent through the plan’s Prior Authorization process AND If the requested agent is Gocovri, the patient will be using levodopa-based therapy in combination with the requested agent AND The patient has had clinical benefit with the requested agent AND The prescriber is a specialist in the area of the patient’s diagnosis (e.g., neurologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND The patient does NOT have any FDA labeled contraindications to the requested agent Length of Approval: 12 months NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Module

Clinical Criteria for Approval

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

ONE of the following:
1. The requested agent is Gocovri AND ALL of the following:
  1. The patient has a diagnosis of Parkinson’s disease AND
  2. ONE of the following:
    1. The requested agent will be used for the treatment of dyskinesia OR
    2. The requested agent will be used for the adjunctive treatment in patients experiencing “off” episodes AND
  3. BOTH of the following:
    1. The patient is currently treated with levodopa-based therapy AND
    2. The patient will continue levodopa-based therapy in combination with the requested agent OR
2. The requested agent is Osmolex ER AND ONE of the following:
  1. The patient has a diagnosis of Parkinson’s disease OR
  2. The patient has a diagnosis of drug-induced extrapyramidal reactions AND the prescriber has assessed and adjusted, if applicable, any medications known to cause extrapyramidal symptoms OR
3. The patient has another FDA approved indication for the requested agent AND
If the patient has an FDA approved indication, then ONE of the following:
1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
2. The prescriber has provided information in support of using the requested agent for the patient’s age for the requested indication AND
ONE of the following:
1. The patient has tried and had an inadequate response to immediate release amantadine OR
2. The patient has an intolerance or hypersensitivity to immediate release amantadine that is not expected to occur with the requested agent OR
3. The patient has an FDA labeled contraindication to immediate release amantadine that is not expected to occur with the requested agent AND
The prescriber is a specialist in the area of the patient’s diagnosis (e.g., neurologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval: 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

*Step therapy requirement may not apply if a prior health plan paid for the medication - documentation of a paid claim may be required.

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

The patient has been previously approved for the requested agent through the plan’s Prior Authorization process AND
If the requested agent is Gocovri, the patient will be using levodopa-based therapy in combination with the requested agent AND
The patient has had clinical benefit with the requested agent AND
The prescriber is a specialist in the area of the patient’s diagnosis (e.g., neurologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval: 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

QUANTITY LIMIT CLINICAL CRITERIA FOR APPROVAL

Module	Clinical Criteria for Approval
QL with PA	Quantity Limit for the Target Agent(s) will be approved when ONE of the following is met: The requested quantity (dose) does NOT exceed the program quantity limit OR ALL of the following: The requested quantity (dose) exceeds the program quantity limit AND The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit OR ALL of the following: The requested quantity (dose) exceeds the program quantity limit AND The requested quantity (dose) exceeds the maximum FDA labeled dose for the requested indication AND The prescriber has provided information in support of therapy with a higher dose for the requested indication Length of Approval: 12 months

Module

Clinical Criteria for Approval

QL with PA

Quantity Limit for the Target Agent(s) will be approved when ONE of the following is met:

The requested quantity (dose) does NOT exceed the program quantity limit OR
ALL of the following:
1. The requested quantity (dose) exceeds the program quantity limit AND
2. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
3. The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit OR
ALL of the following:
1. The requested quantity (dose) exceeds the program quantity limit AND
2. The requested quantity (dose) exceeds the maximum FDA labeled dose for the requested indication AND
3. The prescriber has provided information in support of therapy with a higher dose for the requested indication

Length of Approval: 12 months

This pharmacy policy is not an authorization, certification, explanation of benefits or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All pharmacy policies are based on (i) information in FDA approved package inserts (and black box warning, alerts, or other information disseminated by the FDA as applicable); (ii) research of current medical and pharmacy literature; and/or (iii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.
The purpose of Blue Cross and Blue Shield of Alabama’s pharmacy policies are to provide a guide to coverage. Pharmacy policies are not intended to dictate to physicians how to practice medicine. Physicians should exercise their medical judgment in providing the care they feel is most appropriate for their patients.
Neither this policy, nor the successful adjudication of a pharmacy claim, is guarantee of payment.