A Proven Option for Reversing Morning Akinesia for Patients With Parkinson Disease


The results of a phase 4 study demonstrate the efficacy of APOKYN® (apomorphine hydrochloride injection) treatment.

This article is sponsored by Supernus Pharmaceuticals, Inc.


Clinical Burden of OFF Episodes of Parkinson Disease

Parkinson disease (PD) is a progressive neurodegenerative disorder that is characterized by bradykinesia, rigidity, and tremor. Although levodopa is the standard treatment for PD, the effects of levodopa therapy may subside, and patients can experience a return of symptoms during OFF episodes.1,2

There are distinct types of OFF episodes, including wearing OFF (wearing OFF of levodopa effect), delayed ON (delayed onset of levodopa effect), suboptimal ON, unpredictable OFF, morning akinesia, and nocturnal akinesia.3 Morning akinesia, which can be a common clinical manifestation of delayed ON, describes the scenario when the first morning dose of levodopa has either a delayed or failed onset.3-5 Morning akinesia is one of the earliest manifestations of motor fluctuations associated with PD,6 and affected patients may have difficulty starting their day, as the therapeutic response to levodopa, or “time to ON,” can be prolonged by up to 2 times the duration of wearing OFF.4,7

The development of OFF episodes is a key limitation to the use of levodopa for the long-term management of PD.2 As PD advances, OFF episodes can impact up to 50% of a patient’s waking hours,8 affecting a patient’s ability to perform normal daily activities.9 In a 2014 survey of more than 3000 patients with PD, nearly half of respondents reported OFF episodes that were moderate to severe, causing them to avoid or stop activities they could perform when ON.10

Causes of OFF Episodes

OFF episodes are caused by both central and peripheral mechanisms. In the central nervous system, the pathophysiology of motor complications is not well understood. Mechanisms related to the ongoing loss of dopaminergic neurons in the substantia nigra and compromised neuronal firing in the globus pallidus and subthalamic nucleus are two possible mechanisms related to abnormal motor movements in PD.2 In the periphery, gastrointestinal dysfunction, such as delayed gastric emptying (gastroparesis) and H. pylori infection, develops in all stages of PD.11 Gastroparesis affects over 70% of patients with PD and can significantly impact the absorption of levodopa in the small intestine, contributing to dose response fluctuations.12,13

Adjunctive Therapies to Reduce Total OFF Time

Adjunctive levodopa therapies, such as catechol-O-methyltransferase inhibitors (COMT), monoamine oxidase (MAO) inhibitors, and dopamine agonists, can reduce total OFF time in patients with PD. However, many patients continue to experience delayed ON, dose failures, and/or additional residual OFF time with these adjunctive medications.4 Neurologists should be aware of treatment options that can help minimize the burden of OFF episodes, including that of morning akinesia.


APOKYN (apomorphine hydrochloride injection) is indicated for the acute, intermittent treatment of hypomobility, “OFF” episodes (“end-of-dose wearing-off” and unpredictable “ON-OFF” episodes) in patients with advanced PD. APOKYN has been studied as an adjunct to other medications. Patients who use APOKYN should continue to receive their appropriate daily dose of oral PD medications.14

APOKYN has been shown to be a reliable, rapid, robust on-demand therapy that can give patients on-demand control of their OFF episodes when needed (up to 5x/day, ≥2 hours apart).14-16 In a prospective, randomized, double-blind, placebo-controlled trial in 62 patients, APOKYN demonstrated a robust 24.2-point reduction in mean Unified Parkinson’s Disease Rating Scale (UPDRS) Part III (Motor Examination) motor scores at 20 minutes(primary end point); treatment with APOKYN helped patients walk, talk, and move more easily.14,16 APOKYN, as an acute subcutaneous injection, may be used adjunctively with most PD treatment regimens.14 APOKYN rapidly enters the systemic circulation providing an onset of benefit that is not affected by gastroparesis or intestinal absorption.4,14 The APOKYN pen device uses a very fine gauge (29 gauge) needle for subcutaneous administration that is similar to that used for insulin injections in patients with diabetes.17,18



Concomitant use of APOKYN with 5HT3 antagonists is contraindicated based on reports of profound hypotension and loss of consciousness when APOKYN was administered with ondansetron.

APOKYN is contraindicated in patients who have demonstrated hypersensitivity/allergic reaction to the drug or any of its excipients (notably sodium metabisulfite). Angioedema or anaphylaxis may occur.

Warnings and Precautions

Serious Adverse Reactions After Intravenous Administration: APOKYN must be administered by subcutaneous injection only, NOT intravenously, because serious adverse events like thrombus formation and pulmonary embolism may occur. Patients and care partners must receive detailed instructions about preparing and injecting doses, with particular attention paid to the correct use of the dosing pen.

See additional safety information below.

The effectiveness of APOKYN for treatment of the OFF episodes in patients with advanced PD was established in randomized, placebo-controlled trials. The change from baseline in Part III of the UPDRS served as the primary assessment measure in each study.14

A randomized, double-blind, placebo-controlled, parallel-group trial was conducted in 29 patients with advanced PD who had at least 2 hours of “OFF” time per day despite an optimized oral regimen for PD including levodopa and an oral dopaminergic agonist. After PD medications were withheld overnight, patients were titrated on APOKYN or placebo until they achieved a therapeutic response, defined as a response similar to the response to their usual dose of levodopa. Ninety percent of patients receiving APOKYN vs none on placebo achieved a therapeutic response within 20 minutes of dosing.14 APOKYN-treated patients had a 23.9-point change compared with minimal change with placebo (P <.001); in addition, APOKYN aborted 95% of OFF episodes compared with 23% for placebo (P <.001).

In a similar study with 62 patients, APOKYN reversed OFF episodes in as early as 10 minutes. When used during an OFF episode APOKYN improved mobility quickly, with a robust 24.2-point reduction in mean UPDRS Part III motor scores at 20 minutes (primary end point) and a 19.9-point reduction at 10 minutes (secondary end point).16


Warnings and Precautions (Cont’d)

Nausea and Vomiting: At recommended doses of APOKYN, severe nausea and vomiting can be expected. Therefore, trimethobenzamide hydrochloride should be started 3 days prior to the initial dose of APOKYN and continued as long as necessary to control nausea and vomiting, and generally no longer than 2 months. In clinical trials, 50% of patients (262/522) discontinued trimethobenzamide hydrochloride after about 2 months of APOKYN.

Falling Asleep During Activities of Daily Living (ADL) and Somnolence: There have been reports of patients treated with APOKYN who suddenly fell asleep without prior warning of sleepiness while engaged in ADL. If a patient develops significant daytime sleepiness or falls asleep during activities that require active participation, APOKYN should be discontinued. Patients should be advised not to drive or participate in potentially dangerous activities. Patients should be continually reassessed for daytime drowsiness or sleepiness since some events occur well after start of treatment. Somnolence was reported in patients treated with APOKYN.

See additional safety information below.


A phase 4, multi-center, open-label study in adult patients with morning akinesia was conducted to assess the effect of APOKYN on time-to-ON. Morning akinesia was defined as ≥45-minute time-to-ON following the first morning dose of levodopa for 3 or more days over a 1-week baseline period. Treatment that did not induce a response within 60 minutes was considered a dose failure.

A total of 96% of patients demonstrated improvement in time-to-ON, with a mean (+/- SD) reduction of 37 minutes between the levodopa baseline period (60.86 ± 18.11 minutes) to the APOKYN treatment period (23.72 ± 14.55 minutes; P <.0001). Dose failures were less frequent during the APOKYN treatment week than during the levodopa baseline week (7% vs 46%, respectively). In addition, APOKYN treatment was associated with an 18-point improvement in UPDRS Part III motor scores after 15 minutes.

Figure. Average Time to ON Per Patient in a Phase 4 Morning Akinesia Study4,19

Figure. Average Time to ON Per Patient in a Phase 4 Morning Akinesia Study4,19

No new safety issues with APOKYN were observed during this study. The most common adverse events with an incidence of at least 5% in the safety population were nausea (26.8%), dizziness (16.5%), yawning (10.2%), somnolence (7.9%), hypotension (7.9%), and vomiting (7.1%). Twenty-three patients discontinued due to an adverse event; 20 of the 23 discontinuations occurred during the titration phase. The most common adverse events leading to discontinuation were nausea, vomiting, and hypotension.

Study limitations include its open-label design and the pragmatic definition of “dose failure” in which all patients who did not turn ON within 60 minutes had their time-to-ON imputed to 100 minutes. This was an arbitrary threshold, and it is possible that this imputation strategy might have led to overestimation of the mean time-to-ON with levodopa (if patients turned ON within 60-100 minutes) or, conversely, an underestimation (if patients turned ON after >100 minutes). The study was designed to evaluate the time to onset of apomorphine response in patients with morning akinesia and therefore does not fully reflect clinical practice in which intermittent subcutaneous apomorphine injections can be added on to oral PD treatments throughout the day.

In summary, APOKYN significantly reduced time-to-ON in PD patients with morning akinesia related to delayed onset of their morning levodopa dose. APOKYN was well tolerated in most patients.


APOKYN can help manage OFF episodes of PD and provide patients with a reliable, on-demand treatment option.14 Results from clinical trials have shown that APOKYN quickly reverses OFF episodes at both first daily dose and last daily dose of levodopa within 20 minutes.15 With APOKYN, OFF episodes may be reversed in as early as 10 minutes.16 Phase 4 clinical trial results have demonstrated that patients treated with APOKYN experienced rapid and reliable improvements in time to ON and that it was well tolerated in most patients.4


Warnings and Precautions (Cont’d)

Syncope/Hypotension/Orthostatic Hypotension: Dopamine agonists, including APOKYN, can cause hypotension, orthostatic hypotension, and syncope. Alcohol, antihypertensive medications, and vasodilating medications may potentiate the hypotensive effect of apomorphine. Patients should avoid alcohol when using APOKYN. Patients taking APOKYN should lie down before and after taking sublingual nitroglycerin.

Falls: Patients with PD are at risk of falling due to underlying postural instability, possible concomitant autonomic instability, and from syncope caused by the blood pressure lowering effects of the drugs used to treat PD. APOKYN might increase the risk of falling by simultaneously lowering blood pressure and altering mobility.

Hallucinations/Psychotic-like Behavior: APOKYN has been associated with new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior. Patients with a major psychotic disorder should not be treated with APOKYN.

Dyskinesias: APOKYN may cause dyskinesia or exacerbate pre-existing dyskinesia.

Impulse Control/Compulsive Behaviors: Some people with PD have reported new or increased gambling urges, increased sexual urges, and other intense urges while taking PD medicines, including APOKYN. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their care partners about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with APOKYN. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking APOKYN.

Cardiac Events: Coronary events—APOKYN reduces resting systolic and diastolic blood pressure and has the potential to exacerbate coronary (and cerebral) ischemia. Therefore, exercise caution when prescribing APOKYN for patients with known cardiovascular and cerebrovascular disease.

QTc Prolongation and Potential for Proarrhythmic Effects: There is a dose-related prolongation of QTc interval after exposure similar to therapeutic doses of APOKYN. Drugs that prolong the QTc interval have been associated with torsades de pointes and sudden death. The risks and benefits of APOKYN should be considered prior to initiating treatment with APOKYN in patients with risk factors for prolonged QTc.

Withdrawal-Emergent Hyperpyrexia and Confusion: A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or change in antiparkinsonian therapy.

Priapism: APOKYN may cause prolonged painful erections in some patients. Although no patients in the clinical studies required surgical intervention, severe priapism may require surgical intervention.


The most common adverse reactions seen in controlled trials were yawning, drowsiness/somnolence, dyskinesias, dizziness/postural hypotension, rhinorrhea, nausea and/or vomiting, hallucinations/confusion, and edema/swelling of extremities. Injection site reactions, including bruising, granuloma, and pruritus, have been reported.

Please see full Prescribing Information and Pen Instructions for Use / Patient Information.

All trademarks are the property of their respective owners.

1. Chen JJ, Obering C. A review of intermittent subcutaneous apomorphine injections for the rescue management of motor fluctuations associated with advanced Parkinson's disease. Clin Ther. 2005;27(11):1710-1724. doi:10.1016/j.clinthera.2005.11.016
2. Olanow CW, Obeso JA, Stocchi F. Continuous dopamine-receptor treatment of Parkinson's disease: scientific rationale and clinical implications. Lancet Neurol. 2006;5(8):677-687. doi:10.1016/S1474-4422(06)70521-X
3. Chou KL, Stacy M, Simuni T, et al. The spectrum of "off" in Parkinson's disease: What have we learned over 40 years? Parkinsonism Relat Disord. 2018;51:9-16. doi: 10.1016/j.parkreldis.2018.02.001
4. Isaacson S, Lew M, Ondo W, Hubble J, Clinch T, Pagan F. Apomorphine subcutaneous injection for the management of morning akinesia in Parkinson's disease. Mov Disord Clin Pract. 2017;4(1):78-83. doi:10.1002/mdc3.12350
5. Obering CD, Chen JJ, Swope DM. Update on apomorphine for the rapid treatment of hypomobility ("off") episodes in Parkinson's disease. Pharmacotherapy. 2006;26(6):840-852. doi:10.1592/phco.26.6.840
6. Aquino CC, Fox SH. Clinical spectrum of levodopa-induced complications. Mov Disord. 2015;30(1):80-89. doi:10.1002/mds.26125
7. Merims D, Djaldetti R, Melamed E. Waiting for ON: a major problem in patients with Parkinson disease and ON/OFF motor fluctuations. Clinical Neuropharmacol. 2003;26(4):196-198. doi:10.1097/00002826-200307000-00009
8. Pietz K, Hagell P, Odin P. Subcutaneous apomorphine in late stage Parkinson's disease: a long term follow up. J Neurol Neurosurg Psychiatry. 1998;65(5):709-716. doi:10.1136/jnnp.65.5.709.
9. Chapuis S, Ouchchane L, Metz O, Gerbaud L, Durif F. Impact of the motor complications of Parkinson’s disease on the quality of life. Mov Disord. 2005;20(2):224-230. doi:10.1002/mds.20279
10. Michael J. Fox Foundation. Capturing and elevating the patient voice. November 10, 2014. Accessed September 28, 2021. https://www.michaeljfox.org/news/capturing-and-elevating-patient-voice
11. Marrinan S, Emmanuel AV, Burn DJ. Delayed gastric emptying in Parkinson's disease. Mov Disord. 2014;29(1):23-32. doi:10.1002/mds.25708
12. Fasano A, Visanji NP, Liu LW, Lang AE, Pfeiffer RF. Gastrointestinal dysfunction in Parkinson's disease. Lancet Neurol. 2015;14(6):625-639. doi:10.1016/S1474-4422(15)00007-1
13. Pfeiffer RF, Isaacson SH, Pahwa R. Clinical implications of gastric complications on levodopa treatment in Parkinson's disease. Parkinsonism Relat Disord. 2020;76:63-71. doi:10.1016/j.parkreldis.2020.05.001
14. APOKYN. Prescribing information. US WorldMeds, LLC; 2020. Accessed October 20, 2021. https://www.apokynhcp.com/sites/all/themes/apokyn/content/resources/apokyn_pi.pdf
15. Dewey RB, Hutton JT, LeWitt PA, Factor SA. A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events. Arch Neurol. 2001;58(9):1385-1392. doi:10.1001/archneur.58.9.1385
16. Pfeiffer RF, Gutmann L, Hull KL Jr, Bottini PB, Sherry JH; The APO302 Study Investigators. Continued efficacy and safety of subcutaneous apomorphine in patients with advanced Parkinson's disease. Parkinsonism Relat Disord. 2007;13(2):93-100. doi:10.1016/j.parkreldis.2006.06.012
17. APOKYN. Pen instructions for use. Supernus Pharmaceuticals; 2019. Accessed October 24, 2021. https://www.apokyn.com/sites/all/themes/apokyn/content/resources/apokyn_PPI.pdf
18. American Diabetes Association. 7. Diabetes Technology: Standards of Medical Care in Diabetes-2021. Diabetes Care. 2021;44(suppl 1):S85-S99. doi:10.2337/dc21-S007
19. Lew M, Isaacson S, Pagan F, Ondo W. Predictability of response to apomorphine subcutaneous injections: responder analyses from the AM-IMPAKT trial [abstract 259]. Presented at: Movement Disorder Society’s 19th International Congress of Parkinson’s Disease and Movement Disorders; June 14-18, 2015; San Diego, CA. https://movementdisorders.onlinelibrary.wiley.com/doi/full/10. 1002/mds. 26295

MDD US Operations, LLC is the exclusive licensee and distributor of APOKYN in the United States and Its territories.

© 2021. APOKYN is a registered trademark of BRITUSWIP.

APO.2021-0063 11/21

© 2024 MJH Life Sciences

All rights reserved.